Chapter 281 Amebiasis

Edsel Maurice T. Salvana and Robert A. Salata

Entamoeba species infects or colonizes up to 10% of the world’s popula- tion, particularly in resource-limited
settings. In most infected indi- viduals, Entamoeba histolytica or a related species parasitizes the lumen of the
gastrointestinal tract and causes few symptoms or sequelae. E. histolytica is the only invasive species and can cause
amebic colitis with parasitic invasion of the intestinal mucosa and amebic liver abscess with dissemination of the
parasite to the liver.

ETIOLOGY
Three morphologically identical but genetically distinct species of Entamoeba commonly infect humans. Entamoeba
dispar, the most prevalent species, does not cause symptomatic disease. Entamoeba moshkovskii, previously thought
to be nonpathogenic, has been shown to cause diarrhea in infants. E. histolytica, the main pathogenic species, causes
a spectrum of disease and can become invasive in 4-10% of infected patients. Patients previously described as
asymptomatic carriers of E. histolytica based on microscopy findings were likely harboring E. dispar. Four other
species of nonpathogenic Entamoeba are known to colonize the human gastrointestinal tract: E. coli, E. hartmanni,
E. gingivalis, and E. polecki.

Infection is acquired through the ingestion of parasite cysts, which measure 10-18 μm in diameter and contain 4
nuclei. Cysts are resistant to harsh environmental conditions, including chlorine concentrations commonly used in
water purification, but can be killed by heating to 55°C (131°F). After ingestion, cysts are resistant to gastric acidity
and digestive enzymes and germinate in the small intestine to form trophozoites. These large, actively motile
organisms colonize the lumen of the large intestine and may invade the mucosal lining. Infection is not usually
transmitted by trophozoites, as these rapidly degenerate outside the body and are unable to survive the low pH of the
stomach if swallowed.

EPIDEMIOLOGY
Prevalence of infection with E. histolytica varies greatly depending on region and socioeconomic status. Most
prevalence studies have not distinguished between E. histolytica and E. dispar, and thus the true prevalence of E.
histolytica infection is not known. It is estimated that infection with E. histolytica leads to 50 million cases of
symptomatic disease and 40,000-110,000 deaths annually. Amebiasis is the second leading parasitic cause of death
worldwide, after malaria. Prospective studies show that 4-10% of individuals infected with E. histolytica develop
amebic colitis and that <1% of infected individuals develop disseminated disease, including amebic liver abscess.
These numbers vary by region; for example, in South Africa and Vietnam, liver abscesses form a disproportionately
large number of the cases of inva- sive disease caused by E. histolytica. Amebic liver abscesses are rare in children
and occur equally in male and female children; in adults, amebic liver abscesses occur predominantly in men.
Amebiasis is endemic to Africa, Latin America, India, and Southeast Asia. In the United States, amebiasis is seen
most frequently in immi- grants from and in travelers to developing countries. Residents of mental health
institutions and men who have sex with men are also at increased risk for invasive amebiasis. Food or drink
contaminated with Entamoeba cysts and oral-anogenital sex are the most common means of infection. Untreated
water and night soil (human feces used as fertil- izer) are important sources of infection. Food handlers shedding
amebic cysts play a role in spreading infection. Direct contact with infected feces can also result in person-to-person
transmission.

PATHOGENESIS
Trophozoites are responsible for tissue invasion and destruction. These attach to colonic epithelial cells by a
galactose and N-acetyl-d- galactosamine–specific lectin. This lectin is also thought to be respon- sible for resistance
to complement-mediated lysis. Once attached to the colonic mucosa, amebas release proteases that allow for
penetration through the epithelial layer. Host cells are destroyed by cytolysis and apoptosis. Cytolysis is mediated by
trophozoite release of amoebapores (pore-forming proteins), phospholipases, and hemolysins. Amoe- bapores,
which cause a massive influx of extracellular calcium, may also be partially responsible for the induction of
apoptosis that occurs with amebic liver disease and colitis. Once host cells are partially digested by amebic
proteases, the degraded material is internalized through phagocytosis. Early invasive amebiasis produces significant
inflammation, due in part to parasite-mediated activation of nuclear factor-κB. Once E. histolytica trophozoites
invade the intestinal mucosa, the organisms multiply and spread laterally underneath the intestinal epithelium to
produce the characteristic flask-shaped ulcers. Amebas produce similar lytic lesions if they reach the liver. These
lesions are commonly called abscesses, although they contain no granu- locytes. Well-established ulcers and amebic
liver abscesses demonstrate little local inflammatory response.

Immunity to infection is associated with a mucosal secretory IgA response against the galactose/N-acetyl-d-
galactosamine lectin. Neu- trophils appear to be important in initial host defense, but E. histolytica– induced
epithelial cell damage releases neutrophil chemoattractants, and E. histolytica is able to kill neutrophils, which then
release media- tors that further damage epithelial cells. The disparity between the extent of tissue destruction by
amebas and the absence of a local host inflammatory response in the presence of systemic humoral (antibody) and
cell-mediated responses may reflect both parasite-mediated apop- tosis and the ability of the trophozoite to kill not
only epithelial cells but neutrophils, monocytes, and macrophages. Studies show a protec- tive role of the hormone
leptin in mucosal resistance. A malnourished state, in which leptin levels are low, and a genetic polymorphism in the
leptin receptor can increase susceptibility to invasive disease.

The sequencing of the E. histolytica genome has led to further insights into the pathogenesis of E. histolytica
disease. The genome is

functionally tetraploid and contains evidence of lateral gene transfer from bacteria. It has been demonstrated that the
amoebapore-A (Ap-A) gene, along with other important genes, can be epigenetically silenced using plasmids with
specifically engineered sequences or short hairpin RNAs. Transcriptional profiling using proteomics and micro-
arrays has likewise identified several candidate virulence factors. Several classes of proteases that may be associated
with pathogenesis have been identified, including the cysteine proteases binding family proteins (CPBF8), which
modulate lysosome and phagosome function, and M8 metalloprotease EhMSP-1, which likely has a key role in
amebic invasion and is notably absent in E. dispar.

CLINICAL MANIFESTATIONS
Clinical presentations range from asymptomatic cyst passage to amebic colitis, amebic dysentery, ameboma, and
extraintestinal disease. Up to 10% of infected persons develop invasive disease within a year. Thus, asymptomatic
carriers should be treated. Severe disease is more common in young children, pregnant women, malnourished
individuals, and persons taking corticosteroids, and invasive disease is more common in men. Extraintestinal disease
usually involves the liver, but less common extraintestinal manifestations include amebic brain abscess,
pleuropulmonary disease, ulcerative skin, and genitourinary lesions.

Amebic Colitis

Amebic colitis may occur within 2 wk. of infection or may be delayed for months. The onset is usually gradual, with
colicky abdominal pains and frequent bowel movements (6-8/day). Diarrhea is frequently associated with tenesmus.
Almost all stool is hemepositive, but most patients do not present with grossly bloody stools. Generalized
constitutional symptoms and signs are characteristically absent, with fever documented in only one third of patients.
Amebic colitis affects all age groups but is strikingly common in children 1-5 yr of age. Severe amebic colitis in
infants and young children tends to be rapidly progressive with more frequent extraintestinal involvement and high
mor- tality rates, particularly in tropical countries. Amebic dysentery can result in dehydration and electrolyte
disturbances.

Amebic Liver Abscess

Amebic liver abscess, a serious manifestation of disseminated infection, is uncommon in children. Although diffuse
liver enlargement has been associated with intestinal amebiasis, liver abscesses occur in <1% of infected individuals
and may appear in patients with no clear history of intestinal disease. Amebic liver abscess may occur months to
years after exposure, so obtaining a careful travel history is critical. In children, fever is the hallmark of amebic liver
abscess and is frequently associated with abdominal pain, abdominal distention, and enlargement and tenderness of
the liver. Changes at the base of the right lung, such as elevation of the diaphragm and atelectasis or effusion, may
also occur.

Men Who Have Sex with Men
 and HIV Coinfection
 Epidemiologic studies from both developed and
developing countries have shown an increased risk for E. histolytica infection among men who have sex with men.
This risk is further increased in HIV because of increased host susceptibility, and is particularly pronounced in men
who have sex with men with HIV infection.

LABORATORY FINDINGS
Laboratory examination findings are often unremarkable in uncomplicated amebic colitis. Laboratory findings in
amebic liver abscess are a slight leukocytosis, moderate anemia, high erythrocyte sedimentation rate, and elevations
of hepatic enzyme (particularly alkaline phosphatase) levels. Stool examination for amebas is negative in more than
half of patients with documented amebic liver abscess. Ultrasonography, CT, or MRI can localize and delineate the
size of the abscess cavity (Fig. 281-1). The most common finding is a single abscess in the right hepatic lobe in
about one half of these cases. Higher-resolution ultrasound and CT studies show that left lobe abscess and multiple
abscesses occur more often than previously recognized.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

A diagnosis of amebic colitis is made in the presence of compatible symptoms with detection of E. histolytica
antigens in stool. This approach has a >95% sensitivity and specificity and coupled with a positive serology test is
the most accurate means of diagnosis in developed countries. The E. histolytica II stool antigen detection test
(TechLab, Blacksburg, VA) is able to distinguish E. histolytica from E. dispar infection. Microscopic examination
of stool samples has a sensitivity of 60%. Sensitivity can be increased to 85-95% by examining 3 stools, as excretion
of cysts can be intermittent. However, microscopy cannot differentiate between E. histolytica and E. dispar unless
phagocytosed erythrocytes (specific for E. histolytica) are seen. In highly endemic areas, trophozoites without
phagocytosed erythrocytes may reflect coinfection with E. dispar in a patient with another cause of colitis, such as
shigellosis. Endoscopy and biopsies of suspicious areas

Figure 281-1 Abdominal CT scan of a patient with an amebic liver abscess. (From Miller Q, Kenney JM, Cotlar AM: Amebic abscess of
the liver presenting as acute cholecystitis, Curr Surg 57:476–479, 2000, Fig. 1, p. 477.)

should be performed when stool sample results are negative and suspicion for amebiasis remains high.
Various serum antiamebic antibody tests are available. Serologic results are positive in 70-80% of patients with
invasive disease (colitis or liver abscess) at presentation and in >90% of patients after 7 days of disease symptoms.
The most sensitive serologic test, indirect hemagglutination, yields a positive result even years after invasive
infection. Therefore, many uninfected adults and children in highly endemic areas demonstrate antibodies to E.
histolytica. Polymerase chain reaction detection in stool of E. histolytica is also able to distinguish E. histolytica
from E. dispar but is less sensitive (72%) than the stool antigen test. Rapid antigen and antibody tests for bedside
diagnosis in the developing world have been developed and are currently being tested. A high-throughput Luminex
technique for simultaneous detection and differentiation of Entamoeba species has also been developed. In addition,
a loop-mediated isothermal amplification assay that can be optimized for field use is under development.

The differential diagnosis for amebic colitis includes colitis caused by bacterial (Shigella, Salmonella,
enteropathogenic Escherichia coli, Campylobacter, Yersinia, Clostridium difficile), mycobacterial (tuberculosis and
atypical mycobacteria), and viral (cytomegalovirus) pathogens, as well as noninfectious causes such as
inflammatory bowel disease. Pyogenic liver abscess from bacterial infection, hepatoma, and echinococcal cysts are
in the differential diagnosis for amebic liver abscess. However, echinococcal cysts are rarely associated with sys-
temic symptoms such as fever unless there is cyst rupture or leakage.

COMPLICATIONS
Complications of amebic colitis include acute necrotizing colitis, ameboma, toxic megacolon, extraintestinal
extension, or local perforation and peritonitis. Less commonly, a chronic form of amebic colitis develops, often
recurring over several years. Amebomas are nodular foci of proliferative inflammation that sometimes develop in
the wall of the colon. Chronic amebiasis should be excluded before initiating corticosteroid treatment for
inflammatory bowel disease, as corticosteroid therapy given during active amebic colitis is associated with high
mortality rates.

An amebic liver abscess may rupture into the peritoneum, pleural cavity, skin, and pericardium. Cases of amebic
abscesses in extrahepatic sites, including the lung and brain, have been reported.

TREATMENT
Invasive amebiasis is treated with a nitroimidazole such as metronida- zole or tinidazole and then a luminal
amebicide (Table 281-1).
Tinidazole has similar efficacy to metronidazole with shorter and simpler dosing and less-frequent adverse effects.
These adverse effects include nausea, abdominal discomfort, and a metallic taste that disappears after completion of
therapy. Therapy with a nitroimidazole should be followed by treatment with a luminal agent, such as paromomycin
(which is preferred) or iodoquinol. Diloxanide furoate can also be used in children older than 2 yr. of age, but it is no
longer avail- able in the United States. Paromomycin should not be given concurrently with metronidazole or
tinidazole, because diarrhea is a common side effect of paromomycin and may confuse the clinical picture.
Asymptomatic intestinal infection with E. histolytica should be treated preferably with paromomycin or alternatively
with either iodoquinol or diloxanide furoate. For fulminant cases of amebic colitis, some experts suggest adding
dehydroemetine (1 mg/kg/day subcutaneously or IM, never IV), available only through the Centers for Disease
Control and Prevention. Patients should be hospitalized for monitoring if dehydroemetine is administered.
Dehydroemetine should be discontinued if tachycardia, T-wave depression, arrhythmia, or proteinuria develops.

Broad-spectrum antibiotic therapy may be indicated in fulminant colitis to cover possible spillage of intestinal
bacteria into the peritoneum and translocation into the bloodstream. Intestinal perforation and toxic megacolon are
indications for surgery. In amebic liver abscess, image-guided aspiration of large lesions or left lobe abscesses may
be necessary if rupture is imminent or if the patient shows a poor clinical response 4-6 days after administration of
amebicidal drugs. A Cochrane metaanalysis comparing metronidazole and metronidazole plus aspiration in
uncomplicated amebic liver abscess showed that there is insufficient evidence to make any recommendation for or
against this approach. Chloroquine, which concentrates in the liver, may also be a useful adjunct to nitroimidazoles
in the treatment of amebic liver abscess. To confirm cure, stool examination should be repeated every 2 wk
following completion of therapy until clear.

PROGNOSIS
Most infections evolve to either an asymptomatic carrier state or eradication. Extraintestinal infection carries about a
5% mortality rate.

PREVENTION
Control of amebiasis can be achieved by exercising proper sanitation and avoiding fecal-oral transmission. Regular
examination of food handlers and thorough investigation of diarrheal episodes may help identify the source of
infection. No prophylactic drug or vaccine is currently available for amebiasis. Immunization with a combination of
galactose/N-acetyl-d-galactosamine lectin and CpG oligodeoxynucle- otides is protective against amebic trophozoite
challenge in animals, and an intranasal galactose-lectin subunit vaccine is protective in baboons.
Bibliography is available at Expert Consult.