An unexpected case of Borrelia garinii liver infection

In humans, only five cases of clinical liver damage have been reported to date in Lyme borreliosis [6,7,8,9,10]. Chavanet et al. reported a case of febrile granuloma hepatitis in a 46-year-old man with no medical history [6]. Goellner et al. described a case of hepatitis in a 73-year-old woman that appeared to be the result of direct tissues invasion by the spirochete [8]. Histopathology of liver biopsy showed ballooning of hepatocytes, marked hepatocyte mitotic activity, prominent microvesicular fat, Kupffer cell hyperplasia, and sinusoidal infiltration by mononuclear cells and polynuclear neutrophils. Dieterle silver-staining showed spirochetes within hepatic sinusoids and parenchyma, but molecular identification was not performed and culture remained negative. Dadamessi et al. described a case of liver injury in a 71-year-old man who presented with febrile jaundice; liver biopsy revealing a non-specific sinusoidal inflammatory infiltrate without necrosis [7]. Zanchi et al. reported a case of Lyme borreliosis with necrotizing granulomas and eosinophilic infiltration of the hepatic parenchyma [9]. Then, Middelveen et al. described a case of granulomatous hepatitis associated with chronic Lyme borreliosis in a 53-year-old woman [10]. Spirochetes were observed within parenchyma of the liver biopsy tissue on histological examination, and identification of B. burgdoferi s.s was performed from positive blood cultures using molecular methods [10]. Although it is possible to see spirochetes on liver biopsy in patients with Lyme borreliosis and hepatitis, in the majority of these cases, no organisms are identified and diagnosis relies on positive serological tests. Spirochetes cannot be detected by Gram staining, whereas Warthin Starry staining revealed them in liver biopsy in the present case, allowing the subsequent diagnosis of B. garinii infection by 16S rRNA gene-based molecular methods. This is the third case where the spirochete was directly demonstrated in liver biopsy.

The pathogenesis of liver injury in patients with Lyme borreliosis includes an interplay of direct hepatic invasion by the spirochete and immunologic responses. Lyme borreliosis can result in a variety of histologic abnormalities in the liver, in particular, sinusoidal infiltration by a mixed inflammatory infiltrate [8]. Rarely, B. burgdoferi s.l. can result in granulomatous hepatitis.

B. burgdoferi s.l. strains are not known to produce toxins. Most tissue damage seems to result from host inflammatory reactions. The intensity of inflammatory response varies according to the Borrelia species that causes an infection [11].

In the present case, the patient did not remember a tick bite or erythema migrans, as also described in other cases [6, 7, 9]. Erythema migrans is the most common skin finding seen in more than 80% of patients with early Lyme borreliosis [12]. It typically develops 7 to 14 days (range, 3 to 30) after tick detachment [13]. The erythema migrans lesions are often found in or near the armpit, inguinal region, or popliteal fossa but can occur in any part of the body.

Gastrointestinal signs and symptoms are common in the early stages of the disease. In a study of 314 patients, approximately 10% of the patients had symptoms that were suggestive of hepatitis [14]. In another study, 27% of the patients had subclinical hepatitis during the early stages of disease [15]. Patients with early disseminated Lyme borreliosis are more likely to have abnormal liver function test finding than are patients with localized disease [16]. However, elevations in aspartate aminotransferase may indicate Lyme disease-associated myositis in some patients and may not be related to underlying hepatic injury.

In our patient, serological assays that detect antibodies for B. burgdorferi s.l. were negative while it is generally accepted that patients with disseminated Lyme borreliosis with symptoms for more than six weeks usually reveal positive Borrelia serology [17]. This was explained by the lymphopenia and the reduction of total IgA/IgM/IgG concentrations, in agreement with other observations [18]. Cultivation and isolation from clinical material is a golden standard for confirmation of Borrelia infection [19]. However, many factors influence in vitro Borrelia growth such as medium ingredients and its pH, temperature of incubation, the presence of contaminants, sample’s cell density, number of Borrelia strains in the sample, antecedent antibiotic therapy or capacity of particular Borrelia species to grow [17, 19, 20]. Indeed, Borrelia culture is impractical for routine clinical use [17, 19, 20]. In the present case, diagnosis was established using molecular methods, directly performed on liver biopsy, and permitted the official identification of the bacterium. The gold standard for genotyping of B. burgdorferi s.l. nowadays is MLST, which undergo slow evolution and show nearly neutral variation [5]. Of interest, MLST analysis of B. garinii isolates from bird-derived ticks, questing ticks and humans revealed that there was little overlap among genotypes from different continents, no geographical structuring within Europe, and no evident association pattern detectable among B. garinii genotypes from ticks feeding on birds, questing ticks or human isolates [21]. This provides supporting evidence that birds act as important reservoirs for B. garinii and are a main source of infection of this species to ticks and ultimately humans (through the bite of an infected tick).

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