GASTROINTESTINAL DISEASES IN WOMEN

WOMEN’S HEALTH ISSUES, PART I 0025-7125/98 $8.00 + .OO

GASTROINTESTINAL DISEASES IN WOMEN

Marie L. Borum, MD, MPH

Gastrointestinal disorders are among the most common disorders for which women seek medical attention. Most gastrointestinal diseases in women are not inherently different from those that occur in men. There are several disorders, however, that occur more frequently or manifest themselves differently in women. This article reviews common gastrointestinal disorders affecting women. The pathophysiology, clinical manifestations, management, and gender-specific issues of gastroesophageal reflux disease, peptic ulcer disease, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD) are discussed.

GASTROESOPHAGEAL REFLUX DISEASE

Gastroesophageal reflux, the effortless movement of gastric contents into the esophagus, is estimated to occur daily in 7% of U.S. adults. Approximately 44% of U.S. adults report monthly symptoms related to gastroesophageal reflux. It occurs more frequently in men than women (2 to 3:1).lz6 There are clinical circumstances, however, in which women are more likely to develop symptoms or have worsening of their symptoms. Increased awareness and special management concerns should be given to women during pregnancy, during oral contraceptive use, and with certain rheumatologic conditions.

From the Department of Medicine, The George Washington University Medical Center, Washington, DC

MEDICAL CLINICS OF NORTH AMERICA

VOLUME 82 * NUMBER 1 *JANUARY 1998 21

22 BORUM

Pathophysiology

Gastroesophageal reflux causes esophagitis when the caustic gastric contents remain in contact with the esophageal mucosa for a sufficient amount of time to overcome esophageal defenses and tissue resistance. The antireflux defenses of the esophagus include the increased pressure of the lower esophageal sphincter (LES) and maintaining an intra-abdominal distal esophageal segment. The diaphragmatic crura, the phreno- esophageal ligament, and the acute angle of His can provide additional anatomic defense. Esophageal clearance is enhanced with gravity and peristalsis. Salivary and esophageal gland secretion of bicarbonate result in acid neutralization. In addition, esophageal cellular membranes and intercellular junctional complex may protect against mucosal injury by limiting H + diffusion into the cells and the intercellular spaces.28, 128

The relationship between a sliding hiatal hernia and reflux esophagitis remains controversial. The majority of individuals with a hiatal hernia do not have reflux esophagitis, which suggests that hiatal hernia is not a causative factor in reflux disease. Most individuals with esophagitis, however, have hiatal hernia, which implicates it as a factor in the promotion of re flu^.^^, 12*

Clinical Manifestations

Gastroesophageal reflux can produce a variety of symptoms as well as esophageal, oropharyngeal, laryngeal, and respiratory tract tissue injury. The most common symptom includes substernal burning (heartburn) occurring most often after meals or on reclining. Atypical chest pain, which must be distinguished from cardiac pain, can also occur. Other common symptoms include regurgitation causing a bitter or sour taste in the mouth; water brash from increased salivary secretion; and dysphagia resulting from inflammation, scarring, or malignancy. Non- esophageal symptoms can result from mucosal injury of the oropharynx, larynx, and respiratory tract. Irritation to the oropharynx can result in sore throat, earaches, gingivitis, poor dentition, and globus hystericus. When the reflux material irritates the larynx and respiratory tract, hoarseness, wheezing, bronchitis, asthma, and aspiration pneumonia can 0 ~ ~ ~ r . 2 8 . 63. 152

Diagnostic Tests

A large number of diagnostic tests have been developed for investi- gating gastroesophageal reflux. Most tests, however, are unnecessary to establish the diagnosis or to begin treatment. Investigations should be performed in individuals with persistent symptoms or signs suggestive of tissue injury (i.e., dysphagia, guaiac-positive stool, anemia). Early

GASTROINTESTINAL DISEASES IN WOMEN 23

assessment is also important in patients with equivocal symptoms that make the diagnosis uncertain.

The most common diagnostic tests used for gastroesophageal reflux are barium studies, endoscopy, acid reflux tests, pH monitoring, and radionuclide scanning. The most readily available tests for identifying gastroesophageal reflux are barium studies. Although these tests are highly specific, low sensitivity rates have been reported. Acid perfusion tests require the placement of an esophageal pH probe 5 cm above the LES to test for the presence of refluxed acidic contents (confirmed by pH <4) into the esophagus. Continuous intraesophageal pH monitoring records the esophageal pH for 24 hours, and patients' symptoms are correlated with activities and pH recordings. Radionuclide scans are also used to assess for reflux by identifying radiolabeled colloid in the area of the esophagus. The Bernstein test assesses symptoms occurring with normal saline and 0.1 N HC1 infusion into the esophagus and is useful for determining whether atypical chest pain is related to acid reflux. All of these tests have a wide range of sensitivity and specificity depending on the investigator and their technique.28* 78, lZ9

Upper endoscopy is the best method for assessing mucosal injury. The endoscopic findings can vary from normal mucosa, erythema, and edema to friability, erosions, ulcers, strictures, and Barrett's esophagus. These findings can be correlated to symptoms, and biopsies can be performed for histologic e~a lua t ion .~~

Clinical Course

The clinical course of gastroesophageal reflux varies. In many patients, symptoms may occur for brief periods of time and be controlled with diet and episodic antacids. In other individuals, however, the symptoms may be poorly responsive to lifestyle modification and require prolonged pharmacologic intervention. A limited number of patients require surgery for control of reflux symptoms and complications. In a retrospective study of patients with reflux symptoms, abnormal 24- hour pH monitoring, and no endoscopic mucosal abnormalities, 42% were asymptomatic at 6 months and required no further medical therapy. In the remaining 52% who required continued medical management, 15% progressed to erosive esophagitis. The degree of pH monitoring abnormalities did not predict the response to therapy or the progression of the disease.130 Investigators have also demonstrated that after pharmacologically induced healing of esophagitis, approximately 78% remained healed or had only symptomatic relapse, and approximately 22% had symptomatic relapse associated with complication^.^^

Complications

The primary complications of gastroesophageal reflux disease include stricture formation, Barrett's esophagus, bleeding, and perforation.

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Strictures

Strictures can develop at sites of significant recurrent inflammation. Radiographically, they appear as a smooth-walled, tapered narrowing of the lower esophagus. They range in length from 1 to 4 cm and become clinically apparent with the development of dysphagia. A reduction in substernal burning may reflect the ability of the stricture to act as a barrier to reflux. Endoscopy should be performed to confirm the benign nature of the abnormality. Dilation can increase the diameter of the esophageal lumen and decrease the symptoms. Failure to dilate a stricture successfully or to prevent its recurrence is an indication for surgery.lZ8

Barrett’s Esophagus

Barrett’s esophagus is considered to be an acquired lesion from recurrent reflux in which the stratified squamous epithelium of the lower esophagus is replaced by columnar epithelium. It occurs in 10% to 15% of patients with erosive esophagitis and up to 40% of patients with peptic strictures. Barrett’s esophagus does not result in worsening of the symptoms but is of particular importance because it is a premalig- nant condition for adenocarcinoma.”, lz5, lz8

Medical therapy is employed in an attempt to produce a regression of Barrett’s esophagus or prevent malignant degeneration. Serial endoscopic surveillance is recommended. Laser ablation is presently being evaluated as a management tool for Barrett’s esophagus but remains e~perimental.’~

Bleeding

Patients with reflux esophagitis do not typically have evidence of bleeding. Patients with severe mucosal injury associated with erosions and ulcerations, however, can develop chronic bleeding and anemia. Rarely, life-threatening bleeding has occurred as a result of deep esophageal ulcers.’28

Perforations

Gastroesophageal reflux can rarely result in a perforation. This complication most often results from deep esophageal ulcerations. Perfo- rations are a surgical emergency because the resulting mediastinitis can be life-threatening. Survival depends on early recognition and intervention.lz8

Management

Gastroesophageal reflux can be treated with lifestyle modification, medications, and rarely surgery. The goal of therapy is to control symp-


toms and heal any mucosal lesions. The majority of patients can be empirically managed with dietary changes with antacids or a short course of acid-suppression therapy. Those who fail to improve with empiric therapy should undergo upper endoscopy to assess the extent of esophageal injury and to eliminate other potential diagnoses. Patients with erosive esophagitis are at relatively high risk for the development of major complications.

Lifestyle Modifications

Lifestyle modifications can effectively reduce symptoms and prevent symptom recurrence. Nonpharmacologic management includes ele- vation of the head of the bed, reducing the size of meals, decreasing fat and caffeine intake, avoidance of the supine position after eating, and cessation of tobacco and alcohol. Weight reduction can be helpful in obese patients.

Medications

Medications used in the management of gastroesophageal reflux include antacids, sucralfate, H,-receptor antagonists, proton-pump inhibitors, bethanechol, metoclopramide, and cisapride. Initial management often includes lifestyle modifications and antacid neutralization. If this provides incomplete relief, acid suppression therapy with sucralfate, H,- receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine), or proton-pump inhibitors (omeprazole, lansoprazole) should be initiated. If acid suppressive agents are not adequate in achieving treatment goals, adjunctive therapy with a prokinetic agent (i.e., bethanecol, metoclopramide, cisapride) can be used. Cisapride is the best-tolerated prokinetic agent and is most frequently used (Table l).17, 22* loR, 12*, 138, I4l, 145, 159, 176

Surgery

Despite the wide array of medications that can be used for gastroesophageal reflux, a limited number of patients require surgical intervention. The indication for antireflux surgery is the failure to prevent symptoms or heal or prevent esophagitis or its complications. Belsey’s and Nissen’s fundoplication and Hill’s posterior gastropexy are the most widely used procedures and are estimated to be 85% successful. Symp- toms are estimated to recur in 10% of patients who had initially successful surgery. The morbidity rates of the procedures are estimated to be 2% to 8%, and the mortality rate is approximately 1%. The most common complications from these surgical procedures are dysphagia and the inability to belch or vomit. Increasingly the Nissen procedure is being performed laparoscopically. The laparoscopic approach may offer a decreased short-term morbidity and a shortened hospital

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Table 1. THERAPY FOR GASTROESOPHAGEAL REFLUX DISEASE

Agent Mechanism of Action Selected Side Effects

Antacids

Sucralfate (Carafate)

H,-receptor antagonists Cimetidine (Tagamet) Ranitidine (Zantac) Famotidine (Pepcid) Nizatidine (Axid)

Proton-pump inhibitors Omeprazole (Prilosec) Lansoprazole (Prevacid)

Prokinetic agents Bethanechol

(Urecholine) (cholinergic agonist)

Metoclopramide (Reglan) (dopamine antagonist)

Cisapride (Propulsid) (increases acetylcholine release)

Acid neutralization

Buffers acid Binds pepsin and bile acids Decreases acid secretion by

inhibiting parietal cell histamine receptors

Decreases acid secretion by irreversibly inhibiting parietal cell H+-K+ pump

Increases lower esophageal sphincter pressure

Increases gastric motility

Mg-induced diarrhea Al-induced constipation Mg and Al renal toxicity Constipation

Central newous system effects

Bone marrow suppression Elevated liver enzymes

Diarrhea

Flushing, blurry vision, headaches, abdominal pain, urinary frequency

Drowsiness, insomnia, agitation, dyskinesias

Diarrhea, abdominal pain

Mg = Magnesium; Al = aluminum.

GASTROESOPHAGEAL REFLUX AND WOMEN

Clinical circumstances in women that deserve special attention when considering gastroesophageal reflux include pregnancy and the use of oral contraceptives. In addition, scleroderma is a rheumatologic condition that occurs more frequently in women, which can be associated with significant gastroesophageal reflux.

Pregnancy

It is estimated that gastroesophageal reflux occurs in 60% to 70% of pregnant women. The symptoms increase with increasing gestational age. It has been reported that women who have a history of gastroesophageal reflux before pregnancy are the most likely to have reflux symptoms during pregnan~y.~, Io3

Mechanisms that may be associated with gastroesophageal reflux during pregnancy include a hormonally induced decrease in LES tone and the mechanical pressure of the gravid uterus.166 Laboratory and clinical studies suggest that circulating estrogens and progesterones have a relaxant effect on the LES. It appears, however, that progesterone is the primary hormone responsible for the effects on the LES.46, lo3 In addition, there is a positive correlation between reflux symptoms and


the size of the uterus. Factors that have been proposed to influence the reflux episodes during pregnancy include placement of the LES segment in the thoracic cavity, alterations of the anatomic structures surrounding the LES, and delayed gastric emptying.179

Confirmatory tests are rarely needed to diagnose gastroesophageal reflux during pregnancy. Radiographic studies should be avoided. En- doscopy can be safely performed, however, if clinical concerns warrant an endoscopic evaluation.

Treatment regimens must consider the potential adverse reactions of medications on the fetus. Standard intervention should include lifestyle modifications. Antacids and sucralfate are considered safe and are used frequently during the second and third trimester.95 All H,-receptor antagonists cross the placenta, and there are no controlled studies that have evaluated the effect of H,-receptor antagonists on the fetus. Cimetidine, however, has been used in pregnancy to treat peptic ulcer disease without apparent adverse fetal effects and has, therefore, been used to treat gastroesophageal reflux in pregnant women.4o, 110, I8O Ranitidine appears to have a similar safety profile as cimetidine.',, 95 A prospective cohort study suggested that first-trimester H,-receptor antagonists do not affect pregnancy outcome, cause major fetal malformations, or influence neonatal health. Little information and experience are available on the use of the proton-pump inhibitors omeprazole and lansoprazole.lol Although prokinetic agents have been used to treat reflux during pregnancy, there have been no controlled studies on these agents during pregnancy.76 It continues to be recommended that H,-receptor antagonists, proton-pump inhibitors, and promotility agents be used judicious- ly during pregnancy.

Oral Contraceptives

A number of medications can decrease the LES tone and cause an increase in episodes of gastroesophageal reflux. These medications include anticholinergics, calcium channel blockers, theophylline, and ni- trates. There is also experimental and clinical evidence to suggest that a reduction in LES tone can occur as a result of estrogens and progester- o n e ~ . ~ ~ Women taking sequential oral contraceptives have been reported to have increased gastroesophageal re flu^.'^^ When estrogen replacement is used with progesterone, however, there has not been a reported increase in reflux symptoms.

In women in whom hormone replacement is related to the onset or the worsening of gastroesophageal reflux symptoms, adjustment of hormonal therapy should be initially considered. If adjustment of hormonal therapy is not possible or desired, however, the symptoms are usually adequately controlled with lifestyle modification and acid suppression therapy. Adjunctive treatment with motility agents can be used if there is insufficient relief of symptoms with acid suppression.

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Scleroderma

Scleroderma occurs more often in women and is frequently associated with esophageal involvement. It is a collagen vascular disease that can result in fibrosis and degenerative changes in the skin and synovium and parenchymal changes of the heart, kidneys, lungs, intestines, and esophagus. The esophageal involvement results in motility abnormalities in 75% to 85% of patients. The severity of the esophageal disease is variable, however, and does not coincide with the extent of the cutaneous changes or other systemic manifestation^.^^, 85

Smooth muscle atrophy and submucosal fibrosis in the distal two thirds of the esophagus can cause a decrease in peristalsis, poor esophageal clearance, and incompetence of the LES. This can result in significant gastroesophageal reflux, esophagitis, and possible complica-

There is no effective treatment to prevent esophageal involvement in scleroderma. The gastroesophageal reflux associated with this disorder, however, should be aggressively treated. Chronic H,-receptor antagonists and proton-pump inhibitors are most often used in this disorder for management of esophageal symptoms and mucosal injury. Serial endoscopy may be required to assess injury and response to therapy. Stricture formation is a common complication of inadequately controlled reflux and can require dilation. Severe cases of intractable esophagitis may require antireflux surgery.

tions.32, 124

PEPTIC ULCER DISEASE

Peptic ulcer disease develops in approximately 10% of U.S. adults during their lifetime. There are an estimated 500,000 new cases and 4 million recurrences each year.88 This has a significant economic impact with annual direct costs of $8 to 10 billion.*O

There is no apparent difference in the gastric acid secretion or fasting gastric and duodenal pH between men and ~ 0 r n e n . I ~ ~ Few studies have compared the natural history of ulcers between genders. It has been documented, however, that the incidence of ulcers increases with age in both women and men. In one study, the ulcer prevalence was estimated to be 0.3 per 1000 for women 25 to 29 years old, 0.62 per 1000 in women 35 to 39 years old, and 0.84 per 1000 for women greater than 50 years old. There is an increasing prevalence of ulcers in geriatric women attributed to nonsteroidal anti-inflammatory drug (NSAID) use.'42

Pathophysiology

The pathogenesis of ulcer disease appears to be a result of an imbalance between aggressive and defensive factors. Aggressive factors


include acid-induced and pepsin-induced mucosal injury. Defense mechanisms include the production of a mucus-bicarbonate barrier, which serves as a barrier for H + and pepsin diffusion and protects against mucosal damage.3,

In patients with duodenal ulcer disease, there has been a report of increased or normal gastric acid secretion, decreased duodenal bicarbonate secretion, or Helicobacter pylori infection. The majority of gastric ulcers are associated with NSAID and H . pylori infection. It has been reported that mucus production may be inhibited by NSAIDS.~ Laboratory evidence has also revealed that H . pylori can produce proteases that are capable of degrading mucins.122

Potentially Related Factors

Age U.S. studies have found that there has been a substantial increase

in hospitalization rates of elderly patients for ulcer bleeding and perforation. Although the overall mortality rate for patients with ulcers remained stable during the past two decades, the mortality rate has risen significantly in patients older than 75 years. The rise has been attributed to increased NSAID use in the geriatric population.82, 169 The availability of H2-receptor antagonists, proton-pump inhibitors, and prostaglandin analogues has not decreased the incidence of ulcer complications in the geriatric population.

Genetic Factors

Genetic factors may have a role in ulcer pathogenesis. The concor- dance for peptic ulcer disease among identical twins is approximately 50% and is also increased among nonidentical twins. Studies have suggested that the lifetime prevalence of developing an ulcer in first-degree relatives of ulcer patients is about threefold greater than that in the general population. Approximately 20% to 50% of duodenal ulcer patients report a family history of duodenal ulcers. Gastric ulcer prevalence may also cluster in families.

The inheritance of blood group 0 is associated with a modest (1.3- fold) increase in duodenal ulcer incidence.2 Human leukocyte antigen (HLA) subtypes (HLA-B5, HLA-B12, HLA-Bw35) have been identified as possible genetic markers for duodenal disease. Further study on the association of HLA types with ulcer disease is necessary.8o

Helicobacter pylori

The identification of H. pylori has increased the understanding of the pathogenesis of peptic ulcer disease. H. pylori has been identified as the primary cause of most cases of histologic gastritis and is considered

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to be an important factor in the development of ulcers. Although almost all patients infected with H. pylori develop gastritis, only 15% develop ulcer disease. The frequency of Helicobacter-induced gastritis is associated with increasing age and has a higher prevalence in minority populations and populations of lower socioeconomic status. H. pylori is not related to gender, cigarette smoking, or alcohol use.7o, Io7

The transmission of H. pylori is incompletely understood. Evidence suggests that there is an increased prevalence of this infection among family members of patients with H. pylori. This may suggest that person- to-person transmission, infection from a single environmental source, and fecal-oral transmission may have roles in the infe~ti0n.I~. 53, lo*

Approximately 90% to 100% of patients with duodenal ulcers and 70% to 90% of patients with gastric ulcers are infected with H. p y l ~ r i . ~ ' , 36, 13*, 137 Despite the apparent association with H. pylori infection and peptic ulcer disease, a definitive pathogenic mechanism has not been determined. Nevertheless, multiple prospective treatment trials have demonstrated that the eradication of H. pylori is associated with a decrease in ulcer re~urrence.~~, 75, *O Several investigations have also reported that treatment directed at H. pylori may lead to more rapid ulcer healing and a higher rate of ulcer healing.69, 75, 79

Nonsteroidal Anti-Inflammatory Drugs

Chronic NSAID ingestion has been reported to cause gastroduodenal ulceration. The relative risk is uncertain, but it is estimated that the risk is increased 46-fold for gastric ulcer and 8-fold for duodenal ulcers. The prevalence of gastric ulcers associated with NSAID ranges from 9% to 31%, and the prevalence of duodenal ulcers is 0 to 19%.109,150

NSAID use is associated with a significantly increased risk of gastrointestinal compli~ations.~~~ Factors that appear to influence NSAID-induced ulcerations include prior history of ulcer disease, advancing age, and medication 71, 72 The risk of complications, especially hemorrhage, is highest in the first 1 to 3 months after the initiation of NSAID therapy.", 71 Studies have also implicated tobacco and alcohol as possible factors in the potentiation of ulcers. In addition, some investigators have suggested that women may be at greater risk than men for NSAID- induced

Tobacco

Most studies reveal a strong positive association between cigarette smoking and ulcer incidence, mortality, complications, recurrences, and delayed healing rates.33, 47, 151 In a 12.5-year U.S. prospective study, the cumulative incidence was 10% for current smokers and 5% for those who had never smoked. Among nonsmokers, the ulcer risk was greater in men than women. Among smokers, there was no gender difference.lo5


Stress

The role of stress in the pathogenesis and natural history of peptic ulcer disease has been the subject of numerous studies. The results of these studies have reported conflicting results. Although many individuals associated stressful events and ulcer exacerbation, the role of psychological factors in ulcer disease is difficult to confirm.80

Steroids

The role of steroids in the development of peptic ulcer disease remains controversial. A review of multiple randomized studies con- cluded that adrenocorticosteroids may be associated with ulcer pathogenesis in patients who receive daily steroids for more than 1 month and in those with prior ulcer disease. Other studies, however, have failed to confirm this ass~ciation.~~, 116, 132


Abdominal pain is the most frequent symptom of ulcer disease. It is often a burning discomfort localized in the epigastric area occurring 2 to 3 hours after a meal or at night and is relieved by food or antacids. Nocturnal pain awakening the patient at night can be a symptom of ulcer disease. Despite the fact that abdominal pain is common, it does not occur in all patients. Nocturnal pain affects only two thirds of patients with duodenal ulcer and one third of patients with gastric ulcer. Nocturnal pain, however, may be present in up to one third of patients with nonulcer conditions.80

Complications

The major complications of peptic ulcer disease are hemorrhage, perforation, penetration, and obstruction.

Hemorrhage

Hemorrhage occurs in approximately 10% to 15% of ulcer patients. Although ulcer hemorrhage occurs at all ages, it is more common in patients in their 50s or older. Bleeding is related to an increased use of NSAIDs and may be more common in elderly women. Approximately 10% to 20% of patients who bleed from a gastric or duodenal ulcer do not have preceding ~ymptoms.~, 148

Perforation and Penetration

Perforation occurs in approximately 5% to 10% of patients with ulcers. Duodenal ulcers tend to perforate anteriorally, and gastric ulcers

32 BORUM

tend to perforate along the anterior wall of the lesser curvature of the stomach. With the increased use of NSAIDs, the incidence of perforation is increasing and is particularly apparent in the geriatric population.80

Penetration is similar to perforation except that the ulcer crater burrows through the gastric or intestinal wall into an adjacent viscus. Most commonly, the gastric ulcers penetrate into the left lobe of the liver. Colonic penetration of gastric ulcers has also been reported resulting in gastrocolonic fistula. Duodenal ulcers can penetrate into the adjacent pancreas, often resulting in clinical pancreatitis.80

Gastric Outlet Obstruction

Gastric outlet obstruction occurs in approximately 2% to 5% of ulcer patients and can result from acute inflammation and edema or scarring near the gastroduodenal junction. When the obstruction is a result of inflammation and edema, it usually resolves with medical treatment. When scarring has resulted in outlet obstruction, however, surgical intervention or endoscopic balloon dilation is required.80

Diagnosis

Radiologic evaluation and upper endoscopy are used to diagnose ulcer disease. Double-contrast barium studies are accurate in determining the presence of an ulcer. The upper endoscopy, however, allows for direct mucosal visualization. Endoscopic biopsies can determine whether an ulcerative lesion is benign; tissue specimens can also be obtained to diagnose H . pylori.

There is no role for the routine measurement of gastrin in ulcer patients. Gastrin measurements are appropriate in patients in whom there is the possibility of multiple endocrine neoplasia (type I) or gas- trinoma or in patients who have refractory ulcer disease or are scheduled for surgery for intractable ulcer symptoms.

Management

Lifestyle

Patients with ulcer disease should be advised to discontinue NSAIDs, alcohol, tobacco, and caffeine. NSAIDs and alcohol may cause direct mucosal damage or worsening of an existing ulceration. Tobacco and caffeine have been reported to delay healing.

Medications

A variety of medications have established efficacy in the treatment of duodenal and gastric ulcers. The goals of acute ulcer treatment are to


relieve pain, expedite ulcer healing, prevent ulcer complications, and prevent recurrences. Pregnant and lactating women, however, were excluded from medication trials. Special consideration should be given in these circumstances.

The agents that have been proven to be most effective in ulcer management are those that neutralize acid, inhibit gastric acid secretion (H,-receptor antagonists, proton-pump inhibitors), promote healing through stimulation of mucosal defensive mechanisms (i.e., antacids, sucralfate, prostaglandins), and promote healing through eradication of H. pylori (Tables 2 and 3).

In patients with documented H. pylori infection, the use of antisecre-

Table 2. TREATMENT FOR PEPTIC ULCER DISEASE

Selected Side Agents Doses Duration Effects

Acid neutralization Antacids

Acid buffering Sucralfate (Carafate)

Acid inhibition H,-receptor

antagonists Cimetidine

(Tagamet)

Ranitidine (Zantac)

Famotidine (Pepcid)

Nizatidine (Axid)

Proton-pump inhibitors Omeprazole

(Prilosec) Lansoprazole

(Prevacid)

Prostaglandin analog Misoprostol (Cytotec)

5-30 mL qid as directed

1 g qid

300 mg qid 400 mg bid 800 mg qhs 150 mg bid 300 mg qhs 20 mg bid 40 mg qhs 150 mg bid 300 mg qhs

20 mg qd 40 mg qd

200 p.g qid

Mg-induced diarrhea Al-induced

constipation

4-8 wk Constipation Similar healing rates

4-8 wk Central nervous system effects

No significant Bone marrow difference between suppression agents

Elevated liver enzymes

to H,-blockers

4-8 wk Diarrhea

May heal faster with more rapid pain relief than H, blocker

Take for the duration Dose-related diarrhea of NSAlD Abdominal pain treatment Menstrual

prevention of NSAID-induced ulcers

Primary role is the irregularities

qid = Four times/day; bid = twice a day; qhs = every hour of sleep; qd = every day; Mg = magnesium; Al = aluminum; NSAID = nonsteroidal anti-inflammatory drugs.

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Table 3. TREATMENT REGIMENS FOR HELlCOBACTER PYLORl

Duration Success Medications Doses (days) Rate (%)

Bismuth subsalicylate Tetracycline Metronidazole H,-receptor antagonist or

proton pump inhibitor Bismuth subsabylate Tetracycline Clarithromycin H,-receptor antagonist or

proton pump inhibitor Amoxicillin Omeprazole Clarithromycin Omeprazole Clarithromycin Metronidazole Omeprazole Amoxicillin Clarithromycin H,-receptor antagonist or

proton pump inhibitor Ranitidine-bismuth

subcitrate Clarithromycin

14 >90

2 tabs qid 7-1 4 >90 500 mg qid 250 mg qid Ulcer treatment doses

2 tabs qid

Ulcer treatment doses

1000 mg bid 14 75-90

500 mg tid 14 75-90 20 mg bid

40 mg qd 250 mg bid 7-1 4 >90 500 mg bid 30 mg bid 750 mg tid 14 >90 500 mg tid Ulcer treatment doses

400 mg bid 28 69.1

500 mg tid 14

tory agents with anti-H. pylori agents has been reported to result in more rapid duodenal ulcer healing. Bismuth compounds and a variety of antibiotics are effective against H. pylori, including penicillin, ampicillin, amoxicillin, metronidazole, gentamicin, cephalosporins, tetracyclines, quinolones (i.e., ciprofloxacin, norfloxacin), imipenem, and macrolides (i.e., erythromycin, clarithromycin).

Although multiple agents are active against H. pylori, single-agent treatment results in low rates of eradication. Combination therapies have, therefore, been used in H. pylori treatment. Table 3 lists examples of treatment regimens.

Surgery

The availability of effective acid suppression medications has made surgical intervention for peptic ulcer much less frequent. Surgery is presently reserved for individuals with ulcers that are refractory to medications or are associated with complications. The evolution of a laparoscopic approach for the treatment of ulcer disease may alter surgical management of this condition. The experience with this type of surgery is limited, however, and prospective clinical trials have not yet been conducted.


Management During Pregnancy

Studies have revealed that there is low ulcer disease occurrence during pregnancy.95 For the unusual patient who develops an ulcer while pregnant, careful consideration should be given to medical management.

Antacids and sucralfate have limited absorption and have been the preferentially used agents during the second and third trimester of pregnancy.95 The four-times-a-day dosing regimen, however, can result in limited compliance.

All H2-receptor antagonists cross the placenta, which has limited their use during pregnancy. Studies have evaluated cimetidine use for peptic ulcer disease during pregnancy and have reported no significant adverse fetal effects.40* 110, 180 A prospective cohort study suggested that first-trimester H,-receptor antagonists do not affect pregnancy outcome, cause major fetal malformations, or influence neonatal health.166 There is little information on and minimal experience with the use of proton- pump inhibitors during pregnancy. The impact of these agents on pregnancy and fetal outcome is unknown.

Misoprostol should not be used during pregnancy. It can stimulate uterine smooth muscle, resulting in an increase in uterine pressure and reports of spontaneous abortions. Uterine bleeding has been reported in approximately 30% of women during the first trimester of pregnancy.

IRRITABLE BOWEL SYNDROME

IBS is a common bowel disorder that has been estimated to account for 20% to 50% of referrals to gastroenterology clinics.162 Studies suggest that there is a female-to-male ratio of approximately 2 to 3:l. It is typically diagnosed between the ages of 20 and 40 years.49, 83, 146, 158

Pathophysiology

The pathogenesis of IBS remains unknown. The mechanisms that have been proposed include altered gut motility and increased visceral perception. A number of studies have demonstrated motility disorders in the colon, rectum, or small bowel of patients with 1BS.l. 97, lI2, 113, 156, 178

Most of the typical symptoms of IBS have been attributed to altered colonic motility.loO Investigators have reported that there is an increase in three-cycle-per-minute slow wave activity in the distal colon and rectum of patients with IBS when compared with normal controls.51 It has also been proposed that the altered colonic motility demonstrated in patients with predominantly diarrhea results from sympathetic adren- ergic dysfunction, whereas patients with predominantly constipation may have vagal cholinergic dysfuncti~n. '~~

Patients with IBS have also been documented to have hypersensitiv-

36 BORUM

ity to intestinal distention.140, 174 This may be associated with a nonspecific, centrally mediated dysfunction of a viscerosomatic referral system.' Some investigators have suggested that extreme hypersensitivity to intestinal distention may occur in patients who differ psychologically from the general population.156, 178 Studies continue to address visceral hypersensitivity and IBS.


IBS is characterized by continuous or recurrent episodes of abdominal pain associated with alteration of bowel habits in the absence of biochemical, structural, or infectious causes.51, 157, I6O The abdominal pain can be localized in any area, although it most frequently occurs in the lower abdomen. The discomfort can accompany constipation, diarrhea, or bowel habits in which there is constipation alternating with diarrhea. Abdominal bloating or the feeling of incomplete evacuation of stool is frequently present.Io0 Fever, weight loss, bleeding, voluminous diarrhea, greasy foul-smelling stools, recent changes in bowel habits, and abdominal pain and diarrhea that awaken the patient from sleep are not typical of IBS.'O0, 161

Patients presenting with IBS can also have a wide variety of other complaints. In comparison to other bowel disorders, IBS patients are more likely to complain of noncolonic symptoms, such as gastroesophageal reflux, heartburn, dysphagia, and globus sensation, as well as noncardiac chest pain.39, 139, 149 Furthermore, patients with IBS may have symptoms suggestive of gynecologic disorders and urologic dysfunc- t i ~ n . ' ~ ~

Associated Factors

A number of factors have been associated with IBS. Symptoms may be precipitated by certain dietary constituents, medications, alcohol consumption, tobacco use, stress, and psychological factors.Is It is un- likely that a single dietary factor is the cause of IBS. Low dietary fiber, however, has been associated with the symptoms.60 Dietary components that increase intestinal gas may exacerbate complaints. In addition, some IBS patients have been found to be intolerant to wheat, dairy products, coffee, tea, or citrus fruits. Other studies have not been able to support consistent intolerance to specific food constituents or true food aller-

Certain medications are well known to disturb bowel function. Antibiotics, P-blockers, bronchodilators, cardiac medications, diuretics, and narcotics have been demonstrated to disrupt gastrointestinal pro- cesses and may produce IBS symptoms.160 There are conflicting reports about the impact of tobacco and alcohol on IBS symptoms. It has been suggested that intestinal motility may be affected by these factors. In

gies.13, 51, 84, 111, 161


addition, tobacco has the potential to contribute to increased intestinal gas, which may exacerbate symptoms in patients with hypersensitivity to intestinal distention.86

Stressful life events have been proposed to contribute to the clinical manifestations of IBS. Many IBS patients describe acute episodes of stress preceding the onset of bowel symptoms. In addition, approximately half of IBS patients have noted that their symptoms can be made worse by stress.61,92 It has also been reported that IBS patients seek medical attention more often than others after a stressful or undesirable incident.I4O Other investigators, however, challenge the idea that there is a direct association between stress and ~ymptoms.~', 50, 61, 92, l h l , 173

Psychiatric disorders have been shown to have a role in the clinical expression of IBS in a subset of patients. Studies have reported that psychological disorders may occur in up to 50% of IBS patients seeking medical attention. Anxiety and depression also appear to occur more frequently in patients with IBS than in other gastrointestinal diseases.37 It has also been found that patients with IBS often have family histories of psychiatric Some investigators, however, suggest that it is only patients presenting to a physician for IBS symptoms who have a higher prevalence of psychiatric disorders. Patients with IBS who do not seek medical advice may have psychological profiles similar to the general pop~lat ion.~~, 48

Diagnosis

IBS is considered to be a diagnosis of exclusion. This has often compelled clinicians to evaluate symptoms with multiple and potentially costly tests. Most IBS patients, however, can be recognized from history and physical examination.160 The abdominal pain can be localized in any area, although it most frequently occurs in the lower abdomen. Abdomi- nal bloating or the feeling of incomplete evacuation of stool is frequently present.Io0 Fever, anemia, weight loss, bleeding, voluminous diarrhea, greasy foul-smelling stools, recent changes in bowel habits, and abdominal pain and diarrhea that awaken the patient from sleep are not typical

There are no distinct physical findings, although abdominal tender- ness may be present.'6o Laboratory tests are usually normal. It is prudent, however, to check a complete blood count, erythrocyte sedimentation rate, chemistry panel, and thyroid function tests to eliminate the possibility of organic disease.'O"Z I6O Stool should also be tested for occult blood. Additional testing should be individualized depending on the predominant symptoms. Studies for enteric pathogens, ova and parasites, and fecal leukocytes should be considered if diarrhea is present. Upper gastrointestinal symptoms may also warrant radiographic or endoscopic assessment.

of IBS.39, 100, 139, 149, 161, 175

38 BORUM

Management

Because the risk factors for IBS are not entirely clear, the preventive strategies and recommendations for IBS management have been varied. Education and reassurance are the first-line approaches in managing IBS. It is important to emphasize that IBS is a benign disorder that does not progress to or increase the risk of any other disease. There should be no expectation of a cure but rather an improvement of Early interventions to prevent exacerbation of IBS include increasing dietary fiber intake, abstaining from foods known to cause symptoms, and avoidance of medications resulting in complaints. Fiber supplementation, used for both constipation-predominant and diarrhea-predominant IBS, has been helpful in many patients. Dietary and supplemental fiber can hasten gut transit, soften hard stools, increase stool bulk, and allow for easier evac~at ion.~~, lZ3 Caffeine, gaseous-producing dietary components, sorbitol-containing gums, carbonated beverages, and alcohol should be limited. Food fads and diets that emphasize a limited spectrum of food should be discontinued. Intestinal gas can be decreased by limiting the intake of brans, cabbage, legumes, apples, grapes, and raisins. Simethicone, charcoal, and Beano (a-galactosidase which may partially metabolize insoluble sugars) can also be used to decrease intestinal gas and abdominal bloating.51

Stress management and mental health intervention should be considered in some patients. Patients can be evaluated for depression; anxiety; and a history of physical, sexual, and narcotic abuse. The diagnosis and management of psychological problems may decrease the clinical expression of IBS symptoms. Psychotherapeutic agents, psycho- therapy, hypnotherapy, and biofeedback, alone or in combination, have been demonstrated to be efficacious in some patients with IBS.73, 136, 172

In patients who develop debilitating IBS despite the employment of prevention strategies and early therapeutic intervention, drug treatment that targets the presumed pathophysiology and dysmotility or visceral hyperalgesia may be warranted. There is no single drug therapy that has been shown to be of benefit for all patients. Patients with diarrhea, constipation, abdominal pain, or flatulence as a dominant complaint should be given a trial of symptom-specific medication. Anticholinergic agents, such as dicyclomine (Bentyl) and hyoscyamine (Levsin), are the most frequently used agents in the treatment of IBS. They can be benefi- cial for abdominal pain and diarrhea when administered before meals and at bedtime as needed. Trials of prokinetic agents, such as metoclopramide and cisapride, may also be helpful in the management of intestinal symptoms.

INFLAMMATORY BOWEL DISEASE

IBD is classified as ulcerative colitis or Crohn’s disease. Ulcerative colitis is a recurrent inflammatory process that involves the mucosa and


submucosa of the colon. The disease may be limited to the rectum or can extend proximally to involve other areas of the colon. In contrast, Crohn’s disease is a recurrent focal inflammatory process that transmu- rally involves any portion of the gastrointestinal tract.

There are ethnic, racial, and gender variations in the incidence of IBD. The estimated ulcerative colitis rate is 2 to 10 per 100,000 and the estimated Crohn’s disease rate is 1 to 6 per 100,000 in the white population of northern Europe and North America. Rates in central and south- ern Europe are lower. The lowest rates are found in South America, Asia, and Africa. Ulcerative colitis is two to four times higher in Jews. Similarly, Crohn’s disease is three to eight times higher in Jews. In the United States, the incidence of both ulcerative colitis and Crohn‘s disease in African-Americans has been one fifth to one half the incidence rate of

The peak incidence of both diseases is between 15 and 25 years. In many series, there is a second peak, of lesser incidence, between 55 and 65 years. The similarities in geographic, ethnic, racial, gender, and age distribution support the assumption that these diseases are related.

whites.25. 65. 115

Gender

Some series show that there is an approximately equal rate of ulcerative colitis and Crohn’s disease in men and women. Other studies reveal that the incidence is up to 30% greater in women. Although the precise incidence rates among the genders is uncertain, it is generally accepted that there is a greater incidence among women than men.25

Genetic Factors

The most firmly established risk factor for IBD is a positive family history. Approximately 10% to 25% of patients with IBD have first- degree relatives who also have IBD.57, 171, In The incidence of IBD among first-degree relatives is 30 to 100 times that of the general population. HLA class I1 genes have been associated with Crohn’s disease and ulcerative colitis. The DR1 /DQw5 haplotype has been associated with Crohn’s disease, and HLA-DR2 has been associated with ulcerative colitis.lZ7, 163 Although numerous theories have been proposed, neither the cause nor pathogenesis of ulcerative colitis or Crohn’s disease has been determined.

Ulcerative Colitis


The major clinical features of ulcerative colitis include diarrhea with frequent, often watery stools; rectal bleeding; and abdominal pain. The

40 BORUM

inflammatory process is confined to the mucosa and submucosa. The major features of the process include diffuse inflammation, crypt ab- scesses, and chronic mucosal changes. The disruption of normal colonic architecture is accompanied by diminished ability to absorb water and sodium, leading to the diarrhea with a loss of protein causing hypoal- buminemia. The clinical presentation can vary in severity and can be classified as mild, moderate, and severe.*O, 153

Diagnosis

The diagnosis of ulcerative colitis depends on history, physical examination, and endoscopic evaluation. The findings of physical examination are nonspecific. Pallor, evidence of weight loss, abdominal tender- ness, and blood on a rectal examination can be present. Laboratory studies that can reflect the level of disease activity include hemoglobin level, leukocyte count, and erythrocyte sedimentation rate. Hypoalbu- minemia is a sign of chronic and severe disease. Electrolyte disturbances, especially hypokalemia, can be seen with severe diarrhea. The key to the diagnosis is the direct visualization of the colonic mucosa. Because ulcerative colitis always affects the rectum, the diagnosis can be established by sigmoidoscopy. A barium enema can serve as an adjunct to endoscopic findings. The barium enema can be normal in mild disease, however, and in more advanced disease, the procedure can increase morbidity without altering clinical management. A colonoscopy does not need to be done initially, but once the clinical status improves, it can be performed to document the extent of the disease.154

Crohn’s Disease


Crohn’s disease can affect any portion of the gastrointestinal tract. The transmural inflammation, however, affects certain areas more often than others. Approximately one third of the cases involve only the small intestine, primarily affecting the ileum. Approximately 20% involve only the colon. The remaining 50% involve both the small and the large

The inflammation in Crohn’s disease can be interspersed between areas of normal mucosa and can cause disruption of the sodium and water absorption. Significant ileal involvement can result in bile acid malabsorption, which can worsen diarrhea. Mucosal inflammation with friability and ulcerations can result in bleeding. Fibrosis from the transmural involvement can cause stricturing and narrowing of the lumen.

The predominant symptoms of Crohn’s disease are diarrhea, abdominal pain, and weight loss. Diarrhea is the major manifestation. Bleeding can occur, but it is not as common as in ulcerative colitis. Cramping abdominal pain correlates with disease location. Weight loss


of some degree occurs in most patients with Crohn‘s disease. Loss of more than 20% of body weight is uncommon.154

Diagnosis

The patient’s history is most suggestive of Crohn’s disease. Similarly to ulcerative colitis, the physical examination is not usually diagnostic. The diagnosis of Crohn’s disease depends on endoscopic and radiographic studies of the bowel. Because of the segmental nature of the disease, a complete colonoscopy is the most effective way to diagnose Crohn’s disease of the colon. Although not as sensitive as colonoscopy, an air-contrast barium enema can be used to diagnose the disorder. The upper gastrointestinal series and small bowel x-ray film remain the method of choice for diagnosing Crohn‘s disease of the small intestine. The typical mucosal biopsy specimen shows a focal ulcerative and inflammatory process. Granulomas, found in approximately 50% of patients, may be found in any layer of the bowel wall. The absence of granulomas, however, does not eliminate the possibility of Crohn’s disease.

Extraintestinal Manifestations of Ulcerative Colitis and Crohn’s Disease

The extraintestinal manifestations described in ulcerative colitis and Crohn’s disease are cutaneous lesions (including erythema nodosa, pyo- derma gangrenosum), ophthalmologic lesions (including uveitis, epi- scleritis), arthritis (including peripheral, central), and hepatobiliary disease (including sclerosing cholangitis). Complications unique to Crohn’s disease can include fistulas, gallstones, kidney stones, fat malabsorption owing to bile acid loss, and vitamin B,, and folate deficiency owing to ileal dysfunction.7,30,45,59,74. 117. 118. 154

Management

Medications used for ulcerative colitis and Crohn’s disease include aminosalicylates, steroids, immunosuppressants, and antibiotics. Sulfa- salazine was the first aminosalicylate available for treatment. Recently developed aminosalicylates that have been used in IBD management include mesalamine (Asacol, Pentasa) and olsalazine (Dipentum). Topi- cal aminosalicylates (mesalamine) [Rowasa] enemas and suppositories) can be used to supplement oral therapy. Courses of topical and paren- teral steroids can also be used with exacerbations that are inadequately responsive to aminosalicylates. Immunosuppressive medications, such as 6-mercaptopurine, azathioprine, and cyclosporin, can be reserved for disease that is not controlled with aminosalicylates and steroids or in patients who are steroid dependent. Additionally, in Crohn’s disease,

42 BORUM

various antibiotics (metronidazole and ciprofloxacin) have been used as adjuvant therapy. In patients with steatorrhea related to severe ileal disease or ileal resections, a low-fat diet with medium-chain triglycer- ide oil may diminish the diarrhea and improve the nutritional status. Calcium, vitamin D, and vitamin K supplements can also be use-

Surgery is indicated in ulcerative colitis when a patient with severe disease fails medical therapy or has impending or actual perforation, persistent bleeding, high-grade dysplasia, or actual carcinoma. Surgical intervention in Crohn’s disease is reserved for intractable symptoms; bowel obstruction; local perforation; or persistent, bothersome enterocu- taneous, enterovesical, or enterovaginal fistula. Resection for Crohn’s disease is not curative, and postoperative recurrence frequently occurs.38

fU1.42, 43, 93, 133, 155, 165

Pregnancy and Inflammatory Bowel Disease

Because IBD affects many women in early adulthood, the effect on pregnancy is an important clinical issue. In women, fertility is normal or only minimally impaired.87, I7O Fertility in men using sulfasalazine is diminished because of drug-induced azoospermia but returns to normal a few months after the cessation of the drug.

A number of studies have evaluated the course of IBD during pregnancy. If the disease is inactive at the time of conception, it will most likely remain inactive during the course of the pregnancy.M* If the disease is active at the time of conception, the course is harder to predict. Active ulcerative colitis at the time of conception often worsens. In patients with active Crohn’s disease at the time of conception, two thirds with Crohn’s disease remain the same, and the remaining one third improve or deteri~rate.‘~~

Pregnancies in women with IBD result in healthy infants. The incidence of prematurity, stillbirth, and developmental defects is similar to that of the general population.8 The incidence of spontaneous abortion, however, is slightly higher (12.2%) than in the general population (9.9%). Some studies suggest that fetal complications, prematurity, and spontaneous abortion are higher in cases of women who have clinically active disease, independent of drug therapy.ls The presence of a proctocolec- tomy or ileostomy does not compromise a pregnancy.135

Many women need to take medication on a long-term basis. Studies have shown that sulfasalazine taken throughout the course of pregnancy did not cause fetal harm and had no effect on the incidence of spontaneous abortion, prematurity, or fetal weight.l19 Pregnant women, however, have increased requirements for folic acid, and sulfasalazine can inter- fere with folate absorption. Therefore, folate supplementation should be prescribed to ensure normal fetal development.

The use of corticosteroid in pregnant women is not associated with increased rate of fetal complication^.^^^ It is generally considered that the risks of treatment during pregnancy are less than the risks of allowing


the disease to go untreated. It is advised to pregnant women that they should minimize their exposure to medications as much as possible. In contrast, immunosuppressants and metronidazole are teratogenic in animals. Although women have received these medications during pregnancy and have delivered normal infants, it is unwise to continue these medications when a women learns that she is pregnant.

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