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.

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).

Differential diagnosis

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

Laboratory diagnosis

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.

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.
  
  
• 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.
  
  
• 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.