Alterations of Digestive Function

Constipation can occur as a primary or secondary condition. Chronic idiopathic or primary constipation is generally classified into three categories: functional defecation disorder, slow transit constipation (STC), and constipation-predominant irritable bowel syndrome (IBS-C). Overlap may exist between these three classifications, and the classifications are not mutually exclusive.6Functional constipation is similar between children and adults, but differences exist regarding the symptomology and pathophysiology of disease, as well as differences in required diagnostic work-up and treatment modalities.⁷ Functional constipation involves a normal rate of stool passage but difficulty with stool evacuation. STC involves impaired colonic motor activity with symptoms of infrequent bowel movements, straining to defecate, mild abdominal distention, and palpable stool in the sigmoid colon. IBS-C is associated with chronic constipation and abdominal pain. The exact cause of IBS-C is poorly understood, but various factors that may contribute to the pathology of the disease include diet, genetics, colonic motility, absorption, socioeconomic status, daily behaviors, and medication use.⁸ Lack of access to toilet facilities, consistent suppression of the urge to empty the bowel, pelvic floor dyssynergia, and dehydration may be other causes of primary constipation.

Secondary constipation can be caused by diet, medications, or neurogenic disorders (e.g., stroke, Parkinson disease, spinal cord lesions, multiple sclerosis, and Hirschsprung disease) in which neural pathways or neurotransmitters are diseased or degenerated, resulting in altered or delayed colon transit time. Rectal fissures, strictures, or hemorrhoids also may cause constipation. Antacids containing calcium carbonate or aluminum hydroxide, anticholinergics, iron, and bismuth tend to inhibit bowel motility causing constipation. Opioid-induced constipation is caused by drugs that activate μ-opioid receptors in the gut and slow transit time. Endocrine or metabolic disorders, which may also be associated with constipation, include hypothyroidism, diabetes mellitus, hypokalemia, and hypercalcemia. Pelvic hiatal hernia (herniation of the bowel through the floor of the pelvis), diverticula, irritable bowel syndrome (IBS) (constipation predominant), and pregnancy are associated with constipation. Aging may result in decreased mobility, changes in neuromuscular function, use of medications, and comorbid medical conditions causing constipation. Pain or weakness of the abdominal muscles may interfere with the generation of adequate intra-abdominal pressure needed to evacuate stool from the rectum. Depression may also impair bowel evacuation due to a sedentary lifestyle and diet changes. It is important to remember that constipation or a notable change in bowel habits can be an indication of colorectal cancer (CRC).

Indicators of primary or functional constipation (not including IBS-C) are guided by the Rome IV criteria. The Rome IV criteria define chronic constipation as including at least two of the following symptoms: straining with defecation at least 25% of the time; lumpy or hard stools at least 25% of the time; sensation of incomplete emptying at least 25% of the time; feeling of anorectal obstruction/blockage at least 25% of the time; manual maneuvers to facilitate stool evacuation for at least 25% of defecations; and fewer than three bowel movements per week (see Table 41.1 for Rome IV criteria).^6,8 Changes in bowel evacuation patterns, such as less frequent defecation, smaller stool volume, hard stools, difficulty passing stools (e.g., straining), a feeling of bowel fullness and discomfort, or blood in the stools, require further assessment. Straining to evacuate stool may cause engorgement of the hemorrhoidal veins and hemorrhoidal disease or thrombosis with rectal pain, bleeding, and itching. Passage of hard stools can cause painful anal fissures. Fecal impaction (hard, dry stool retained in the rectum) is associated with rectal bleeding, abdominal or cramping type pain, nausea and vomiting, weight loss, and episodes of diarrhea. If left untreated, fecal impaction may cause increased pressure on the intralumen of the colon that may lead to ischemia with possible perforation of the colon and even death.⁹

The treatment for constipation is to manage the underlying cause or disease. Lifestyle modifications can often help immensely. Management of constipation usually consists of bowel retraining, in which the individual establishes a satisfactory bowel evacuation routine without becoming preoccupied with bowel movements. The individual also may need to engage in moderate exercise and increase fluid and fiber intake. Fiber supplements and stool softeners are useful for some individuals. Many different types of laxatives are available; however, studies are lacking comparing the efficacy and safety of different categories of laxatives. Choice of laxative for an individual should be guided by a healthcare professional and should take into account individual preferences and cost.5 Enemas can be used to establish a bowel routine, but they should not be used routinely. Biofeedback may be beneficial in some instances for forming new bowel evacuation habits. Colectomy with ileorectal anastomosis is rarely performed but may be done with individuals with severe symptoms that have not responded to other treatments.⁵

The intestinal mucosa is made up of a complex epithelium where absorption and secretion occur. The majority of water and electrolyte absorption occurs in the small intestine.11 Diarrhea in which the volume of feces is increased is called large-volume diarrhea. It generally is caused by excessive amounts of water or secretions in the intestines. Small-volume diarrhea, in which the volume of feces is not increased, usually results from excessive intestinal motility and may be caused by an inflammatory disorder of the intestine, such as ulcerative colitis (UC), Crohn disease (CD), or microscopic colitis, but also can result from colon cancer or fecal impaction.

The three major mechanisms of diarrhea are osmotic, secretory, and motile.

Treatment for diarrhea includes restoration of fluid and electrolyte balance, administration of antimotility (e.g., loperamide) and/or water-absorbent (e.g., attapulgite and polycarbophil) medications, and treatment of causal factors. Natural bran and commercial preparations of psyllium are inexpensive and effective treatments for mild diarrhea. Probiotics can be useful for preventing and treating C. difficile–associated diarrhea as an approach to restoring normal microflora in addition to antibiotic therapy. Fecal transplantation can be used for cases that are resistant to conventional therapies, particularly C. difficile–associated diarrhea. Nutritional deficiencies need to be corrected in cases of chronic diarrhea or malabsorption.12

The individual is taught to manage symptoms by eating small meals slowly, taking fluid with meals, and sleeping with the head elevated to prevent regurgitation and aspiration. Food and medications may need to be formulated with a thickening agent so they can be swallowed. Tube feedings may be required for some individuals, particularly following stroke. Mechanical dilation of the esophageal sphincter and surgical separation of the lower esophageal muscles with a longitudinal incision (myotomy) may be an effective treatment for achalasia.19

Abnormalities in LES function, esophageal motility, and gastric motility or emptying can cause GERD. The resting tone of the LES has an average pressure of approximately 20 mm Hg that prevents gastric content from refluxing into the esophagus. Spontaneous relaxation of the LES may be triggered by gastric distention after meals and trigger acid reflux. Acid reflux may be triggered by diet and lifestyle factors such as food intake that causes delayed gastric emptying, acidic foods, and obesity. Sliding hiatal hernia facilitates reflux.21 Vomiting, coughing, lifting, bending, and pregnancy also increase abdominal pressure, contributing to the development of reflux esophagitis.

The severity of the esophagitis depends on the composition of the gastric contents and the esophageal mucosa exposure time. If the gastric contents are highly acidic or contain bile salts and pancreatic or intestinal enzymes, reflux esophagitis can be severe. In individuals with weak esophageal peristalsis, refluxed chyme remains in the esophagus longer than usual. The refluxate causes mucosal injury and inflammation, with hyperemia, increased capillary permeability, edema, tissue fragility, and erosion (Fig. 41.2). Fibrosis and thickening may develop. Precancerous lesions (Barrett esophagus [BE]; see the Esophageal Cancer section) can be a long-term consequence. Precancerous lesions can progress to adenocarcinoma.

The clinical manifestations of erosive reflux esophagitis are related to mucosal injury from acid regurgitation. Manifestations are heartburn (e.g., pyrosis) and acid regurgitation. Dysphagia, chest pain, chronic cough, asthma attacks (see Chapter 35), laryngitis, hoarseness, and upper abdominal pain that occurs within 1 hour of eating are less common. The symptoms worsen if the individual lies down or if intra-abdominal pressure increases (e.g., as a result of coughing, vomiting, or straining at stool). Edema, strictures, esophageal spasm, or decreased esophageal motility may result in dysphagia with weight loss. Alcohol or acid-containing foods, such as citrus fruits, can cause discomfort during swallowing.

Treatment includes once-daily proton pump inhibitors (PPIs) for 4 weeks, and continuing therapy if esophagitis or BE is present.21 Weight reduction, smoking cessation, elevation of the head of the bed 6 inches, and avoiding tight clothing may also help to alleviate symptoms. The most common surgical treatment is laparoscopic fundoplication. Emerging surgical treatments include magnetic sphincter augmentation (a device placed around the distal esophagus and comprises titanium beads with magnets in the center that augment lower esophageal tone and thus prevent reflux), radiofrequency ablation, and transoral incisionless fundoplication.

Eosinophilic esophagitis (EoE) is an idiopathic chronic allergic/immune disease of the esophagus characterized by infiltration of eosinophils in the esophagus. EoE is most associated with atopic disease, including asthma, allergic rhinitis, eczema, and food allergies that occur in both children and adults, but the symptoms may vary by age. EoE causes many white blood cells to be found in the inner lining of the esophagus. Typically, eosinophils are not found in the esophagus, although other conditions (e.g., acid reflux disease) may contribute to the presence of eosinophils in the esophagus. Manifestations of the disease are caused by esophageal inflammation (See Chapter 42).²² Dysphagia, decreased appetite, recurring abdominal pain, vomiting, and weight loss are common symptoms. Diagnosis is made by endoscopy with biopsy that identifies the eosinophilic infiltration and differentiates this condition from GERD. Treatment is symptomatic and includes acid inhibitors, elimination diets, and corticosteroids.²² Other conditions associated with EoE, such as food allergies, asthma, or eczema, must also be treated appropriately (see Chapter 42).

Hiatal hernia is a common disorder characterized by a protrusion or bulging of an abdominal structure into the thoracic cavity. Causation is from a weakening of the diaphragm muscle.23 (Fig. 41.3) The most common type is a sliding hiatal hernia (type 1) (see Fig. 41.3 A). In this type of hernia, the proximal portion of the stomach moves into the thoracic cavity through the esophageal hiatus. The esophageal hiatus is an opening in the diaphragm for the esophagus and vagus nerves. A congenitally short esophagus, fibrosis, excessive vagal nerve stimulation, or weakening of the diaphragmatic muscles at the gastroesophageal junction contributes to this type of hernia. Laying in the supine position causes the lower esophagus and stomach to be pulled into the thorax. As an individual stands, the organs slide back into the abdomen. Coughing, bending, tight clothing, ascites, obesity, and pregnancy accentuate the hernia in association with the resting pressure of the LES.

Three illustrations depict the three types of hiatal hernia. Illustration A depicts the sliding hernia, which shows the G E junction above the level of diaphragmatic hiatus. Illustration B depicts the rolling hernias, which shows a normal position to the G E junction, but a portion of the fundus above the hiatus. Illustration C depicts the mixed hernia, which shows displacement of both the G E junction and fundus above the hiatus.

Paraoesophageal hiatal hernia (type 2) is a herniation of the greater curvature of the stomach through a secondary opening in the diaphragm alongside the esophagus that moves into the thorax above the diaphragm (see Fig. 41.3 B). This abnormal positioning of a portion of the stomach causes congestion of mucosal blood flow, leading to gastritis and ulcer formation. Reflux is uncommon with this type of hernia. Strangulation of the hernia is a major complication that results with occlusion of blood vessels and causes vascular engorgement with resulting edema, ischemia, and hemorrhage. Manifestations or symptoms of this type of hernia include vomiting and epigastric/retrosternal epigastric pain and is a surgical emergency.

Mixed hiatal hernia (type 3), less common, is a combination of sliding and paraoesophageal hiatal hernias (see Fig. 41.3 C). It tends to occur in conjunction with several other diseases, including reflux esophagitis, peptic ulcer, cholecystitis, cholelithiasis, chronic pancreatitis, and diverticulosis. A mixed hiatal hernia may progress to a type 4 hernia. This type of hernia involves the presence of a structure other than the stomach (e.g., omentum, colon, or small bowel) within the hernia sac.²³

Many diagnostic procedures may be indicated in diagnosing a hiatal hernia. The mainstays of evaluation are upper endoscopy and barium swallows.23 Plain chest radiographs, contrast studies, esophagogastroduodenoscopy (EGD), manometry, pH testing, and nuclear medicine studies may also be ordered. Computed tomography (CT) scan may be indicated in an urgent situation for an individual with suspected complications.²³

Treatment for a sliding hiatal hernia is usually conservative. The individual can diminish reflux by eating small, frequent meals and avoiding the recumbent position after eating. Abdominal supports and tight clothing should be avoided, and weight control is recommended for obese individuals. Antacids may help to alleviate reflux esophagitis. Individuals who are uncomfortable at night may benefit from sleeping with the head of the bed elevated 6 inches. PPIs alleviate reflux esophagitis. Histamine 2 (H₂) receptor antagonists and antacids are typically less effective treatments. Drugs that relax the LES, such as anticholinergic type drugs, nitrates, and calcium channel blockers, are contraindicated due to delaying gastric emptying. If medical management fails to provide symptom control or a paraesophageal hiatal hernia is present, a laparoscopic fundoplication may be indicated, and permanent mesh maybe used to prevent recurrence.²⁴

Gastroparesis is delayed gastric emptying in the absence of a mechanical gastric outlet obstruction. It is most associated with diabetes mellitus, surgical vagotomy, or fundoplication but may be idiopathic. The pathophysiology is not well understood but involves abnormalities of the autonomic nervous system, smooth muscle cells, enteric neurons, and GI hormones. Diabetic gastroparesis represents a form of neuropathy involving the vagus nerve. Symptoms include nausea, vomiting, abdominal pain, and postprandial fullness or bloating. Treatment options for gastroparesis are challenging due to the availability of therapies demonstrating poor evidence of efficacy or long-term safety concerns.²⁵ Current treatments include dietary management, prokinetic drugs, endoscopic techniques, and, in some cases, gastric electrical stimulation or surgical venting gastrostomy.^25–27

Pyloric obstruction (gastric outlet obstruction) is the consequence of diseases causing narrowing or blocking of the opening between the stomach and the duodenum. This condition can be congenital (e.g., infantile hypertrophic pyloric stenosis; see Chapter 42) or acquired. Acquired obstruction is caused by peptic ulcer disease or carcinoma near the pylorus. Duodenal ulcers are more likely than gastric ulcers to obstruct the pylorus. Ulceration causes obstruction resulting from inflammation, edema, spasm, fibrosis, or scarring. Tumors cause obstruction by growing into the pylorus.

Obstructions resulting from ulceration often resolve with conservative management. A nasogastric tube is used to aspirate stomach contents and relieve distention. Nasogastric suction is typically placed to decompress the stomach and to help restore normal motility. Gastric secretions that contribute to inflammation and edema can be suppressed with PPIs or H₂-receptor antagonists. Fluids and electrolytes (saline and potassium) are given intravenously to promote rehydration and correct hypokalemia and alkalosis (see Chapter 3). Severely malnourished individuals may require parenteral hyperalimentation (artificial nutrients, usually intravenous nutrition). Surgery or the placement of pyloric stents may be required to treat gastric carcinoma or persistent obstruction caused by fibrosis and scarring.²⁸

The consequences of intestinal obstruction are related to the onset and location of the obstruction, as well as the presence and severity of associated ischemia. The major pathophysiologic alterations are presented in Fig. 41.5. The exact cause of postoperative paralytic ileus remains unknown, but it is thought to be a multifactorial and complex interaction between the autonomic and central nervous system that alters the equilibrium of the intestine, resulting in disorganized electrical activity and paralysis.³²

A flow diagram illustrates the pathophysiology of intestinal obstruction. The diagram begins as follows. • Intestinal obstruction due to sequestration of gas and fluid proximal to obstruction leads to distention and loss of water and electrolytes. • Distention leads to a prolonged increase of intraluminal wall tension, pressure on the diaphragm, and colicky abdominal pain. •Pressure on the diaphragm leads to decreased respiratory volume, leading to atelectasis and causing pneumonia. • Colicky abdominal pain leads to nausea and vomiting with decreased food intake, nutrient absorption, carbohydrates reserves ketosis leads to loss of water and electrolytes, causing dehydration, hypokalemia, and hypochloremia. • Prolonged increase of intraluminal wall tension leads to decrease venous return, arterial BF causing intestinal bowel wall edema and ischemia. • Ischemia leads to perforation. • Intestinal bowel wall edema leads to increase capillary permeability or fluid loss to the peritoneum, causing hypovolemia which leads to shock. • An increase in capillary permeability also leads to the release of toxins and bacterial translocation, causing peritonitis and fever. • The loss of water and electrolytes leads to alkalosis, acidosis, increased ketosis, and lactic acidosis. • Dehydration, hypokalemia, and hypochloremia lead to a decrease in extracellular fluid volume, plasma volume, hemoconcentration, central venous pressure tachycardia, causing hypovolemia which leads to shock.

Small bowel obstruction (SBO) is often caused by postoperative adhesions, tumors, CD, and hernias. SBO leads to distention caused by impaired absorption and increased secretion with the accumulation of fluid and gas inside the lumen proximal to the obstruction.33 Distention decreases the intestine's ability to absorb water and electrolytes and increases the net secretion of these substances into the lumen. Copious vomiting or sequestration of fluids in the intestinal lumen prevents their reabsorption and produces severe fluid and electrolyte disturbances. Extracellular fluid volume and plasma volume decrease, causing dehydration, increased hematocrit level, hypotension, and tachycardia. Severe dehydration leads to hypovolemic shock. Metabolic alkalosis initially develops because of excessive loss of hydrogen ions that would normally be reabsorbed from the gastric juice and vomiting. Prolonged obstruction or obstruction lower in the intestine may contribute to metabolic acidosis because bicarbonate from pancreatic secretions and bile cannot be reabsorbed. Hypokalemia from vomiting and decreased potassium absorption can be extreme, promoting acidosis and atony of the intestinal wall. Metabolic acidosis also may be accentuated by ketosis, which is the result of declining carbohydrate stores caused by starvation. In addition, lack of circulation permits the buildup of significant amounts of lactic acid, which worsens the metabolic acidosis. If pressure from the distention is severe enough, it occludes arterial circulation and causes ischemia, necrosis, perforation, and peritonitis. Fever and leukocytosis are often associated with overgrowth of bacteria, ischemia, and bowel necrosis. Bacterial proliferation and translocation across the mucosa to the systemic circulation cause peritonitis or sepsis. The release of inflammatory mediators into the circulation causes remote organ failure.

Large bowel obstruction is less common and often related to cancer. Diverticulitis, IBD, and other causes of obstruction are less common. Acute colonic pseudo-obstruction (Ogilvie syndrome) is a pathologic massive dilation of the colon without underlying mechanical obstruction or other identified organic causes. This occurs mostly in individuals with serious comorbidities. The pathologic basis remains unclear but may be caused from a functional disturbance in the enteric nervous system.³⁴

Evaluation is based on clinical manifestations and imaging studies. Successful management requires early identification of the location and type of obstruction. Replacement of fluid and electrolytes and decompression of the lumen with gastric or intestinal suction are essential forms of therapy. Laparoscopic procedures can release adhesions. Immediate surgical intervention is required for strangulation, complete obstruction, or perforation. Colonic stents may be placed for malignant obstruction. If conservative methods are not successful, neostigmine, a parasympathomimetic, may be used for colonic pseudo-obstruction. Neostigmine increases the activation of muscarinic receptors by inhibition of the breakdown of acetylcholine. This stimulates colonic motor activity and increases intestinal transit time. Pseudo-obstruction is often managed symptomatically.31,35

Causative factors, independently or in combination, cause acid and pepsin concentrations in the duodenum to increase and penetrate the mucosal barrier, causing ulceration (Fig. 41.9). The host response to chronic stomach antral H. pylori infection is increased levels of gastrin resulting in increased stomach acid secretion and an increased acid load in the duodenum. The increased duodenal acid promotes gastric metaplasia in the duodenum and favors H. pylori colonization. Both H. pylori and the increased acid result in decreased duodenal bicarbonate production. In addition, H. pylori infection activates immune cells (T and B lymphocytes with the infiltration of neutrophils) and the release of inflammatory cytokines which damage the mucosa. H. pylori also produces a toxin that causes loss of protective mucosal cells, resulting in ulceration. H. pylori mucosal infection can promote gastric cancer, but the incidence is lower for duodenal ulcer than for gastric ulcer, and the mechanism is unknown.⁴⁶

Illustration A depicts the cutaway section of the ulcerated duodenal wall with labels indicating ulcer crater, mucosa, submucosa, circular muscle coat, longitudinal muscle coat, and serosa or visceral peritoneum. Illustration B depicts the cross-section of the stomach with labels indicating ulcer, duodenum, common bile duct, duodenal papilla, head of the pancreas, superior mesenteric artery and vein, and pyloric valve or sphincter. Image C represents the endoscopic view of bilateral duodenal ulcers.

The characteristic manifestation of a duodenal ulcer is chronic, intermittent pain in the epigastric area. The pain begins 2 or 3 hours after eating, when the stomach is empty. It is not unusual for pain to occur in the middle of the night and disappear by morning. Pain is relieved rapidly by ingestion of food or antacids, creating a typical pain-food-relief pattern. Some individuals with a duodenal ulcer may have no symptoms; the first manifestation may be hemorrhage or perforation, particularly with a history of NSAID or anticoagulant use. Complications of a duodenal ulcer include bleeding, perforation, and obstruction of the duodenum or outlet of the stomach. Bleeding is the most common cause of mortality, particularly among the elderly. Bleeding from duodenal ulcers causes hematemesis or melena. Perforation occurs with destruction of all layers of the duodenal wall and causes sudden, severe epigastric pain. Obstruction may be the result of edema from inflammation or scarring from chronic injury. Duodenal ulcers often heal spontaneously. However, repeat imaging is indicated if the ulcer was large, associated complications were present, or the individual has continued pain.47

Several diagnostic approaches are used to differentiate duodenal ulcers from gastric ulcers or gastric carcinoma. Endoscopic evaluation allows visualization of lesions and biopsy. Radioimmune assays of gastrin levels are evaluated to identify ulcers associated with gastric carcinomas. H. pylori is detected using the urea breath test, H. pylori–specific serum immunoglobulin G (IgG) and IgA antibodies, and the measurement of H. pylori stool antigen levels. Findings from the gastric biopsy detect H. pylori infection and can also confirm eradication after treatment. Polymerase chain reaction testing provides additional virulence and antibiotic sensitivity profiling.48

The management of duodenal ulcers is aimed at relieving the causes of the ulceration. The effects associated with the hyperacidity and pepsin present in the gut should be managed with diet and pharmacotherapy. Antacids neutralize gastric contents and relieve pain. Acid secretion can be suppressed with drugs that block H₂ receptors and inhibit the secretion of acid. PPIs inhibit acid production. H. pylori is treated with a combination of antibiotics and PPIs, but antibiotic resistance is an increasing problem.⁴⁹ Surgical resection may be required for bleeding or perforating ulcers, obstruction, or peritonitis.

In general, gastric ulcers develop in the antral region, adjacent to the acid-secreting mucosa of the body. The primary defect is an abnormality that increases the mucosal barrier's permeability to hydrogen ions. Gastric secretion may be normal or less than normal, and there may be a decreased mass of parietal cells. Chronic gastritis is often associated with the development of gastric ulcers and may precipitate ulcer formation by limiting the mucosa's ability to secrete a protective layer of mucus (Fig. 41.10). Other factors include:

A flow diagram illustrates the pathophysiology of gastric ulcer formation. The diagram begins as follows. • H. pylori, bile salts, N S A I Ds, alcohol, ischemia leads to damaged mucosal barrier. • Damaged mucosal barrier leads to decrease function of mucosal cells, quality of mucus, loss of tight junctions between cells which further leads to back-diffusion of acid into gastric mucosa. • The diffusion of acid into gastric mucosa leads to the conversion of pepsinogen to pepsin and the formation and liberation of histamine. •Conversion of pepsinogen leads to further mucosal erosion, destruction of blood vessels, and bleeding, causing ulceration. • H. pylori leads to mucosal injury and also causes ulceration. • Formation and liberation of histamine increase acid secretion, leads to stimulation of intramural cholinergic plexus causes muscle spasms and further mucosal erosion, destruction of blood vessels, and bleeding. • Formation and liberation of histamine lead to local vasodilation and causes increased capillary permeability, loss of plasma proteins, mucosal edema, and loss of plasma into the gastric lumen.

A break in the mucosal barrier permits hydrogen ions to diffuse into the mucosa, where they disrupt permeability and cellular structure. A vicious cycle can be established as the damaged mucosa liberates histamine, which stimulates the increase of acid and pepsinogen production, blood flow, and capillary permeability. The disrupted mucosa becomes edematous and loses plasma proteins. Destruction of small vessels causes bleeding.

The clinical manifestations of gastric ulcers are similar to those of duodenal ulcers (see Table 41.6). The pattern of pain is common, but the pain of gastric ulcers also occurs immediately after eating. Gastric ulcers also tend to be chronic rather than alternating between periods of remission and exacerbation, and they cause more anorexia and vomiting than duodenal ulcers. The pain associated with eating tends to suppress food intake, resulting in weight loss. The evaluation and treatment of gastric ulcers are similar to those for duodenal ulcers. However, long-term use of PPIs is a reported risk factor for gastric cancer after H. pylori eradication and is related to hypergastrinemia and hyperplasia of enterochromaffin-like cells that promote the secretion of gastric acid.⁵⁰

The primary lesion of UC begins with inflammation at the base of the crypt of Lieberkühn in the large intestine. The disease begins in the rectum (proctitis) and may extend proximally to the entire colon (pancolitis). The lesions are limited to mucosal epithelium, are not transmural, and do not involve skip lesions. There is decreased secretion of mucin, which is antimicrobial and provides a protective layer against pathogens. Loss of this protection leads to increased permeability of the mucosa, increased passage of pathogens and other antigens, and stimulation of the gut immune system with an inflammatory response. There is activation of T cells and dendritic cells, triggering the production of proinflammatory cytokines and chemokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-12 and IL-23, toxic oxygen free radicals, and interferon-gamma (IFN-γ), producing damage to the intestinal epithelium. In addition, there is activation of vascular adhesion molecules (integrins, e.g., mucosal addressin cellular adhesion molecule-1 [MadCAM-1]) which promote the trafficking of lymphocytes into the gut, furthering potentiation of the inflammatory response. Some of these molecules have become important targets for treatment.62

The mucosa is inflamed and is involved in a continuous fashion. With milder inflammation, the mucosa is hyperemic and edematous and may appear dark red. In more severe inflammation, the mucosa becomes hemorrhagic, and small erosions form and coalesce into ulcers. Abscess formation, necrosis, and ragged ulceration of the mucosa ensue. Edema and thickening of the muscularis mucosae may narrow the lumen of the involved colon. Mucosal destruction and inflammation cause bleeding, cramping pain, and an urge to defecate. Frequent diarrhea, with passage of small amounts of blood and purulent mucus, is common. Loss of the absorptive mucosal surface and rapid colonic transit time cause large volumes of watery diarrhea.

The course of UC consists of intermittent periods of remission and exacerbation. Mild UC involves less mucosa, so the frequency of bowel movements, bleeding, and pain is minimal. Severe forms may involve the entire colon and are characterized by abdominal pain, fever, an elevated pulse rate, frequent diarrhea (10 to 20 stools/day), urgency, bloody stools, and continuous, crampy pain; dehydration, weight loss, anemia, and fever result from fluid loss, bleeding, and inflammation. Complications include anal fissures, hemorrhoids, and perirectal abscess. Severe hemorrhage is rare. Edema, strictures, or fibrosis can obstruct the colon. Perforation is an unusual but possible complication. Extraintestinal manifestations include cutaneous lesions (erythema nodosum), polyarthritis, episcleritis, uveitis, disorders of the liver, and alterations in coagulation.63

The diagnosis of UC is based on the medical history, clinical manifestations, and laboratory, serologic, imaging, endoscopic, and histology findings. Infectious causes are ruled out by stool culture. Endoscopic evaluation shows an inflamed and hemorrhagic mucosa. Radiologic assessment may show ulceration and irregular mucosa. The laboratory data include low hemoglobin levels, hypoalbuminemia, and low serum potassium levels. The gold standard in making the diagnosis remains biopsy and histology.63 The symptoms of UC are often similar to those of CD, making differential diagnosis challenging.

Treatment is individualized and depends on the severity of symptoms and the extent of mucosal involvement. A goal is to promote mucosal healing and avoid surgery. Mild to moderate disease is treated with 5-aminosalicylate therapy followed by steroids. Immunomodulatory agents are used for failure of first-line treatments or serious recurrent disease including TNF-α–blocking agents (e.g., tacrolimus) or antiadhesion agents (i.e., vedolizumab). New small molecule drugs are being investigated.⁶⁴ New oral agents have recently been approved (see Emerging Science Box: Oral Treatments for Ulcerative Colitis). Severe, unremitting disease can require hospital admission for administration of intravenous fluids and steroids. Extreme malnutrition may require total parenteral nutrition (TPN). Surgical resection of the colon may be performed if other forms of therapy are unsuccessful or if there are acute serious complications (sepsis, hemorrhage, perforation, or obstruction). Surgical approaches for severe UC include total proctocolectomy with end ileostomy or ileorectal anastomosis, or ileal pouch–anal anastomosis (IPAA). Pouchitis is a common complication of restorative proctocolectomy with IPAA performed as surgical treatment for both UC and CD. There are more frequent bowel movements, urgency to defecate, blood in the stool, incontinence, and abdominal pain. Antibiotic treatment is usually successful, and chronic symptoms may be managed with steroids or immune modulators.⁶⁵

Inflammation begins in the intestinal submucosa and spreads with discontinuous transmural involvement or “skip lesions” that can involve any part of the GI tract from the mouth to the perianal area. Skip lesions are distinguished by inflamed areas mixed with uninflamed areas, noncaseating granulomas, fistulas, and deep penetrating ulcers. The distal small intestine and proximal large colon are most involved. The ulcerations of CD can produce fissures that extend inflammation into lymphoid tissue. The typical lesion associated with CD is a granuloma or a mass of inflammatory tissue with a cobblestone appearance of inflamed tissue (Fig. 41.12) surrounded by ulceration. Fistula may form in the perianal area between loops of intestine and may extend into the bladder, rectum, or vagina and form intra-abdominal abscesses. Strictures may develop, promoting obstruction.⁶⁷

A. Close shot of gross specimen of the colon showing ulcerative colitis. B. Close shot of gross specimen representing longitudinal serpiginous ulcers separated by irregular islands of edematous mucosa. C. Close shot of gross specimen representing ileal segments, the mesenteric fat creeps from the mesentery to surround the bowel wall.

Individuals with CD may have no specific symptoms for several years. Symptoms vary according to the location of the disease but are similar to those for UC. Diarrhea is one of the most common symptoms, and occasionally rectal bleeding is noted if the colon is involved. Weight loss and abdominal pain accompany CD. Abdominal tenderness may also be noted over the lesions. If the ileum is involved, the individual may be anemic as a result of malabsorption of vitamin B₁₂. There also may be deficiencies in folic acid and vitamin D absorption. In addition, proteins may be lost, leading to hypoalbuminemia. Extraintestinal complications are similar to those occurring in UC. Additional complications include anal fissure, perianal abscess, and fistula. Individuals with CD of long duration also are at risk for intestinal adenocarcinoma. Extraintestinal manifestations include arthropathies, skin, oral, and ocular lesions.68

The diagnosis and treatment of CD are similar to the diagnosis and treatment of UC. Imaging of the small intestine is used in the diagnosis of CD, including either a small bowel series or a capsule endoscopy (camera pill). There are no specific biomarkers or definitive treatments for the disease. Smoking cessation is a component of therapy. Steroids are used to induce remission, and immunosuppressants (e.g., thiopurines and methotrexate) are used to sustain remission. Anti–TNF-α, antiintegrins (target the adhesion molecular inhibiting leukocyte migration), and IL inhibitors (target IL-12 and IL-23) are used for the most severe forms of the disease. Surgery may be performed to manage complications, such as fistula, abscess, or obstruction. When treatment involves surgical resection of small intestinal segments, complications related to short bowel syndrome may occur. Complications of short bowel syndrome include malabsorption, diarrhea, and nutritional deficiencies. Since malnutrition affects a significant number of individuals with CD, diet management is a significant component of the care plan.69 Routine colonoscopy for cancer screening should be performed for long-standing colonic disease.⁶⁶

The individual may be evaluated for food allergies, parasites, or bacterial growth. The Rome IV criteria for diagnosing IBS are presented in Box 41.2.

There is no cure for IBS, and treatment is individualized.74 Treatment of symptoms may include laxatives, fiber, antidiarrheals, antispasmodics, prosecretory drugs, low-dose antidepressants, visceral analgesics, and serotonin agonists or antagonists and supportive care is symptom related. Alternative therapies include prebiotics and probiotics to manipulate the microflora. Hypnosis, acupuncture, yoga, cognitive behavioral therapy, and dietary interventions have been used with varying results.⁷⁵ Research continues to advance the management and understanding of the pathophysiology of this complex syndrome.

Diverticula can occur anywhere in the GI tract, particularly at weak points in the colon wall, usually where arteries penetrate the tunica muscularis. The most common sites are the left sigmoid colon (more prevalent in Western countries) and the right colon (more prevalent in Asian countries). A common associated finding of the disease is thickening of the circular muscles and shortening of the longitudinal (teniae coli) muscles surrounding the diverticula. Although not characterized as muscle hypertrophy, diverticular disease may cause increased collagen and elastin deposition and is associated with muscle thickening. This contributes to increased intraluminal pressure and herniation. According to the law of Laplace (see Chapter 34), wall pressure increases as the diameter of a cylindrical structure decreases. Therefore pressure within the narrow lumen can increase enough to rupture the diverticula, causing inflammation and diverticulitis. Bacteria and local ischemia also may be contributing factors. Complicated diverticulitis includes abscess, fistula, obstruction, bleeding, or perforation.

An increase in dietary fiber intake often relieves symptoms by increasing bulk and lowering colonic pressure. Uncomplicated diverticulitis is usually treated with bowel rest and a clear, liquid diet, analgesia, and selective use of antibiotics. Complicated cases may require intravenous antibiotics and abscess drainage if needed. In severe cases, bowel resection surgery may be needed with or without a colostomy.79

The exact mechanism of the cause of appendicitis is not well understood. Obstruction of the lumen with stool, tumors, or foreign bodies, with consequent bacterial infection, is the most common theory. The obstructed lumen does not allow drainage of the appendix, and as mucosal secretion continues, intraluminal pressure increases. The increased pressure decreases mucosal blood flow, and the appendix becomes hypoxic. The mucosa ulcerates, promoting bacterial or other microbial invasion, with further inflammation and edema. Inflammation may involve the distal or entire appendix. Gangrene develops from thrombosis of the luminal blood vessels, followed by a periappendicular abscess and perforation resulting in peritonitis in complex cases.80,81

In addition to clinical manifestations, there is pain with abdominal palpation and rebound tenderness, usually referred to the right lower quadrant. The white blood cell count is greater than 10,000 cells/mm³, with increased neutrophils and C-reactive protein. Abdominal ultrasound, CT scans, and magnetic resonance imaging (MRI) (particularly for pregnant women and children) assist with diagnostic accuracy and help to rule out nonappendiceal disease. Antibiotics and appendectomy are the treatment for simple appendicitis.82 Treatment for complicated appendicitis (perforation, abscess formation, peritonitis) also includes antibiotics and appendectomy; however, recovery may be more complicated.^80,83 There is an increased risk of colon cancer post appendectomy among individuals aged 50 to 54 years, and follow-up colonoscopy is recommended.⁸⁴

Portal hypertension is caused by disorders that obstruct or impede blood flow through any component of the portal venous system or vena cava. Intrahepatic causes result from vascular remodeling with shunts, thrombosis, inflammation, or fibrosis of the sinusoids, as occurs in cirrhosis of the liver, biliary cirrhosis, viral hepatitis, or schistosomiasis (a parasitic infection). Posthepatic causes occur from hepatic vein thrombosis or cardiac disorders that impair the pumping ability of the right side of the heart. This causes blood to collect and increases pressure in the veins of the portal system. The most common cause of portal hypertension is fibrosis and obstruction caused by cirrhosis of the liver. Long-term portal hypertension causes several pathophysiologic problems that are difficult to treat and can be fatal. These problems include varices, splenomegaly, ascites, hepatic encephalopathy, and hepatopulmonary syndrome (HPS) (see Emerging Science Box: Portal Hypertension).

Varices are distended, tortuous collateral veins. Prolonged elevation of pressure in the portal vein causes collateral veins to open between the portal vein and systemic veins. The prolonged pressure is distributed throughout the GI tract and results in transformation into varices, particularly in the lower esophagus and stomach, but also over the abdominal wall (known as the caput medusae [Medusa head]) and rectum (hemorrhoidal varices) (Fig. 41.14). The hyperdynamic circulation in the stomach and esophagus impairs mucosal defenses, promotes inflammation, and disrupts healing with increased risk of mucosal erosion, ulceration, and bleeding.⁸⁹ Rupture of varices can cause life-threatening hemorrhage.⁹⁰

An illustration depicts the varices encountered in portal hypertension showing the digestive system with labels indicating azygos, esophageal and gastric varices, short gastric, veins of Sappey, portal, superior mesenteric, hemorrhoidal varices, inferior mesenteric, coronary, splenic.

Splenomegaly is enlargement of the spleen caused by increased pressure in the splenic vein, which branches from the portal vein. Thrombocytopenia is the most common symptom of congestive splenomegaly. The enlarged spleen can often times be palpated. HPS and portopulmonary hypertension (PPH) are respiratory complications of liver disease and portal hypertension. The pathophysiology of both is complex and involves different effects of vasoactive substances. In HPS there is pulmonary vasodilation, probably because of the increased nitric oxide synthesis, increased pulmonary venous congestion, and right-to-left shunting that induces hypoxemias. PPH is associated with vasoconstriction and arterial vascular remodeling with thickening and fibrosis of the arterial wall that increases pulmonary artery resistance. Individuals may be asymptomatic, or fatigue, dyspnea, cyanosis, and clubbing may occur with or without signs of right heart failure (jugular venous distention, ascites, and peripheral edema).

Diagnosis includes pulmonary function tests, arterial blood gas analysis, contrast echocardiography, transthoracic echocardiography, and right heart catherization. In PPH, mean pulmonary artery pressure is greater than 25 mm Hg at rest. There is no specific treatment for HPS. Treatment of PPH includes targeting the pulmonary arterial vasculature to reduce pulmonary hypertension with various medication options that include endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostanoids. Liver transplant may be indicated.91

Portal hypertension is often diagnosed at the time of variceal bleeding and confirmed by upper GI endoscopy and evaluation of portal venous pressure. The individual usually has a history of jaundice, hepatitis, alcoholism, or cirrhosis. Liver elastography is an imaging test that provides a noninvasive measure of liver stiffness and can diagnose the extent of fibrosis.92

Emergency management of bleeding varices includes use of vasopressors and compression of the varices with an inflatable tube or balloon, sclerotherapy, variceal ligation, or portacaval shunt. Surgical construction of transjugular intrahepatic portosystemic shunts (TIPSs) and anastomosis of the portal vein to the inferior vena cava may decompress the varices. This treatment can precipitate encephalopathy. Emergency management will also include stabilization of the individual with fluid resuscitation, red blood cell replacement, and antibiotics. Liver transplantation is the most successful option for liver failure. Nonemergent or long-term management may include nonselective β-blocking drugs to assist reducing the pressure in the portal venous system and to prevent variceal bleeding.⁹³

Several factors contribute to the development of ascites, including portal hypertension, splanchnic vasodilation, decreased synthesis of albumin by the liver, splanchnic arterial vasodilation, and renal sodium and water retention. Portal hypertension causes capillary hydrostatic pressure to exceed capillary osmotic pressure (see Chapter 3), pushing water into the peritoneal cavity. Portal hypertension also increases the production of hepatic lymph, which “weeps” into the peritoneal cavity. Reduced serum albumin levels reduce capillary oncotic pressure adding to the fluid shift. Splanchnic arterial vasodilation is associated with increased nitric oxide produced by the diseased liver and can decrease effective circulating blood volume, activating the renin-angiotensin-aldosterone system and antidiuretic hormone, which in turn promotes renal sodium and water retention. The sodium and water retention expands plasma volume, thereby accelerating portal hypertension and ascites formation. In addition, translocation of bacteria and release of endotoxin cause peritonitis with an inflammatory response that increases splanchnic vasodilation and mesenteric capillary permeability and fluid movement into the peritoneal cavity, promoting ascites. Fig. 41.15 summarizes the mechanisms by which cirrhosis of the liver cause ascites.

A flow chart summarizes the mechanisms of ascites caused by cirrhosis. The diagram begins as follows. • Cirrhosis leads to portal hypertension and hepatocyte failure. • Portal hypertension leads to increased lymph production, splanchnic arterial vasodilation, and increased capillary filtration pressure. • Increased capillary filtration pressure leads to transudation of plasma to the peritoneum, decreasing effective plasm volume, and renal blood flow, or perfusion, causing ascites. • An increase in lymph production leads to lymph leakage to the peritoneal space causing ascites. • The translocation of gut bacteria leads to bacterial peritonitis, which increases capillary permeability, causing ascites. • Hepatocyte failure leads to a decrease in albumin synthesis and altered metabolism. • Albumin synthesis leads to decreased oncotic capillary pressure causing decreased effective plasma volume and renal blood flow perfusion. •Altered metabolism leads to an increase in renin aldosterone and antidiuretic hormone and an increase in renal absorption of sodium and water, causing ascites.

The accumulation of ascitic fluid causes abdominal distention, increased abdominal girth, and weight gain (Fig. 41.16). Large volumes of fluid (10 to 20 L) displace the diaphragm and cause dyspnea by decreasing lung capacity. The respiratory rate increases, and the individual may need to assume a sitting position to relieve the dyspnea. Some peripheral edema is usually present. Dilutional hyponatremia may be noted because of excess fluid volume. Approximately 10% of individuals with ascites develop bacterial peritonitis, either spontaneously or because of paracentesis, which causes fever, chills, abdominal pain, decreased bowel sounds, and cloudy ascitic fluid.

Palliative paracentesis in amounts of 1 or 2 L of ascitic fluid is completed to relieve respiratory distress. However, the removal of too much fluid too quickly relieves pressure on blood vessels and carries the risk of hypotension, shock, or death. Despite repeated paracentesis, ascitic fluid reaccumulates because of the persistent portal hypertension and reduced plasma albumin levels associated with irreversible disease. Peritonitis is treated with antibiotics. Other procedures include placement of a peritoneovenous shunt and TIPS. Individuals with ascites and portal hypertension have a poor prognosis, and liver transplantation is the best treatment option.94

Hepatic encephalopathy results from a combination of biochemical alterations that affect neurotransmission and brain function. Liver dysfunction and the development of collateral vessels that shunt blood around the liver to the systemic circulation permit toxins absorbed from the GI tract and normally removed by the liver, to accumulate and circulate freely to the brain. The accumulated toxins alter cerebral energy metabolism, interfere with neurotransmission, and cause edema. The most hazardous substances are end products of intestinal protein digestion, particularly ammonia, which cannot be converted to urea by the diseased liver. The digestion of blood from leaking or ruptured varices adds to the amount of ammonia present in systemic blood, as does the action of ammonia-forming bacteria in the colon. Ammonia that reaches the brain is metabolized to glutamine, with osmotic disturbances and alterations in cerebral blood flow that interfere with neurotransmitters and cause astrocyte edema or cytotoxic edema and oxidation. Disruption of the blood-brain barrier causes vasogenic edema and contributes to astrocytes swelling, brain edema, and intracranial hypertension. Excessive amounts of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter from intestinal flora, may contribute to reduced levels of consciousness. Infection, systemic inflammation, hemorrhage, and electrolyte imbalance (including zinc deficiency), constipation, and the use of sedatives and analgesics can precipitate hepatic encephalopathy in the presence of liver disease.95

The diagnosis of hepatic encephalopathy is based on a history of liver disease, clinical manifestations, psychometric tests, and exclusion of other causes of brain dysfunction. Electroencephalography and blood chemistry tests provide supportive data. Tracking levels of serum ammonia can assist to assess treatment effectiveness and liver function, but the test is difficult to perform and may be influenced by hemolysis and severe jaundice.96 Correction of fluid and electrolyte imbalances and withdrawal of depressant drugs metabolized by the liver are the first steps in the treatment of hepatic encephalopathy. Dietary protein is maintained to prevent malnutrition but at levels that reduce blood ammonia levels. Lactulose prevents ammonia absorption in the colon, and polyethylene glycol has also been used with success in reducing ammonia levels.⁹⁷ Neomycin eliminates ammonia-producing intestinal bacteria but can be nephrotoxic. Glutamase inhibitors reduce gut ammonia. Rifaximin (a nonabsorbable antibiotic) decreases intestinal production of ammonia and may be combined with lactulose or used alone for lactulose nonresponders. Extracorporeal liver support systems remove toxins from the blood and are an option for managing overt hepatic encephalopathy or as a bridge to liver transplantation.⁹⁶

Obstructive jaundice can result from extrahepatic or intrahepatic obstruction.98Extrahepatic obstructive jaundice develops if the common bile duct is occluded. Occlusion may be from a gallstone, tumor, or inflammation. If occluded, bilirubin conjugated by the hepatocytes cannot flow through the obstructed common bile duct into the duodenum. Therefore bilirubin accumulates in the liver and enters the bloodstream, causing hyperbilirubinemia and jaundice. Intrahepatic (hepatocellular) obstructive jaundice involves disturbances in hepatocyte function and obstruction of bile canaliculi. The uptake, conjugation, or excretion of bilirubin can be affected with elevated levels of both conjugated and unconjugated bilirubin. Obstruction of bile canaliculi diminishes flow of conjugated bilirubin into the common bile duct. In mild cases, some of the bile canaliculi open. Consequently, the amount of bilirubin in the intestinal tract may be only slightly decreased.

Excessive hemolysis (destruction) of red blood cells can cause hemolytic jaundice(prehepatic or nonobstructive jaundice). Increased unconjugated bilirubin is formed through metabolism of the heme component of destroyed red blood cells and exceeds the conjugation ability of the liver, causing blood levels of unconjugated bilirubin to rise. Decreased bilirubin uptake or conjugation also causes unconjugated hyperbilirubinemia, as occurs with reaction to some drugs (e.g., rifampin), and in genetic disorders, such as Gilbert syndrome. Unconjugated bilirubin is not water soluble, so it will not be excreted in the urine. The causes of jaundice are summarized in Table 41.8.

Type 1 HRS–acute kidney injury occurs in less than 2 weeks and accompanies a sudden decrease in blood volume secondary to massive GI or variceal bleeding and hypotension caused by bleeding and peripheral vasodilation associated with failing liver function. Proinflammatory cytokines related to translocation of bacterial to ascetic fluid can promote systemic hypotension and reduced renal blood flow. Hypotension also can be caused by the excessive use of diuretics to treat ascites or decreased cardiac output. The decrease in blood volume and hypotension result in decreased renal perfusion, decreased glomerular filtration, and oliguria (see Chapter 38). The serum creatinine increases to a concentration of greater than 0.3 mg/dL within 48 hours or a urine output less than 0.5 mL/kg body weight for greater than 6 hours.

Type 2 HRS–nonacute kidney injury (HRS-NAKI) develops slowly and is related to ascites resistant to diuretics. Ineffective circulating blood volume causes decreased glomerular filtration and oliguria. Intrarenal vasoconstriction may result from the selective effects of vasoactive substances that accumulate in the blood because of liver failure or as a compensatory response to portal hypertension and the pooling of blood in the splanchnic circulation. Vasoconstriction also may be a compensatory response to portal hypotension and vasodilation in the splanchnic circulation. There are two categories of NAKI. HRS–acute kidney disease (HRS-AKD) is diagnosed when the estimated glomerular filtration rate is less than 60 mL/min/1.73 m² for less than 3 months and the percent increase in serum creatinine is less than 50% compared with a baseline value obtained within the past 3 months. The kidney usually maintains a normal structure with this condition; HRS–chronic kidney disease (HRS-CKD) is diagnosed when the estimated glomerular filtration rate is less than 60 mL/min/1.73 m² for more than 3 months. The kidney usually maintains a normal structure, and there is absence of other structural causes of kidney disease.⁹⁹

Diagnosis of HRS is made by excluding other causes of renal failure. Despite decreased glomerular filtration, serum potassium levels do not become dangerously elevated until the terminal stages of the HRS. Serial changes in serum creatinine provide an index for estimation of GFR, and values increase to 2.5 mg/dL or higher. Guidelines are available for determining AKI or CKD.100 The BUN level increases, and metabolic acidosis develops. Urine osmolality increases, but urine sodium concentrations are less than normal. Urine specific gravity is greater than 1.015.

The prognosis is usually poor and is related to a failing liver, requiring liver transplantation. Secondary problems, including fluid and electrolyte disorders, bleeding, infections, and encephalopathy, are treated. Vasoconstrictors and albumin are often used as first line treatment of HRS. Liver transplant reverses HRS symptoms in most individuals and may be combined with kidney transplant.¹⁰¹