Overall Bottom Line
- ALA is the most common manifestation of extraintestinal amebiasis.
- Untreated amebic liver abscesses are not likely to resolve spontaneously, and will require specific treatment. Post-treatment prognosis is excellent.
- Treatment is twofold and directed against both Entamoeba histolytica trophozoites and cysts to prevent infection relapses.
- Abscess drainage is warranted when antimicrobial therapy is insufficient.
Section 1: Background
Definition of disease
- ALA is the most common manifestation of extraintestinal amebiasis.
Incidence/prevalence
- Amebic infection is estimated to be present in up to 50% of the tropical and subtropical population (e.g. Southeast Asia, India, Egypt, South Africa). Hepatic involvement, in the form of ALA, is noted in up to 1% of those with amebic infection.
- It is more common in men than in women (ratio of 10:1). The age group most commonly affected are those in the fourth and fifth decades of life.
Etiology
- Amebic infection can be caused by two protozoans, notably E. histolytica and E. dispar. However, hepatic amebiasis is caused solely by E. histolytica due to its invasive/pathogenic capacity.
Pathology/pathogenesis
- Ingestion of the Entamoeba cyst from fecally-contaminated food or water results in excystation and subsequent trophozoite formation. Through pathways that remain incompletely understood (and which may include genetic and immune mechanisms), the trophozoite can invade the intestinal mucosa and submucosa and thereby enter the superior mesenteric vein and portal venous system. Due to its increased portal venous drainage, the right hepatic lobe is more commonly the site of amebic abscess formation. The trophozoites cause areas of focal hepatic necrosis with continued amebic lysis of neutrophils at the edge of the lesion releasing mediators that then lead to hepatocyte death and further damage to distant hepatocytes. An increasing number of small necrotic lesions then coalesce to form a larger hepatic abscess.
- Complications from amebic liver abscess are curable but are at times life-threatening. Rupture of the abscess can occur in cephalad and caudad directions. Upward spread of infection can involve the diaphragm and thoracic cavity resulting in inflammation of the diaphragm, pleura, lungs and pericardium. Other thoracic complications include the formation of lung abscess and fistula (broncho-pleuro-hepatic type), and pericardial pathology such as pericarditis and cardiac tamponade. Downward extension of the abscess can result in peritonitis – which is the second most common complication of ALA, after pleuropulmonary disease.
- Left hepatic ALA, although much less common than right hepatic lesions, tend to be more life-threatening due to the development of multiple lesions and their closer proximity to the heart. These lesions are more likely to require invasive treatment strategies (e.g. aspiration, catheter drainage, surgery) – in addition to pharmacologic agents – compared with right hepatic abscesses.
- Culture of the lesion’s material tends to be negative since the abscess is almost always sterile; however, collection at the abscess’ edge can demonstrate the Entamoeba trophozoites.
Predictive/risk factors
- Risk factors for acquiring amebic infection include population overcrowding, poor hygiene and sanitation, and probably genetic and immune factors. Due to the protozoa life cycle, Entamoeba cysts are excreted in stool and thus transmitted to another human vector through the ingestion of fecally-contaminated food and water. Successful eradication of the infection in a person does not decrease the risk of another infection (i.e. the absence of immunologic protection) if the same risk factors remain present.
- Since the incidence of intestinal amebiasis does not demonstrate a sex predominance, male sex predisposes to ALA although the mechanism remains unclear.
Section 2: Prevention
Clinical Pearls
- Prevention of overcrowding.
- Provision of adequate sanitation.
- Continued public health education.
- Proper diagnosis and prompt treatment of primary infection to prevent complications (e.g. extraintestinal amebiasis).
Screening
- Screening for amebic liver abscess is not practical since only up to 1% of people with amebic infections develop this complication. However, prompt diagnosis and treatment of amebic infection will significantly decrease the risk of ALA development.
Primary prevention
- Prevention of overcrowding.
- Provision of adequate sanitation.
- Continued public health education.
Secondary prevention
- Proper diagnosis and prompt treatment of primary infection to prevent extraintestinal complications (e.g. amebic liver abscess formation).
Section 3: Diagnosis
Clinical Pearls
- Patients with ALA typically present with fever and RUQ pain. A prior history of a diarrheal illness is not always present although presentation is typically within 3–4 months of travel to an endemic area.
- Up to half of all patients have tender hepatomegaly on examination.
- All types of abdominal imaging demonstrate ALA.
- Serological testing of E. histolytica antibodies or antigens can be helpful in confirming the diagnosis.
- Aspiration of ALA can be done for therapeutic purposes but is usually not required for a diagnosis.
Differential diagnosis
| Differential diagnosis | Features |
|---|---|
| Pyogenic liver abscess | Recent biliary disease and/or surgery Diabetes mellitus Positive culture growth in aspirate and/or blood Absent E. histolytica serology US may show multiple lesions and irregular (ill-defined) abscess wall |
| Echinococcal/hydatid cyst | More likely to be asymptomatic lesions Eosinophilia Imaging may demonstrate cyst calcification and/or presence of daughter cysts Note: secondary bacterial infection may occur |
Typical presentation
- Patients with amebic liver abscess rarely recall having or have a recent history of gastrointestinal symptoms (e.g. abdominal pain, tenesmus, bloody diarrhea) despite requiring the prerequisite amebic infection – hence decreasing the success rate of ALA screening, if this is ever pursued.
- Travel to an endemic area is typically within the preceding 3–4 months but can be much longer in some cases.
- Signs/symptoms of ALA are generally of acute onset; these usually consist of fever, pain, and hepatomegaly.
Clinical diagnosis
History
- A patient is more likely to be suspected of having amebic liver abscess if living in or having recently resided in an endemic area.
- Fever is commonly of a high temperature, continuous or intermittent, and accompanied by chills and significant sweating. The patient may also have non-specific constitutional symptoms such as malaise, anorexia, and weight loss.
Physical examination
- Physical examination can demonstrate the presence of fever, abdominal pain and an enlarged liver. Other constitutional signs and symptoms (e.g. malaise, nausea, weight loss) may be present. Dyspnea may be noted due to diaphragmatic compression from the enlarging abscess. The patient often finds symptomatic relief when turning to the opposite side of the lesion while lying supine.
- The site of abdominal pain tends to correspond with the abscess location. With right hepatic lesions, pain is described in the right abdomen and may radiate to the right shoulder and the right back region. Pain from left hepatic lesions will be located in the epigastrium and left abdomen, and can radiate to the left back and scapula.
- The degree of hepatomegaly varies with the side and site of the abscess. Large lesions may be palpated. Patients may note breathing difficulty due to diaphragmatic compression of the enlarging abscess.
- The site of abdominal pain tends to correspond with the abscess location. With right hepatic lesions, pain is described in the right abdomen and may radiate to the right shoulder and the right back region. Pain from left hepatic lesions will be located in the epigastrium and left abdomen, and can radiate to the left back and scapula.
- Jaundice is not a typical feature; if present, it corresponds to biliary pathology and may predict a worse prognosis.
Useful clinical decision rules and calculators
- A patient is more likely to be suspected of having amebic liver abscess if living in or having recently resided at an endemic area.
- Microbial and imaging studies have a higher diagnostic yield when compared with basic studies such as a CBC and biochemical tests.
Disease severity classification
- Disease severity is higher among these scenarios:
- Left hepatic abscesses.
- Jaundice and other signs of biliary disease.
- Persistent symptoms (e.g. fever, abdominal pain) despite receiving adequate and appropriate antimicrobial treatment.
- Large right hepatic abscess – which increases the risk of rupture.
- Pulmonary complications from ALA.
- Left hepatic abscesses.
Laboratory diagnosis
List of diagnostic tests
- Demonstration of E. histolytica cysts and/or trophozoites in the feces strengthens the suspicion for ALA. However, it should be noted that it may be difficult to distinguish E. histolytica from E. dispar (a non-invasive and non-pathogenic agent) from stool samples. Furthermore, up to 70% of patients with ALA will not have detectable E. histolytica in the stool.
- Due to the low yield of fecal sample testing, serologic tests have become a valuable tool for making a diagnosis. These tests detect specific circulating antibodies against E. histolytica and can therefore distinguish it from E. dispar and agents causing pyogenic abscesses.
- Examples of these serologic tests include IHA, antigen-based ELISA kits specific for E. histolytica, and PCR testing. Unfortunately, these tests, although highly sensitive when compared with other tests, are not widely available due to their high cost and complicated process.
- A CBC is non-specific and may demonstrate mild–moderate leukocytosis and mild anemia that may be normochromic.
- Liver chemistries also yield non-specific findings.
List of imaging techniques
- A chest X-ray can demonstrate elevation of the right/left hemidiaphragm (depending on the location of the abscess), if present.
- Abdomen US is the most widely-used initial imaging study due to its easier access and lower cost. The amebic liver abscess is most commonly seen as round/oval, hypoechoic, and having well-defined margins. Abdominal CT scans have greater sensitivity and better resolution in detecting ALA, especially the smaller lesions and are thus useful for making an early diagnosis; lesions characteristically appear as a round shape with low density and well-defined margins.
Potential pitfalls/common errors made regarding diagnosis of disease
- The diagnosis of ALA can be missed since it can take up to 7 days for anti-amebic antibodies to become detectable. Although the antibody does not distinguish past from current infection, its specificity becomes more significant when the patient comes from a non-endemic area.
- With increasing global travel, precautions while traveling through endemic areas for amebiasis may be overlooked and thereby increasing the person’s risk for acquiring this infection. A pertinent travel history also needs to be included when interviewing a patient, even if it appears to be unrelated to the person’s symptoms.
Section 4: Treatment
Treatment rationale
- Uncomplicated amebic liver abscess is treated in a twofold manner. The first step involves trophozoite eradication utilizing a nitroimidazole derivative (metronidazole, tinidazole or secnidazole); these agents are given through the oral route.
- Among these agents, metronidazole is the oldest and most studied. Due to its excellent bioavailability as an oral agent, favorable pharmacokinetics and widespread distribution in the intestine and other tissues, it is the drug of choice for treating amebic liver abscess and invasive intestinal amebiasis.
- Metronidazole is given at an oral dose regimen of 750 mg three times daily for 7–10 days.
- Critically-ill patients, and those with large and/or multiple abscesses are given the agent intravenously at 500 mg every 8 hours for 5–10 days.
- Metronidazole is given at an oral dose regimen of 750 mg three times daily for 7–10 days.
- In the absence of complications, cure rate with metronidazole therapy alone has been reported in more than 90% of cases; clinical improvement is noted after 3–4 days of treatment. Upon completion of treatment, the hepatic abscesses may take up to 3–12 months to heal and is monitored through imaging studies (e.g. US).
- Caveats for metronidazole therapy are noted as follows:
- Common adverse effects include nausea and abdominal pain. A particular side-effect is a metallic taste sensation.
- Metronidazole is found in breast milk.
- Metronidazole has disulfiram-like properties; hence, alcohol ingestion during use of this agent must be avoided.
- Common adverse effects include nausea and abdominal pain. A particular side-effect is a metallic taste sensation.
- Both tinidazole and secnidazole are relatively newer agents; although they have been found to be effective against intestinal amebiasis, they are not yet recommended for the treatment of ALA.
- Chloroquine is also effective against amebic liver abscess although it has no activity against intestinal disease. It has excellent tissue distribution and has high concentrations in the hepatic parenchyma. It is still not recommended as the primary treatment of ALA, and serves as adjunct therapy to metronidazole for those with large and multiple abscesses and those with poor response to metronidazole monotherapy.
- The chloroquine dose regimen against ALA is 300 mg every 12 hours followed by 300 mg once daily for 21 days.
- Since the nitroimidazole derivatives remain only in the intestine for a short period, infection relapses may occur. Similar to the treatment of intestinal amebiasis, further therapy with a luminal amebicidal agent – to eradicate Entamoeba cysts – is required after trophozoite eradication.
- Paramomycin is given at a dose regimen of 30 mg/kg/day three times daily for 7 days. Its major adverse effects are abdominal pain, nausea/vomiting, and headache.
- The second-line agent, diloxanide furoate, is given as 500 mg three times daily for 10 days. Its adverse effects include abdominal discomfort, flatulence and nausea.
- In countries where it is available, etofamide is given as 500 mg three times daily for 3 days; adverse effects are abdominal discomfort, nausea/vomiting and dizziness.
- Paramomycin is given at a dose regimen of 30 mg/kg/day three times daily for 7 days. Its major adverse effects are abdominal pain, nausea/vomiting, and headache.
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