Introduction
Liver abscesses, predominantly caused by bacterial or parasitic infections, represent a significant health concern, particularly in low- and middle-income countries (LMICs) where they are a notable cause of hospital admissions. Understanding the distinct pathophysiologies of amoebic and pyogenic liver abscesses is crucial as it dictates divergent diagnostic and management approaches. This article delves into the pathophysiology, epidemiology, and critically, the current diagnostic strategies for liver abscess, highlighting their limitations and exploring management options within resource-constrained environments. Effective Liver Abscess Diagnosis remains a cornerstone for appropriate patient care and improved outcomes, especially in regions facing healthcare resource limitations.
Pathophysiology of Liver Abscess: Amoebic vs. Pyogenic
Liver abscesses are broadly classified into amoebic liver abscess (ALA) and pyogenic liver abscess (PLA) (refer to Table 1 for a detailed comparison). The underlying mechanisms of disease differ significantly between these two entities.1 Amoebic liver abscess pathogenesis involves Entamoeba histolytica-induced hepatic apoptosis, whereas pyogenic liver abscess is characterized by a suppurative infection of the liver parenchyma. Accurate liver abscess diagnosis is paramount, though often challenging in resource-limited settings, as it directly informs the selection of appropriate treatment strategies.
Table 1. Differentiating Features of Amoebic and Pyogenic Liver Abscess
| Feature | Amoebic Abscess | Pyogenic Abscess |
|---|---|---|
| Pathogen | Entamoeba histolytica | Klebsiella pneumoniae, Streptococcus milleri, Escherichia coli, Burkholderia pseudomallei, Staphylococcus aureus, Polymicrobial including anaerobes |
| Epidemiology | Globally distributed, higher prevalence in LMICs, typically affects males aged 30–50 years | Globally distributed, more common in older patients |
| Risk Factors | Poor sanitation, contaminated drinking water | Biliary tract disease (e.g., gallstones), systemic infection |
| Pathogenesis | Inflammation – abundant neutrophils | Necrosis – relative absence of neutrophils |
| Imaging Characteristics | Typically single lesion (can be multiple), predominantly in the right lobe (can occur in the left), “cold” on sulfur colloid scan | Can be single or multiple, any lobe involvement, “hot” appearance on sulfur colloid scan |
| Fine Needle Aspirate | Macroscopic: thick, chocolate brown, odorless, ‘anchovy paste’; Microscopy for trophozoites—insensitive (25%); Antigen testing—sensitive and specific (generally unavailable in LMICs); PCR—sensitive and specific (generally unavailable in LMICs) | Macroscopic: purulent, may be foul smelling; Culture—limited availability in LMICs |
| Other Diagnostic Modalities | Serology—useful in returned travelers, limited role in residents of high endemicity; Antigen testing of serum—sensitive and specific (generally unavailable in LMICs) | Blood cultures—sensitivity 50%, limited availability in LMICs; often compromised by prior antimicrobial use in LMIC patients |
| Treatment | Medical therapy with metronidazole usually effective. (Drainage may be required in cases of co-infection or impending rupture.) | Percutaneous drainage combined with antibiotics is the standard treatment. Antibiotic therapy alone may be considered for small, responsive abscesses. |
Epidemiology of Liver Abscess
Pyogenic liver abscesses exhibit a global distribution, with reported incidences varying significantly across countries. Asian regions like Taiwan, Singapore, and South Korea have reported higher incidences (over 900 cases per decade) compared to non-Asian regions (e.g., 23 cases per decade).2 In the United States,3 the incidence is estimated at 2.3 per 100,000 population, predominantly affecting older males, with diabetes and cancer recognized as significant risk factors. Streptococcus milleri and Klebsiella pneumoniae are commonly identified pathogens in the US, contrasting with South Korea and Taiwan where K. pneumoniae is the predominant causative agent.1,4
Entamoeba histolytica, a protozoan parasite responsible for amebiasis (intestinal infection), is a leading cause of parasitic infections in travelers returning from endemic areas.5 Amoebiasis is globally prevalent, with a higher burden in LMICs compared to high-income countries (HICs). In HICs, a significant proportion of cases are imported, while non-imported cases often occur in immunocompromised individuals.6 Poor sanitation and contaminated water sources are strongly associated with infection. High rates of amoebiasis were observed in Thai-Cambodian border refugees (63 per 1000 children) between 1987 and 1989, highlighting this link.7
Liver abscess is the most common extra-intestinal manifestation of amebiasis, resulting from parasite migration to the liver via the portal vein. Asia bears the highest burden, with incidence rates reaching up to 21 per 100,000 inhabitants annually.8 Amoebic liver abscess predominantly affects men aged 30–60 years. Risk factors include alcohol consumption and malnutrition, specifically low body mass and hypoalbuminemia.9 Understanding these epidemiological differences is crucial for effective liver abscess diagnosis and public health strategies.
Pathogenesis of Liver Abscess: A Deeper Look
A pyogenic abscess is characterized by a localized collection of pus composed of numerous inflammatory cells, primarily neutrophils, and tissue debris.10 Tissue necrosis due to surrounding inflammation is a hallmark of pyogenic abscess formation.
In contrast, the term “abscess” may be a misnomer when describing the pathology of E. histolytica infection in the liver. Amoebic liver abscess formation involves hepatocyte cell death through apoptosis or necrosis.11,12 Characteristically, there is a notable absence of inflammatory cells due to the lysis of neutrophils by the protozoan, leading to the typically described non-purulent ‘anchovy paste’ abscess material.1 Untreated, cell death and abscess expansion continue. Hamster studies have shown that early in E. histolytica liver invasion, polymorphonuclear cells initially surround the parasite but are subsequently lysed along with hepatocytes.13 This fundamental difference in pathogenesis underscores the need for accurate liver abscess diagnosis to guide appropriate treatment.
Causative Organisms of Pyogenic Liver Abscess and Diagnostic Implications
Pyogenic liver abscesses are polymicrobial infections, frequently caused by organisms such as Klebsiella pneumoniae, Escherichia coli, and Burkholderia pseudomallei.14 The specific microbiology often depends on the route of hepatic invasion. Sources of infection can include the biliary tree (often due to gallstones), systemic circulation (portal vein, hepatic artery), contiguous spread from adjacent infections, and penetrating trauma. In Southeast Asia, individuals working in soil and water, particularly those with comorbidities like diabetes, liver or renal failure, and hazardous alcohol consumption, are at increased risk of B. pseudomallei infection.15
Identifying the specific causative pathogens in PLA presents diagnostic challenges. A significant factor is the common practice of collecting pus for culture after antibiotic administration.1 This can lead to an underestimation of the bacterial diversity and potentially skew antibiotic susceptibility profiles, complicating appropriate treatment selection. Pre-treatment with antimicrobials may result in culture-negative results despite ongoing infection, further hindering accurate liver abscess diagnosis and targeted therapy. Limited laboratory capacity in LMICs, including lack of anaerobic culture facilities, further compounds diagnostic difficulties, where a negative culture may not truly indicate the absence of bacterial growth. Studies have consistently identified gram-negative rods (e.g., E. coli, K. pneumoniae), anaerobes, S. milleri, and Staphylococcus aureus as significant pathogens in PLA.16 The biliary tract, intestinal tract, and portal system are the primary sources of infection, leading to liver seeding.
In Taiwan,17 K. pneumoniae is a particularly prevalent pathogen in PLA. While multi-drug resistant K. pneumoniae strains are increasingly observed, isolates from liver abscesses have generally remained susceptible. A study in Taiwan analyzing 182 liver abscess cases between 1990 and 1996 found that 88% (n = 160) were caused by K. pneumoniae, with diabetes being a common risk factor. Gas-forming K. pneumoniae liver abscess is associated with a poorer prognosis.18 Patients with diabetes mellitus are at higher risk of developing gas-forming primary liver abscess and subsequent metastatic infectious complications. The proposed mechanism for gas formation involves high tissue glucose levels promoting vigorous K. pneumoniae metabolism and growth. Accumulation of toxic inflammatory byproducts, coupled with impaired clearance due to microangiopathy in diabetic patients, further exacerbates the condition. This highlights the importance of good glycemic control in managing infection and improving clinical outcomes.18 These microbiological nuances are critical for guiding liver abscess diagnosis and treatment strategies, especially antibiotic selection.
Melioidosis, caused by B. pseudomallei, is a significant cause of liver abscess in Southeast Asia.15 This saprophytic gram-negative bacillus is found in soil and water. Rice farmers and individuals with compromised immune systems (e.g., diabetics, renal or liver impairment, thalassemia) are at highest risk. Transmission occurs through ingestion, inhalation, or inoculation, leading to diverse infections, including sepsis, pneumonia, and deep-seated abscesses. A study in northeast Thailand reported that 33% (n = 77/230) of melioidosis cases presented with deep-seated abscesses, with liver abscesses accounting for 26% (n = 20/77) and combined liver and spleen abscesses for 31% (n = 24/77). Multiple liver lesions were found in the majority (70% n = 31/44) of liver abscess cases. Percutaneous incision and drainage were performed in over one-third (n = 16) of cases, and splenectomy in two.15 Melioidosis is also recognized as endemic in Cambodia and other LMICs in Southeast Asia.14 Increased awareness and utilization of microbiology services are revealing the true burden of this under-recognized disease. Considering melioidosis in the differential liver abscess diagnosis, especially in endemic regions, is crucial.
Diagnosis of Liver Abscess: Current Methods and Limitations
The clinical presentation of amoebic and pyogenic liver abscesses is often indistinguishable, typically involving fever and right upper quadrant tenderness. While laboratory tests such as leukocytosis (neutrophil predominance), elevated inflammatory markers (e.g., C-reactive protein), increased alkaline phosphatase, and abnormal liver function tests are frequently present, they are not reliable in differentiating between ALA and PLA.1 Therefore, relying solely on clinical and basic laboratory findings is insufficient for accurate liver abscess diagnosis.
Imaging modalities, including ultrasonography and computed tomography (CT) scanning, are valuable for detecting space-occupying lesions and confirming the presence of a liver abscess. However, they may not consistently differentiate between PLA and ALA.19 Traditionally, ALA often presents as a solitary lesion in the right lobe, but can also occur in the left lobe or be multiple.1 CT scans offer higher sensitivity (97%) for liver abscess detection compared to ultrasound (85%).20 Despite its superior sensitivity, CT scanning may not be readily accessible in many LMIC settings. Ultrasound, while less sensitive, is more affordable and readily available, making it a crucial tool for initial liver abscess diagnosis in resource-limited areas.
Fine needle aspiration (FNA) for culture is considered the gold standard for diagnosing pyogenic liver abscess. However, this is not the case for ALA, as parasite culture is insensitive and not routinely available in clinical laboratories. Microscopy of aspirate samples is also insensitive for ALA, with trophozoites visualized in only about 10% of cases. Macroscopic examination of the aspirate can offer preliminary clues. ALA aspirate is classically described as odorless, chocolate brown, thick, and resembling anchovy paste,9 whereas PLA aspirate is typically purulent and foul-smelling, especially with anaerobic bacterial infections. While these macroscopic characteristics can be suggestive, their role in definitive liver abscess diagnosis remains limited and unreliable for differentiation.
Blood cultures are an important adjunct in the liver abscess diagnosis of PLA. Although blood culture yield is generally lower than pus aspirate culture, it can provide valuable microbiological information, especially in patients prior to antimicrobial administration or abscess aspiration. Blood culture is recommended for all patients suspected of liver abscess upon admission.1 However, in LMICs, blood culture availability and utilization may be limited, and prior antibiotic use often reduces sensitivity.
Serology can be helpful in returned travelers from endemic regions residing in non-endemic areas. However, due to prolonged antibody positivity after exposure, serology has limited diagnostic value in high-endemicity settings where prior exposure is common.19 False negative serology results can occur in acute presentations, depending on the patient’s immune response, the specific serologic test used, and the pathogen strain.21 Therefore, serology alone is often insufficient for definitive liver abscess diagnosis, particularly in endemic areas.
Antigen testing shows promise for improving liver abscess diagnosis in LMICs. The TechLab E. histolytica II Antigen Detection test, which detects the Gal/GalNAc antigen in serum, exhibits high sensitivity (≥95%) and specificity (100% in a study with 70 controls, including 9 PLA).19 However, sensitivity significantly decreases in patients pre-treated with metronidazole. Accessibility and affordability of antigen detection tests remain potential barriers in LMICs.
Novel diagnostic markers, such as pyruvate phosphate dikinase detected via lateral flow assay, are under investigation for ALA diagnosis and show potential.22 There is a persistent and urgent need for non-invasive, accurate, readily available, and affordable diagnostic tools for ALA, particularly in LMICs where liver abscess diagnosis is most challenging.
Stool examination for ova and parasites and stool antigen testing are insensitive and not recommended for liver abscess diagnosis in ALA, as most patients lack bowel symptoms. Therefore, stool testing is not valuable in this context.
Molecular testing of liver abscess aspirate offers a reliable method for ALA diagnosis.23 While highly accurate for Entamoeba detection, the availability of molecular tests in LMIC settings is limited due to the requirement for specialized equipment and costly consumables. This restricts its widespread use in resource-constrained environments for routine liver abscess diagnosis.
In HICs, a combination of diagnostic strategies, including blood cultures, Entamoeba serology, and liver abscess aspirate culture, molecular, and antigen testing, is typically used to determine the cause of liver abscess. However, each of these options faces significant limitations in LMIC settings. In LMICs, patients often present after failing initial antibiotic therapy, with imaging revealing an abscess of undetermined etiology due to limited diagnostic capacity. Essential microbiology services are often lacking or underutilized in LMICs.24 Ideally, specimen collection should precede antibiotic administration, but in LMICs, collection is frequently delayed and reserved for patients unresponsive to initial antimicrobial treatment. Pre-hospital antibiotic use is common in LMICs, with patients often obtaining medications, including antimicrobials, from pharmacies or private clinics (≥50% of transactions in Asia).25,26,[27](#ref27] Factors contributing to this include easy access, affordability of small quantities, and familiarity with pharmacy dispensers.26 However, insufficient training of pharmacy staff and inadequate regulation of medication dispensing contribute to uncontrolled antimicrobial use and further complicate liver abscess diagnosis and management.28 These pre-analytical factors significantly impact the reliability of diagnostic tests and underscore the urgent need for improved diagnostic strategies tailored to LMIC contexts.
Treatment Strategies for Liver Abscess in LMICs
Antimicrobial guidelines in LMICs often recommend empiric therapy targeting both amoebic and pyogenic causes of liver abscess. As treatment is frequently initiated before obtaining appropriate diagnostic specimens, the causative pathogen and the true prevalence of each type of abscess remain unclear. Developing evidence-based empiric antibiotic guidelines tailored to local epidemiology is hindered by a scarcity of local microbiology data. Consequently, recommendations are often extrapolated from guidelines developed for different settings, potentially leading to suboptimal treatment and contributing to antimicrobial resistance. Improved liver abscess diagnosis is crucial to refine treatment guidelines and minimize empiric antibiotic use.
Amoebic liver abscess is primarily managed medically, while combined infections and PLA typically require both drainage (via repeated needle aspiration or percutaneous catheter drainage)9,29 and appropriate antimicrobial therapy. Surgical drainage is now reserved for complicated cases, with less invasive percutaneous methods becoming the standard of care.9
The cornerstone of ALA treatment is metronidazole or tinidazole, administered orally for 10 or 5 days, respectively. This is often followed by a luminal agent like paromomycin for 5–10 days to eradicate any residual intestinal cysts. Most ALA cases respond well to medical treatment. Drainage is indicated for non-responders and in cases with complications such as secondary bacterial infection (de novo or post-drainage) or high risk of rupture.1,19 Accurate liver abscess diagnosis helps determine the necessity of drainage in ALA.
PLA treatment has evolved from open surgical drainage to image-guided percutaneous drainage. The optimal approach—antibiotics alone versus drainage—remains debated for certain PLA cases.30 Current recommendations suggest that liver abscesses smaller than 3 cm can be treated medically with antibiotics alone.31 Needle aspiration of liver abscesses is effective and achieves resolution in a high proportion of patients. Repeated aspiration incrementally increases the likelihood of successful management.32 Needle aspiration is a particularly attractive option for LMICs due to limited resource availability. In LMICs, avoiding drain insertion is often preferable due to management challenges and the risk of secondary infections. Further research is needed to define the optimal management strategies for liver abscess in LMIC settings, with liver abscess diagnosis guiding treatment decisions.
Antibiotic selection for PLA depends on the identified pathogen, its susceptibility profile, and local epidemiology. For example, ceftazidime is recommended for melioidosis,15 while meropenem may be appropriate for ESBL-producing K. pneumoniae infections. Targeted antibiotic therapy, guided by accurate liver abscess diagnosis, is essential to optimize treatment outcomes and minimize antimicrobial resistance.
Prognosis of Liver Abscess
The prognosis of pyogenic liver abscess is significantly influenced by the time to diagnosis.2 Delayed diagnosis increases the likelihood of requiring drainage procedures in addition to medical treatment. Patients presenting with shock, acute renal failure, and acute respiratory failure have a poorer prognosis. Timely liver abscess diagnosis and intervention are crucial for improving patient outcomes.
Entamoeba histolytica is a globally significant cause of mortality from parasitic diseases, second only to malaria.1 Untreated ALA is a progressive and uniformly fatal condition. However, with timely treatment initiation, ALA patients generally have a favorable prognosis.11 Complicated and ruptured abscesses are associated with increased mortality. Early and accurate liver abscess diagnosis is paramount for preventing complications and improving survival in ALA.
Conclusions: Improving Liver Abscess Diagnosis in LMICs
In LMICs, both amoebic and pyogenic liver abscesses are prevalent and present with similar clinical features. Current diagnostic strategies face significant limitations in LMIC settings, hindering accurate pathogen identification and optimal management. Improving liver abscess diagnosis is therefore a critical priority.
Despite limitations in sensitivity and availability, blood cultures should be performed in all patients presenting with suspected liver abscess. Large pyogenic abscesses require drainage, and repeated needle aspiration is a suitable treatment modality for LMICs. Culture of aspirated liver contents should always be attempted to guide targeted antimicrobial therapy.
There is a significant gap in readily available, rapid, and affordable diagnostic tests for ALA in endemic countries. Introducing reliable point-of-care diagnostic tests, such as serum antigen testing for ALA, in LMICs would improve detection rates. As ALA is primarily treated medically, improved diagnostics would reduce unnecessary drainage procedures and associated complications. This would also contribute to reducing empiric antimicrobial use for PLA and mitigating the selection pressure for antimicrobial resistance. Investing in better liver abscess diagnosis is essential for improving patient care and public health in LMICs.
Future research should focus on leveraging systematic blood cultures and aspiration of drainable abscesses for improved liver abscess diagnosis. While not feasible for small abscesses, macroscopic observation and testing of aspirate contents for E. histolytica (via antigen or molecular testing) and bacterial culture could help stratify patients and guide appropriate treatment protocols. This invasive diagnostic approach would also allow for aspiration and potential elimination of co-infection in patients with E. histolytica infection. Ultimately, enhancing liver abscess diagnosis capacity in LMICs is crucial for optimizing patient management and combating antimicrobial resistance.
Acknowledgements
We gratefully acknowledge support from the Defense Threat Reduction Agency. I would like to show my gratitude to Dr Nikki Townell for providing comments to this paper as well as Dr Mo Satdin and Dr Em Sokhom for agreeing to participate in this review of the literature.
Conflict of interest statement
The authors have no potential conflicts of interest.
References
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