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Harrison's Internal Medicine > Chapter 202. Amebiasis and Infection With Free-Living sl y>
Amebiasis

Definition

Amebiasis is an infection with the intestinal protozoan Entamoeba histolytica. About 90% of infections are asymptomatic, and the
remaining 10% produce a spectrum of clinical syndromes ranging from dysentery to abscesses of the liver or other organs.

Life Cycle and Transmission

E. histolytica is acquired by ingestion of viable cysts from fecally contaminated water, food, or hands. Food-borne exposure is most
prevalent and is particularly likely when food handlers are shedding cysts or food is being grown with feces-contaminated soil,
fertilizer, or water. Besides the drinking of contaminated water, less common means of transmission include oral and anal sexual
practices and—in rare instances—direct rectal inoculation through colonic irrigation devices. Motile trophozoites are released from
cysts in the small intestine and, in most patients, remain as harmless commensals in the large bowel. After encystation, infectious cysts
are shed in the stool and can survive for several weeks in a moist environment. In some patients, the trophozoites invade either the
bowel mucosa, causing symptomatic colitis, or the bloodstream, causing distant abscesses of the liver, lungs, or brain. The
trophozoites may not encyst in patients with active dysentery, and motile hematophagous trophozoites are frequently present in fresh
stools. Trophozoites are rapidly killed by exposure to air or stomach acid, however, and therefore cannot transmit infection.

Epidemiology

About 10% of the world's population is infected with Entamoeba, the majority with noninvasive Entamoeba dispar. Amebiasis results
from infection with E. histolytica and is the third most common cause of death from parasitic disease (after schistosomiasis and
malaria). The wide spectrum of clinical disease caused by Entamoeba is due in part to the differences between these two infecting
species. Cysts of E. histolytica and E. dispar are morphologically identical, but E. histolytica has unique isoenzymes, surface antigens,
DNA markers, and virulence properties (Table 202-1). Most asymptomatic carriers, including homosexual men and patients with
AIDS, harbor E. dispar and have self-limited infections. These observations indicate that E. dispar is incapable of causing invasive
disease, since Cryptosporidium and Isospora belli, which also cause only self-limited illnesses in immunocompetent people, cause
devastating diarrhea in patients with AIDS. However, host factors play a role as well. In one study, 10% of asymptomatic patients who
were colonized with E. histolytica went on to develop amebic colitis, while the rest remained asymptomatic and cleared the infection
within 1 year.

Note: ELISA, enzyme-
linked immunosorbent
assay; Gal/GalNAc,
galactose N-
acetylgalactosamine.
See text.

Areas of highest incidence (due to inadequate sanitation and crowding) include most developing countries in the tropics, particularly
Mexico, India, and nations of Central and South America, tropical Asia, and Africa. In a 4-year follow-up study of preschool children
in a highly endemic area of Bangladesh, 80% of children had at least one episode of infection with E. histolytica and 53% had more
than one episode. Naturally acquired immunity did develop but was usually short-lived and correlated with the presence in the stool of
secretory IgA antibody to the major adherence lectin galactose N-acetylgalactosamine (Gal/GalNAc). The main groups at risk for
amebiasis in developed countries are returned travelers, recent immigrants, homosexual men, and inmates of institutions.

which may be asymptomatic. inflammatory cells. E. Clinical Syndromes Intestinal Amebiasis The most common type of amebic infection is asymptomatic cyst passage. but only trophozoites of E. One consists of the extracellular cysteine proteinases that degrade collagen. Indeed. Inoculation of amebas into the portal system of hamsters results in an acute cellular infiltrate consisting predominantly of neutrophils. Trophozoites attach to colonic mucus and epithelial cells by Gal/GalNAc. human intestinal infection is marked by a paucity of inflammatory cells. while other layers of the wall are thickened. A number of virulence factors have been linked to the ability of E. elastin. dispar. and profuse diarrhea. Uncommonly. and epithelial cells. depletion of intestinal mucus. in the bowel lumen. histolytica to invade through the interglandular epithelium. The stools contain little fecal material and consist mainly of blood and mucus. sigmoid colon. Cecal involvement may mimic acute appendicitis. 202-2) are found in the intestinal lumen. An occasional patient presents with only an asymptomatic or tender abdominal mass caused by an ameboma. The earliest intestinal lesions are microulcerations of the mucosa of the cecum. lymphocytes. histolytica infection by 64%. most patients harbor E. Later.Pathogenesis and Pathology Both trophozoites (Fig. More fulminant intestinal infection. A . The overlying mucosa is usually thin and ulcerated. Studies of animals suggest that cell-mediated immunity may be important for protection. The necrotic contents of a liver abscess are classically described as "anchovy paste. full-thickness necrosis and perforation occur. Proctoscopy reveals small ulcers with heaped-up margins and normal intervening mucosa. titers correlate with the duration of illness rather than with the severity of disease. IgG. Amebas. A gradual onset of lower abdominal pain and mild diarrhea is followed by malaise. In animals. histolytica infection. Submucosal extension of ulcerations under viable-appearing surface mucosa causes the classic "flask-shaped" ulcer containing trophozoites at the margins of dead and viable tissues. The association between severe amebiasis complications and glucocorticoid therapy emphasizes the importance of excluding amebiasis when inflammatory bowel disease is suspected. patients develop a chronic form of amebic colitis. and hemorrhagic. edematous. Occasionally." although the fluid is variable in color and is composed of bacteriologically sterile granular debris with few or no cells. The cytolytic effect of amebas appears to require direct contact with target cells and may be linked to the release of phospholipase A and pore-forming peptides. weight loss. histolytica invade tissue. with severe abdominal pain. Other enzymes may disrupt glycoprotein bonds between mucosal epithelial cells in the gut. if seen. high fever. E. tend to be found near the capsule of the abscess. the neutrophils are lysed by contact with amebas. 202- 3). Trophozoites invade veins to reach the liver through the portal venous system. Patients may develop toxic megacolon. A study in Bangladeshi schoolchildren revealed that an intestinal IgA response to Gal/GalNAc reduced the risk of new E. probably in part because of the killing of neutrophils by trophozoites (Fig. although patients with AIDS appear not to be predisposed to more severe disease. and the anaphylatoxins C3a and C5a. Virtually all patients have heme-positive stools. Serum IgG antibody is not protective. Treated ulcers characteristically heal with little or no scarring. 202-1) and cysts (Fig. or ameboma. E. histolytica is resistant to complement-mediated lysis—a property critical to survival in the bloodstream. Although neutrophilic infiltrates may accompany the early lesions in animals. and disruption of the epithelial barrier occur before trophozoites actually come into contact with the colonic mucosa. monocytes. Bangladeshi children with a serum IgG response were more likely than those without such a response to develop new E. dispar is rapidly lysed by complement and is thus restricted to the bowel lumen. however. and cells of colonic and hepatic lines. or rectum that release erythrocytes. histolytica trophozoites also cause apoptosis of human cells. which can be confused with inflammatory bowel disease. Even in highly endemic areas. Rarely. Symptomatic amebic colitis develops 2–6 weeks after the ingestion of infectious cysts. In contrast. this condition results in exuberant formation of granulation tissue with little fibrous-tissue response. Amebas can lyse neutrophils. fewer than 40% of patients with amebic dysentery are febrile. is rare and occurs predominantly in children. which is easily confused with cancer on barium studies. Blood vessels may be compromised early by wall lysis and thrombus formation. in which there is severe bowel dilation with intramural air. and diffuse lower abdominal or back pain. IgA. Liver abscesses are always preceded by intestinal colonization. Patients with full-blown dysentery may pass 10–12 stools per day. Patients receiving glucocorticoids are at risk for severe amebiasis. diffuse inflammation. In contrast to those with bacterial diarrhea. and the release of neutrophil toxins may contribute to necrosis of hepatocytes. The liver parenchyma is replaced by necrotic material that is surrounded by a thin rim of congested liver tissue. The trophozoite is 20–60 μm in diameter and contains vacuoles and a nucleus with a characteristic central nucleolus. intestinal infection results in the formation of a mass lesion.

Jaundice is rare. Positive results in conjunction with the appropriate clinical syndrome suggest active disease because serologic findings usually revert to negative within 6–12 months. but trophozoites are rare in liver aspirates because they are found in the abscess capsule and not in the readily aspirated necrotic center. Because trophozoites are killed rapidly by water. but frank rupture into the pleural space requires drainage. Abscesses that rupture into the peritoneum may present as an indolent leak or an acute abdomen and require both percutaneous catheter drainage and medical therapy. Enzyme-linked immunosorbent assays (ELISAs) and agar gel diffusion assays are positive in more than 90% of patients with colitis. Amebic Liver Abscess Extraintestinal infection by E. iodine-stained concentrates. with weight loss and hepatomegaly. Fecal findings suggestive of amebic colitis include a positive test for heme. a paucity of neutrophils. Cerebral involvement has been reported in fewer than 0. sigmoidoscopy with biopsy of the edge of ulcers may increase the yield. it can occur during medical therapy and requires surgical drainage. Rupture into the pericardium. Therefore. the clinical diagnosis of an amebic liver abscess may be difficult to establish because the symptoms and signs are often nonspecific. A hepatobronchial fistula may cause cough productive of large amounts of necrotic material that may contain amebas. Entamoeba coli. and Endolimax nana. Even in highly endemic areas such as South Africa. amebomas. fewer than one-third of patients with an amebic abscess have active diarrhea. is the most frequent complication of amebic liver abscess. Cultures of amebas are more sensitive but are not routinely available. 202-1). Most patients are febrile and have right-upper-quadrant pain. Although the initial site of infection is the colon. Painful genital ulcers. If stool examinations are negative. Examination of a combination of wet mounts. About one-third of patients with chronic presentations are febrile. fewer than 10% of asymptomatic . which is reported in 20–30% of patients. Manifestations include sterile effusions. Trophozoites in a biopsy specimen from a colonic mass confirm the diagnosis of ameboma. since the trophozoites may be confused with neutrophils and the cysts must be differentiated morphologically from Entamoeba hartmanni. Point tenderness over the liver and right-sided pleural effusion are common. Accurate diagnosis requires experience. 95% do so within 5 months. and amebic cysts or trophozoites. no evidence of recurrent amebic infection can be found. it is important to examine at least three fresh stool specimens.positive serologic test or biopsy can prevent unnecessary surgery in this setting. histolytica (Fig. drying. or barium. Symptoms and prognosis depend on the size and location of the lesion. which may be dull or pleuritic in nature and may radiate to the shoulder. dispar. the cysts of E. serologic tests. stool diagnostic tests based on the detection of the Gal/GalNAc lectin of E. Both these conditions respond well to medical therapy. amebic liver abscess must be considered in the differential diagnosis of fever of unknown origin (Chap. usually from abscesses of the left lobe of the liver. 202-2) or trophozoites (Fig. and trichrome-stained preparations of fresh stool and concentrates for cysts (Fig. characterized by a punched-out appearance and profuse discharge. Of travelers who develop an amebic liver abscess after leaving an endemic area. 19). Sterile effusions and contiguous spread usually resolve with medical therapy. contiguous spread from the liver. Young patients with an amebic liver abscess are more likely than older patients to present in the acute phase with prominent symptoms of <10 days' duration. histolytica compare favorably with the polymerase chain reaction and with isolation in culture followed by isoenzyme analysis. carries the gravest prognosis. histolytica can be made only by the detection of Entamoeba trophozoites that have ingested erythrocytes. Since 10–15% of patients present only with fever.1% of patients in large clinical series. Serology is an important addition to the methods used for parasitologic diagnosis of invasive amebiasis. Diagnostic Tests Laboratory Diagnosis Stool examinations. This dramatic complication carries a good prognosis. Older patients from endemic areas are more likely to have a subacute course lasting 6 months. Complications of Amebic Liver Abscess Pleuropulmonary involvement. and rupture into the pleural space. Other Extraintestinal Sites The genitourinary tract may become involved by direct extension of amebiasis from the colon or by hematogenous spread of the infection. and re-treatment usually has no effect. Unfortunately. histolytica most often involves the liver. the microscopic diagnosis of E. 202-1) confirms the diagnosis in 75–95% of cases. but this procedure is dangerous during fulminant colitis because of the risk of perforation. and noninvasive imaging of the liver are the most important procedures in the diagnosis of amebiasis. or liver abscess. which do not cause clinical disease and do not warrant therapy. histolytica cannot be distinguished microscopically from those of E. In terms of sensitivity. may develop secondary to extension from either the intestine or the liver. The definitive diagnosis of amebic colitis is made by the demonstration of hematophagous trophozoites of E. Thus. The syndrome of postamebic colitis—persistent diarrhea following documented cure of amebic colitis—is controversial.

146).individuals have a positive amebic serology. but aspiration of the abscess. testing should be repeated in a week. microscopic examination of stools. amebic liver abscess can easily be confused with pulmonary or gallbladder disease or with any febrile illness with few localizing signs. Complete resolution of a liver abscess within 6 months can be anticipated in two- thirds of patients. which may rupture into the pericardium. histolytica develop antibodies. Patients with pyogenic abscess typically are older and have a history of underlying bowel disease or recent surgery. The interpretation of the indirect hemagglutination test is more difficult because titers may remain positive for as long as 10 years. Amebomas are usually identified first by a barium enema. 203) or typhoid fever (Chap. it is prudent to treat asymptomatic individuals who pass cysts unless E. Findings associated with complications include large abscesses (>10 cm) in the superior part of the right lobe. which does not warrant specific therapy. the most important differential diagnosis is between amebic and pyogenic abscess. most asymptomatic carriers of E. More than 80% of patients who have had symptoms for >10 days have a single abscess of the right lobe of the liver (Fig. 146). correct diagnosis requires bacterial cultures. Luminal amebicides are poorly absorbed and reach high concentrations in the bowel. but their activity is limited to cysts and trophozoites close to the mucosa. such as malaria (Chap. and amebic serologic testing.000 cells/μL). in suspected cases with an initially negative result. 149). Serologic tests also should be performed in patients with ulcerative colitis before the institution of glucocorticoid therapy to prevent the development of severe colitis or toxic megacolon owing to unsuspected amebiasis. As has already been mentioned. In contrast to carriers of E. Because of the variety of presenting signs and symptoms. but 10% may have persistent abnormalities for a year. 117) and in inmates of institutions. 143). frequent follow-up ultrasonography may prove confusing. Routine hematology and chemistry tests usually are not very helpful in the diagnosis of invasive amebiasis. Only two luminal drugs are available in the United States: iodoquinol and paromomycin. 147). and MRI are all useful for detection of the round or oval hypoechoic cyst. 202-4). Indications for the use of luminal agents include eradication of cysts in patients with colitis or a liver abscess and treatment of asymptomatic carriers. with Gram's staining and culture of the material. dispar. liver enzyme levels are normal or minimally elevated. cyst-passing individuals in nonendemic areas. Once radiographic studies have identified an abscess in the liver. Invasive amebiasis does not elicit eosinophilia. may be required for differentiation of the two diseases. 148). serologic tests are helpful in assessing the risk of invasive amebiasis in asymptomatic. The majority of asymptomatic individuals who pass cysts are colonized with E. Thus. which may rupture into the pleural space. and lesions of the left lobe. if present. Up to 10% of patients with acute amebic liver abscess may have negative serologic findings. . Differential Diagnosis The differential diagnosis of intestinal amebiasis includes bacterial diarrheas (Chap. Because abscesses resolve slowly and may increase in size in patients who are responding clinically to therapy. multiple lesions. However. but biopsy is necessary for differentiation from carcinoma. and species of Shigella (Chap. which must be differentiated from pyogenic abscesses. Approximately 50% of patients who have had symptoms for <10 days have multiple abscesses. CT. this condition is particularly likely if symptoms are acute or complications have developed. Amebic serology is helpful. About three-fourths of patients with an amebic liver abscess have leukocytosis (>10. and Vibrio (Chap. Even with large liver abscesses. amebiasis must be ruled out in any patient thought to have inflammatory bowel disease. is usually multifactorial. Anemia. The diagnosis should be considered in members of high-risk groups who have recently traveled outside the United States (Chap. Radiographic Studies Radiographic barium studies are potentially dangerous in acute amebic colitis. Radiographic techniques such as ultrasonography. The alkaline phosphatase level is most often elevated and may remain so for months. Amebiasis: Treatment Intestinal Disease (Table 202-2) The drugs used to treat amebiasis can be classified according to their primary site of action. enteroinvasive Escherichia coli (Chap. Aminotransferase elevations suggest acute disease or a complication. dispar. Salmonella (Chap. Although the typical patient with amebic colitis has less prominent fever than in these other conditions as well as heme-positive stools with few neutrophils. dispar colonization can be definitively demonstrated by specific antigen- detection tests. 122) caused by Campylobacter (Chap.

Resistance to metronidazole has been selected in the laboratory but has not been found in clinical isolates. was a major advance in the treatment of invasive amebiasis. all treatment regimens should include a luminal agent to eradicate cysts and prevent further transmission. Another longer-acting imidazole compound. Studies of South Africans with liver abscesses demonstrated that 72% of patients without intestinal symptoms had bowel infection with E. The development of nitroimidazole compounds. (2) the lack of a clinical response in 3–5 days. Longer-acting nitroimidazoles (tinidazole and ornidazole) have been effective as single-dose therapy in developing countries.Tissue amebicides reach high concentrations in the blood and tissue after oral or parenteral administration. Indications for aspiration of liver abscesses are (1) the need to rule out a pyogenic abscess. Amebic liver abscess recurs rarely. is also effective and was recently approved in the United States. . disinfection by iodination (tetraglycine hydroperiodide) is recommended. Surgery should be reserved for instances of bowel perforation and rupture into the pericardium. Side effects include nausea. Since an asymptomatic carrier may excrete up to 15 million cysts per day. There is no effective prophylaxis. and a disulfiram-like reaction. All patients should also receive a full course of therapy with a luminal agent. Aspiration of Liver Abscesses More than 90% of patients respond dramatically to metronidazole therapy with decreases in both pain and fever within 72 h. especially metronidazole. abdominal discomfort. Patients with amebic colitis should be treated with intravenous or oral metronidazole. mortality rates from uncomplicated amebic liver abscess are <1%. There is no evidence that combined therapy with two drugs is more effective than the single-drug regimen. There is no evidence that aspiration. Percutaneous drainage may be successful even if the liver abscess has already ruptured. thus. particularly in patients with multiple lesions. prevention of infection requires adequate sanitation and eradication of cyst carriage. The second-line therapeutic agents emetine and chloroquine should be avoided if possible because of the potential cardiovascular and gastrointestinal side effects of the former and the higher relapse rates with the latter. (3) the threat of imminent rupture. and (4) the need to prevent rupture of left- lobe abscesses into the pericardium. Relapses are not uncommon and probably represent reinfection or failure to eradicate amebas from the bowel because of an inadequate dosage or duration of therapy. Amebic Liver Abscess Metronidazole is the drug of choice for amebic liver abscess. With early diagnosis and therapy. infection can be minimized by the avoidance of unpeeled fruits and vegetables and the use of bottled water. histolytica. since metronidazole does not eradicate cysts. even of large abscesses (up to 10 cm). Prevention Amebic infection is spread by ingestion of food or water contaminated with cysts. tinidazole. In high-risk areas. vomiting. accelerates healing. Because cysts are resistant to readily attainable levels of chlorine.