Amebiasis is infection with the parasitic intestinal protozoan Entamoeba histolytica (the “tissue-lysing ameba”). Most infections are probably asymptomatic, but E. histolytica can cause disease ranging from dysentery to extraintestinal infections, including liver abscesses.
Life Cycle and Transmission
E. histolytica exists in two stages: a hardy multinucleate cyst form (Fig. 209-1) and the motile trophozoite stage (Fig. 209-2). Infection (of which humans are the natural hosts) is acquired by ingestion of cysts contained in fecally contaminated food or water or, more rarely, through oral-anal sexual contact. Cysts survive stomach acidity and excyst within the small intestine to form the 20- to 50-μm trophozoite stage. Trophozoites can live within the large-bowel lumen without causing disease or can invade the intestinal mucosa, causing amebic colitis. In some cases, E. histolytica trophozoites invade through the mucosa and into the bloodstream, traveling through the portal circulation to reach the liver and causing amebic liver abscesses. Motile trophozoites may be excreted into the stool—a diagnostically important event—but are rapidly killed upon exposure to air or stomach acid and therefore are not infectious. Trophozoite cysts within the large bowel are excreted in the stool, continuing the life cycle.
Entamoeba cyst. Three of the four nuclei are clearly visible. (Courtesy of Dr. George Healy, Centers for Disease Control and Prevention.)
E. histolytica trophozoite with ingested red blood cells. Note the single nucleus with central nucleolus. (Courtesy of the Centers for Disease Control and Prevention.)
Molecular diagnostics continue to clarify what was once a confusing picture of the true incidence and prevalence of E. histolytica infection and disease. It was a staple of most textbooks that 10% of the world's population was infected with E. histolytica. We now know that most asymptomatic individuals harboring amebic trophozoites or cysts in their stools are infected with a noninvasive species: Entamoeba dispar or Entamoeba moshkovskii. E. dispar appears not to cause disease, even in the most profoundly immunosuppressed individuals; furthermore, at this time, there is little evidence to suggest that E. moshkovskii causes disease, although epidemiologic studies of this species are in their infancy. In contrast, E. histolytica infection can cause disease, although not all patients develop symptoms. It remains unclear how frequently people infected with E. histolytica do develop symptoms; in one study in a highly endemic area, only 10% of infected patients developed symptoms over a 1-year observation period. A remarkable feature of amebiasis is its more common occurrence in men than in women, although the prevalence of infection with E. histolytica does not appear to differ between the sexes. This pattern is particularly pronounced for amebic liver abscess, whose prevalence is ∼7 times higher among men than among women. The explanation for this difference remains unknown, but less efficient complement-mediated killing of amebic trophozoites by serum from men than by serum from women has been reported.
E. histolytica infections are most common in areas of the world where poor sanitation and crowding compromise the barriers to contamination of food and drinking water with human feces. Endemic areas include parts of Mexico, India, and nations in the tropical regions of Africa, South and Central America, and Asia. E. histolytica was present in ∼2.1% of individuals presenting with diarrhea in a large series from Bangladesh and in 1.4% of the asymptomatic control group. In 2007, amebiasis was listed as the sixth most common cause of disease in Mexico, with an incidence of ∼544 cases per 100,000 population. In the United States and other developed countries, disease is unusual and is found almost exclusively in travelers or immigrants from endemic areas. Rarely, outbreaks take place in institutionalized populations, and infections have been documented with increased frequency among men who have sex with men; however, most of the latter cases have been asymptomatic and probably represent E. dispar infections.
Pathogenesis and Pathology
E. histolytica trophozoites possess a potent repertoire of adhesins, proteinases, pore-forming proteins, and other effector molecules that enable them to lyse cells and tissue, induce both cellular necrosis and apoptosis, and resist both innate and adaptive immune defenses. Disease begins when E. histolytica trophozoites adhere to colonic mucosal epithelial cells. Disruption of the colonic mucin barrier is seen in pathologic sections from the diseased colon, but it is not clear whether this disruption is caused by the parasite, facilitating its adherence to mucosal cells, or occurs as a consequence of the adhesion event, with subsequent mucosal damage. Adherence is mediated primarily by a family of surface lectin molecules capable of binding to galactose and N-acetylgalactosamine residues. E. histolytica can lyse host cells upon contact through a family of amphipathic peptides called amoebapores that form barrel-stave pores in target cell membranes. Both cellular necrosis and apoptosis can occur after E. histolytica comes into contact with host cells, and which outcome predominates may relate to inherent characteristics of the target cell or the tissue environment. One consistent and unequivocal finding is the important role played by amebic cysteine proteinases in the disease process. E. histolytica possesses a large family of cysteine proteinases that are capable of lysing the extracellular matrix between host cells (thus detaching cells and facilitating invasion) and cleaving host defense molecules (including complement components and antibodies). Studies in animal models, including chimeric mice with human intestinal xenografts, have shown that inhibition of E. histolytica cysteine proteinase activity, via either direct gene targeting or chemical inhibitors, significantly reduces disease. The ultimate effect of all these amebic virulence factors on the human colon is the production of small ulcers that have heaped borders and contain focal areas of epithelial cell loss, a modest inflammatory response, and mucosal hemorrhage. The intervening mucosa is usually normal, but diffuse hyperemia is sometimes seen. E. histolytica trophozoites can then invade laterally through the submucosal layer, creating the classic flask-shaped ulcers that appear on pathologic examination as narrow-necked lesions, broadening in the submucosal region, with E. histolytica trophozoites at the margins between dead and live tissues (Fig. 209-3). Ulcers tend to stop at the muscularis layer, and full-thickness lesions and colonic perforation are unusual. Amebomas, a rare complication of intestinal disease, are granulomatous mass lesions protruding into the bowel lumen, with a thickened edematous and hemorrhagic bowel wall that can cause obstructive symptoms.
E. histolytica flask-shaped intestinal ulceration from a kitten. (Courtesy of Dr. Mae Melvin, Centers for Disease Control and Prevention.)
In some individuals with E. histolytica colonic infection, trophozoites invade the portal venous system and reach the liver, where they cause amebic liver abscesses. E. histolytica trophozoites must resist lysis by serum complement to survive in the bloodstream. Amebic liver abscesses have a characteristic appearance on pathologic examination: the roughly circular abscesses contain a large necrotic center resembling anchovy paste that is surrounded by a narrow ring of a few inflammatory cells, fibrosis, and occasionally a few amebic trophozoites. The adjacent liver parenchyma is usually completely normal. Results in experimental rodent models of amebic liver abscess suggest that initial lesions may have more inflammatory cells and that lysis of neutrophils by E. histolytica trophozoites may contribute to tissue damage. In murine models of disease, apoptosis is a prominent component of hepatocyte death and the blockade of caspase activity can significantly reduce liver abscess formation, but whether any of these factors is applicable to human disease is unclear.
The role of innate and adaptive immunity in preventingE. histolytica infection or controlling disease needs further clarification. Studies of children in a highly endemic area have suggested that prior E. histolytica intestinal infection may stimulate mucosal IgA antibodies to amebic antigens, thereby reducing the likelihood of subsequent infections; this protection is relatively short lived. In contrast, among individuals in an area of Vietnam with a high prevalence of amebic liver abscess, a prior episode of disease did not reduce the risk of a second case, despite the presence of serum antibodies. Studies of animal models suggest that cell-mediated immunity may play a role in host defense, and glucocorticoid use has been associated with worse outcomes in patients with amebic colitis. However, individuals with HIV/AIDS do not appear to be at increased risk for infection with E. histolytica, and there is no evidence that they develop more severe disease than do immunocompetent hosts.
Most patients harboring Entamoeba species are asymptomatic, but individuals with E. histolytica infection can develop disease. Symptoms of amebic colitis generally appear 2–6 weeks after ingestion of the cyst form of the parasite. Diarrhea (classically heme-positive) and lower abdominal pain are the most common symptoms. Malaise and weight loss may be noted as disease progresses. Severe dysentery, with 10–12 small-volume, blood- and mucus-containing stools daily, may develop, but only ∼40% of patients are febrile. Fulminant amebic colitis, with even more profuse diarrhea, severe abdominal pain (including peritoneal signs), fever, and pronounced leukocytosis are rare, disproportionately affecting young children, pregnant women, individuals being treated with glucocorticoids, and possibly individuals with diabetes or alcoholism. Paralytic ileus and colonic mucosal sloughing may be seen; intestinal perforation occurs in >75% of patients with this fulminant form of disease. Mortality rates from fulminant amebic colitis exceed 40% in some series. Recognized complications of amebic colitis also include toxic megacolon (documented in ∼0.5% of patients with colitis), with severe bowel dilation and intramural air, and the aforementioned ameboma, which presents as an abdominal mass that may be confused with colon cancer.
Just a century ago, amebic liver abscess—the most common extraintestinal manifestation of amebiasis—was almost always fatal; however, with current rapid diagnostic methods and effective medical treatment, mortality rates are now 1–3%. Disease begins when E. histolytica trophozoites penetrate through the colonic mucosa, travel through the portal circulation, and reach the liver. Most individuals with amebic liver abscess do not have concurrent signs or symptoms of colitis, and most do not have E. histolytica trophozoites in their stools. The exceptions are individuals with fulminant amebic colitis, in which concurrent amebic liver abscess is not uncommon. Disease can arise from months to years after travel to or residence in an endemic area; therefore, a careful travel history is key in making the diagnosis. The classic presentations of amebic liver abscess are right-upper-quadrant pain, fever, and hepatic tenderness. The pace of disease is usually acute, with symptoms lasting <10 days. However, a more chronic presentation, with weight loss and anorexia as prominent accompanying features, does occur. Jaundice is unusual, but dullness and rales at the right lung base (secondary to pleural effusion) are common. The most common laboratory findings are leukocytosis (without eosinophilia), an elevated alkaline phosphatase level, mild anemia, and an elevated erythrocyte sedimentation rate.
Other Extraintestinal Complications of Amebiasis
Right-sided pleural effusions and atelectasis are common in cases of amebic liver abscess and generally require no treatment. However, the abscess ruptures through the diaphragm in ∼10% of patients, causing pleuropulmonary amebiasis. Suggestive symptoms are sudden-onset cough, pleuritic chest pain, and shortness of breath. In some patients, pleuropulmonary amebiasis is the presenting manifestation of amebic liver abscess and may be confused with bacterial pneumonia and empyema. A dramatic complication is the development of a hepatobronchial fistula, in which patients can cough up the contents of the liver abscess—copious amounts of brown sputum that may contain E. histolytica trophozoites. In ∼1–3% of cases, the amebic liver abscess ruptures into the peritoneum, and peritoneal signs and shock develop. Even rarer is rupture of an amebic liver abscess into the pericardium; the signs and symptoms are those commonly seen with pericarditis (chest pain, pericardial rub, dyspnea, tachypnea, or cardiac tamponade), and nearly 30% of cases end in death. Cerebral abscesses complicate <0.1% of cases of amebic liver abscess and are associated with the sudden onset of headache, vomiting, seizures, and mental status changes and a high mortality rate. Cutaneous amebiasis (which usually involves the anal and perianal regions), genital disease (including rectovaginal fistulas), and urinary tract lesions are rare but reported complications of amebiasis.
The diagnosis of amebic colitis has traditionally been based on the demonstration of E. histolytica trophozoites or cysts in the stool or colonic mucosa of patients with diarrhea. However, the inability of microscopy to differentiate between E. histolytica and other Entamoeba species, such as E. dispar and E. moshkovskii, limits its effectiveness as a sole diagnostic method. Examination of three stool samples improves sensitivity for the detection of Entamoeba species, and it has been argued that the presence of amebic trophozoites containing red blood cells in a diarrheal stool is highly suggestive of E. histolytica infection. However, because trophozoites containing red blood cells are not found in most patients with E. histolytica infection, the applicability of this finding is limited.
Despite these inherent limitations, microscopy, often combined with serologic testing, remains the standard diagnostic approach in many hospitals and clinics worldwide. Culture of stools for E. histolytica trophozoites serves as a research tool but is generally not available for clinical use. PCR assay for DNA in stool samples is currently the most sensitive and specific method for identifying E. histolytica infection and has become a valuable epidemiologic and research tool; probes can be configured to detect E. dispar and E. moshkovskii as well. While significant advances are being made in reducing the costs of PCR-based diagnostics, this method still is not feasible for clinical diagnosis in most endemic areas. Commercially available tests that use enzyme-linked immunosorbent assays (ELISAs) or immunochromatographic techniques to detect Entamoeba antigens are less expensive and more easily performed and are being used with increasing frequency. Greater sensitivity than microscopy and the ability to detect E. histolytica specifically are claimed by some of the leading kits, representing significant advantages over microscopy. Unfortunately, not all clinical studies have supported these claims, concerns have been raised about the specificity of the tests in nonendemic areas, and the ELISAs are less sensitive and specific than are PCR-based diagnostics. At this point, antigen detection–based ELISAs that can specifically identify E. histolytica in stool probably represent the best choice in endemic areas; however, the results of any of these diagnostic tests need to be interpreted in light of clinical presentation, and a second confirmatory test (e.g., microscopy and/or amebic serology) may be prudent. In instances in which amebiasis is suspected on clinical grounds in a patient with acute colitis but initial stool samples are negative, colonoscopy with examination of brushings or mucosal biopsies for E. histolytica trophozoites may be helpful in making the diagnosis or in identifying other diseases, such as inflammatory bowel disease or pseudomembranous colitis.
The diagnosis of amebic liver abscess is based on the detection (generally by ultrasound or CT; Fig. 209-4) of one or more space-occupying lesions in the liver and a positive serologic test for antibodies to E. histolytica antigens. As has been noted, amebiasis can present months or years after travel to or residence in an endemic area, and so a careful travel history is mandatory when anyone presents with a liver abscess. Amebic liver abscesses are classically described as single, large, and located in the right lobe of the liver, but sensitive imaging techniques have shown that multiple abscesses are more common than previously suspected. When a patient has a space-occupying lesion of the liver, a positive amebic serology is highly sensitive (>94%) and highly specific (>95%) for the diagnosis of amebic liver abscess. False-negative serologic tests have been reported when serum samples were obtained very early in the course of abscess (within 7–10 days of onset), but repeat tests are almost always positive.
Large amebic abscess in the right lobe of the liver visualized by CT. (Courtesy of Dr. M. M. Reeder, International Registry of Tropical Imaging.)
The differential diagnosis of amebic colitis includes bacterial dysentery (e.g., Shigella and Campylobacter infections), schistosomiasis, Balantidium coli infection, pseudomembranous colitis, inflammatory bowel disease, and ischemic colitis. Stool cultures for bacterial pathogens, microscopic examination of stools, and amebic serology help differentiate amebic colitis from these other entities. Amebomas may be confused with colonic carcinoma; several case reports describe instances in which amebomas and associated liver abscesses were initially considered to be colon cancer with liver metastases. Amebic liver abscess must be distinguished from pyogenic liver abscess, echinococcal cysts, and primary or metastatic liver tumors. It is difficult to differentiate pyogenic from amebic liver abscesses on purely clinical grounds, but amebic serology is usually the key test in excluding or diagnosing amebic liver abscess. Abscesses that rupture into the pleural space may be accompanied by cough, sputum production, and dyspnea and may initially be diagnosed as bronchopneumonia.
The nitroimidazole compounds tinidazole and metronidazole are the drugs of choice for the treatment of amebic colitis and amebic liver abscess (Table 209-1). To date, E. histolytica has not demonstrated resistance to any of the commonly used agents—a situation that greatly simplifies treatment. Tinidazole appears to be better tolerated and slightly more effective than metronidazole for amebic colitis and amebic liver abscess. Metronidazole is available as a parenteral formulation for patients who cannot take oral medications. Whenever possible, fulminant amebic colitis is managed conservatively, even in the presence of perforation, with the addition of antibiotics to treat gut bacteria and percutaneous catheter drainage of fluid collections if needed.
Table 209-1 Recommended Therapeutic Dosages of Antiamebic Drugs |Favorite Table|Download (.pdf)
Table 209-1 Recommended Therapeutic Dosages of Antiamebic Drugs
|Amebic Colitis or Amebic Liver Abscess|
|Tinidazole||2 g/d PO with food||3|
|Metronidazole||750 mg tid PO or IV||5–10|
|Entamoeba histolytica Luminal Infection|
|Paromomycin||30 mg/kg qd PO in 3 divided doses||5–10|
|Iodoquinol||650 mg PO tid||20|
Remarkably, given the large size of amebic liver abscesses, treatment with tinidazole or metronidazole in the same doses used for amebic colitis is almost always successful. More than 90% of patients respond with a decrease in abdominal pain and fever within 72 h of the initiation of therapy. Drainage of amebic liver abscesses is rarely needed; in one large series, neither time to becoming afebrile nor length of hospitalization was significantly different for patients who underwent percutaneous radiography-guided aspiration of the abscess accompanied by medical therapy than for those who received medical therapy alone. Aspiration should be reserved for individuals in whom pyogenic abscess or a bacterial superinfection is suspected but whose diagnosis is uncertain, for patients failing to respond to tinidazole or metronidazole (i.e., those who have persistent fever or abdominal pain after 4 days of treatment), for individuals with large liver abscesses in the left lobe (because of the risk of rupture into the pericardium), and for patients whose large abscesses and accelerated clinical course raise concerns about imminent rupture. In contrast, aspiration and/or percutaneous catheter drainage improves outcomes in patients with pleuropulmonary amebiasis and empyema (where amebic liver abscesses have ruptured into the pleural space), and percutaneous catheter or surgical drainage is absolutely indicated for cases of amebic pericarditis. Rupture of an amebic liver abscess into the peritoneum is generally managed conservatively, with medical therapy and percutaneous catheter drainage of fluid collections as needed.
Neither metronidazole nor tinidazole reaches high levels in the gut lumen; therefore, patients with amebic colitis or amebic liver abscess should also receive treatment with a luminal agent (paromomycin or iodoquinol) to ensure eradication of the infection (Table 209-1). Paromomycin is the preferred agent. Asymptomatic individuals with documented E. histolytica infection should be treated because of the risks of developing amebic colitis or amebic liver abscess in the future and of transmitting the infection to others. Paromomycin or iodoquinol in the doses listed in the table should be used in these cases.
Nitazoxanide, a broad-spectrum antiparasitic drug, is efficacious against E. histolytica trophozoites in both tissue and gut lumen and may become an important addition to the therapeutic repertoire. However, clinical experience with nitazoxanide for the treatment of E. histolytica infection remains limited at this point.
Avoidance of the ingestion of food and water contaminated with human feces is the only way to prevent E. histolytica infection. Travelers to endemic areas should exercise the same measures used to reduce the risk of travelers′ diarrhea (Chap. 117). Treatment of asymptomatic persons who pass E. histolytica cysts in the stool may help reduce opportunities for disease transmission. There is no evidence for any effective prophylaxis, and no vaccine is available.