Gastrointestinal and Hepatobiliary Diseases in Patients with HIV and AIDS

Gastrointestinal Diseases Associated with Human Immunodeficiency Virus (HIV) Infection

The treatment of human immunodeficiency virus (HIV) infection has dramatically improved over the last several years with the use of combination therapy of potent antiretroviral agents including protease inhibitors. With this highly active antiviral therapy (HAART), HIV replication can be profoundly suppressed and in some patients, circulating HIV becomes undetectable. Even patients with advanced HIV disease, the CD4 lymphocyte count rises reflecting a redistribution of CD4 cells. Clinically, with regression of immune suppression, patients become more immunocompetent, the risk for opportunistic infections and processes becomes reduced, and overall survival is improved. Thus, at this time the long-term prognosis is dictated by the severity of the immunodeficiency (absolute number of CD4 cells) and the level of the circulation virus.

Because of HAART, there has been a major change in the management of opportunistic infections (OIs) in HIV and acquired immunodeficiency syndrome (AIDS). When OIs are diagnosed and treated, both the OI and the underlying HIV infection are treated. In fact, in some patients, treatment with HAART alone results in a remission of OI and reduction of relapses. Because of the remarkable success of HAART in reconstitution of the immune system in these patients, the etiology, diagnostic approach, and management of HIV-associated gastrointestinal (GI) diseases learned in the pre-HAART era may not be accurate at this time.

GI complaints and problems are still quite common in HIV-infected patients; however, etiology has shifted toward disorders not associated with HIV-induced immunodeficiency. Also, some of the medications used in HAART regimens have been associated with GI and hepatic side effects. Table 43-1 lists GI pathogens/diseases by location in HIV-infected patients.

I. DISEASES OF THE ESOPHAGUS.

Before HAART, approximately one third of HIV-infected patients developed esophageal disease. In patients treated with HAART, the frequency of OI of the entire GI tract, including the esophagus, has been dramatically reduced. However, as with other OIs, the incidence of opportunistic disorders increases as the immunodeficiency worsens. The esophagus may often be the site of the first AIDS-defining opportunistic disease. OIs are the most common causes of esophageal disease. However, cytomegalovirus (CMV) and idiopathic esophageal ulceration (IEU) are rarely seen until the CD4 count falls below 100/mL. Almost all esophageal infections in patients with AIDS are treatable. A definitive diagnosis and treatment usually results in better nutrition, weight gain, and a better quality of life for the patient.

A. Etiologies

1. Fungi.

Prior to the use of HAART, Candidiasis was the most common cause of esophageal disease in HIV-infected patients. Esophageal involvement by fungi other than Candida is very rare.

2. Viruses.

CMV is the most common cause of esophagitis in patients with AIDS. In contrast to other immunocompromised states, such as in posttransplant patients, infection with herpes simplex virus (HSV) is uncommon in HIV-infected patients. In a prospective study of 100 patients infected with HIV, HSV esophagitis was found only in 5% of these patients compared to a 50% prevalence of CMV esophagitis.

TABLE 43-1 Gastrointestinal Pathogens in HIV-Infected Patients

Site	Organism
Esophagus	Candida albicans
	HSV
	CMV
Stomach	CMV
	MAC
Small intestine	Salmonella
	Campylobacter
	MAC
	Cryptosporidium
	Microsporidia (Enterocytozoon bieneusi)
	Isospora belli
	Giardia lamblia
Large intestine	CMV
	Adenovirus
	Histoplasma
	Shigella
	Salmonella
	Clostridium difficile
	Campylobacter
	MAC
	Cryptosporidium
	Microsporidia
	Entamoeba histolytica
Anus	HSV, Human papilloma virus
HIV, human immunodeficiency virus; HSV, herpes simplex virus; CMV, cytomegalovirus;
MAC, Mycobacterium avium complex.

3. Idiopathic esophageal ulcers (IEUs)

are an important cause of dysphagia and odynophagia in patients with AIDS. IEU is nearly as common as CMV esophagitis, comprising about 40% of esophageal ulcers. The etiology of IEU is unknown and includes disordered immune regulation, increased apoptosis, local HIV infection, and unidentified viruses.

4. Gastroesophageal reflux disease (GERD),

in the era of HAART, probably represents one of the most common causes of esophageal disease.

5. Pill-induced esophagitis

is not uncommon in HIV-infected patients on HAART. Medications unique to these patients include zidovudine (AZT) and zalcitabine (ddC).

B. Clinical presentation

The history is usually helpful in determining the cause and severity of the esophageal disease. Difficulty swallowing (dysphagia), painful swallowing (odynophagia), loss of appetite, and weight loss are the most common complaints. When the pain is unilateral and localized to the neck or hypopharynx, oropharyngeal rather than esophageal disease is likely.

2. Physical examination.

The presence of oropharyngeal lesions may provide a clue to the underlying cause of esophageal complaints. Approximately two thirds of patients with esophageal candidiasis have concomitant thrush. However, the presence of thrush does not necessarily indicate Candida esophagitis. Also, Candida esophagitis may coexist with other esophageal diseases in at least 25% of patients. Oropharyngeal ulcers are rarely associated
with esophageal ulcers. Kaposi’s sarcoma (KS) lesions may be seen in the oropharynx and are associated with GI KS.

3. Laboratory tests.

The stage of immunodeficiency determines the differential diagnosis of esophageal disease. The levels of HIV viremia and CD4 lymphocyte count are the two most important laboratory tests. OIs of the esophagus are uncommon until the CD4 count falls below 200/mm³. IEU and CMV esophagitis are rarely seen until the CD4 count drops below 100/mm³.

4. Empiric therapy.

Because candidiasis is the most common cause of esophageal disease in HIV-infected patients, an empiric trial of antifungal therapy is reasonable. Further diagnostic testing is then based on the clinical response. Empirical therapy with fluconazole 200 mg per day followed by 100 mg per day for a 7- to 10-day treatment course is recommended. The clinical response of Candida esophagitis to the treatment with fluconazole is rapid (within 3 days). If no substantial improvement occurs in 3 to 5 days, endoscopy is recommended. Most patients who fail antifungal therapy do not have candidiasis, but rather esophageal ulcers. Additional empirical trials such as antiviral therapy with acyclovir sodium or ganciclovir sodium are discouraged. In patients with CD4 counts higher than 200/mm³ and with symptoms typical of GERD, a trial of gastric acid suppressive therapy with high-dose, proton pump inhibiters is recommended.

5. Barium swallow/upper GI (UGI) series

may document esophageal candidiasis or ulceration in symptomatic patients. However, because there are many causes of esophageal ulcers in AIDS, patients will require endoscopic examination for biopsies.

6. Endoscopy

is a means of directly visualizing the UGI mucosa as well as for obtaining biopsies for histopathologic examination of the lesions visualized. The endoscopic appearance of a lesion often suggests the diagnosis. Candidiasis appears as cottage cheese-like plaques and coats most of the esophageal mucosa. However, because Candida coexists with other lesions at least in 25% of cases, multiple biopsies are required.

Viral esophagitis may present as diffuse esophagitis or small superficial ulcers with HSV and as one or more large, well-circumscribed ulcers with CMV. Biopsies of the ulcer margins and base are required for histopathologic diagnosis. Immunohistochemical stains of the biopsies will increase the diagnostic accuracy. IEU may resemble CMV ulcers. Multiple biopsies of the ulcer base and margins are required to exclude the presence of CMV. KS appears as elevated blue-violatious nodules.

7. Treatment

is to be directed to the etiology of the esophageal lesion. Esophageal candidiasis responds well to fluconazole or itraconazole. Both agents are also available in liquid formulation for patients who cannot swallow tablets or capsules.

HSV esophagitis is treated with acyclovir sodium or valacyclovir hydrochloride. For CMV disease, ganciclovir sodium is effective. The newer drug, cidofovir, may be administered by a once-weekly injection. IEU may be treated with either prednisone or thalidomide: The response rate is higher than 90%. Patients should be treated or continued on HAART to help expedite healing and to prevent relapse.

II. DISEASES OF THE STOMACH

A. Gastric lesions.

The most common OI of the stomach is CMV, which usually results in gastric ulceration. Gastric neoplasms include non-Hodgkin’s lymphoma and KS. The stomach is the most common site in the GI tract for KS. Patients are usually asymptomatic. Gastric lymphoma may present with epigastric pain, nausea, and vomiting or bleeding. The prevalence of peptic ulcer disease with or without Helicobacter pylori and gastric adenocarcinoma is the same as in the general population.

B. Endoscopy with biopsies

is the preferred diagnostic modality for gastric lesions. The indications for endoscopy include likelihood of an underlying OI, severity of symptoms (nausea, vomiting, early satiety), and the possible need for endoscopic therapy.

C. Treatment

should be directed to the cause of the problem.

III. DISEASES OF THE SMALL INTESTINE AND COLON

A. Diarrhea

is a common complaint in patients with HIV infection especially in patients with CD4 counts of less than 100/mm³. As with the esophagus, OI of the intestines has decreased in prevalence as a cause of diarrhea in HIV-infected patients. However, the overall incidence of diarrhea has not decreased at the same rate because several of the antiviral agents used in HAART regimens can cause diarrhea. In addition, patients with HIV infections are also susceptible to infection by the same enteric pathogens that cause diarrhea in immunocompetent hosts. As the CD count decreases, however, these patients become more susceptible to a wide variety of OI that affect both the small intestine and the colon.

1. Etiologic agents.

The most common identifiable causes of diarrhea in HIV-infected patients are enteric bacteria (e.g., Shigella flexneri, Salmonella enteritidis, Campylobacter jejuni, and Clostridium difficile. When the CD count becomes less than 100/mm³, CMV, cryptosporidiosis, microsporidia, Mycobacterium avium complex (MAC), and other OIs become more commonly seen in these patients.

CMV is the most common viral agent identified from mucosal biopsy specimens from HIV-infected patients with diarrhea. Other viruses reported to involve the GI tract in patients with AIDS include adenovirus, rotavirus, astrovirus, pecorino virus, and coronavirus. The clinical importance of these viruses has not been well established.

Among the protozoa Cryptosporidium parvum and microsporidia (Enterocytozoon bieneusi and Encephalitozoon intestinalis) are the most potent causes of chronic diarrhea in AIDS patients.

MAC, which was very commonly seen in patients with AIDS, has become rare in patients undergoing HAART. Neoplasms such as KS or lymphoma and other OIs such as histoplasmosis do not lead to diarrhea.

2. Clinical presentation

a. History. Diarrhea resulting from enteritis or the involvement of the small intestine is typically manifested by large-volume, watery stools associated with dehydration, electrolyte disturbances, and malabsorption. Abdominal pain and cramps are usually located in the periumbilical area. Associated symptoms include nausea, vomiting, abdominal bloating, and borborygmi.

Diarrhea arising from colonic involvement and colitis is characterized by frequent, small-volume stools, which often contain mucus, blood, and pus. Symptoms include tenesmus, urgency, and rectoanal pain. Abdominal pain is less likely to be crampy and is usually located in the lower quadrants.

b. Physical exam. Physical findings are nonspecific. Fever usually suggests bacterial or mycobacterial infection. If CMV is suspected, funduscopic examination may reveal retinitis. CMV colitis/ulcers are more common in the ascending colon, thus the abdominal tenderness may be on the right lower quadrant.

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