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Invasive zymodemes of the enteric protozoan Entamoeba histolytica infect the large intestine and cause extra-intestinal lesions such as amebic liver abscess (ALA). The clinical manifestations of ALA are protean, particularly in patients presenting in a non-endemic, desert country such as Kuwait, and diagnosis becomes problematic. In this study, we present cases of ALA to illustrate the clinical and diagnostic challenges. For serodiagnosis of ALA, we compared the sensitivity and specificity of the indirect hemagglutination assay (IHA) with the ImmunoTab assay and an enzyme-linked immunosorbent assay (ELISA) for this geographic region. We tested sera of 110 patients with ALA, 1,224 patients suspected of having invasive amebic infection, and 50 Europeans with no travel history to an amebic-endemic area. The IHA was simple, rapid, easy to perform, and reliable (sensitivity = 99%, specificity > 95%). The performance of the IHA in detecting ALA in suspected cases was significantly better than that of the ELISA and the ImmunoTab test. Compared with the IHA, both the ELISA and ImmunoTab assay detected relatively higher numbers of false-positive cases (4.7% and 3.6%, respectively). With the availability of ultrasound and computed tomography scans, the serology correlates excellently with the clinical presentation. In chronic cases where fibrosis may be present around the abscess, the IHA has limitations, as in the follow-up of treated patients. Pitfalls in diagnosis are highlighted by discussing the differential diagnosis of ALA from bacterial hepatic abscesses and infected hydatid cysts. Most importantly, the IHA in such cases was invariably at a titer that is considered not significant.