Primary hepatic actinomycosis is a rare disease that should be considered in the differential diagnosis of liver masses. The symptoms are usually non-specific and include upper abdominal pain, weight loss, a palpable mass, and low-grade fever (or no fever). Microcystic anemia and hypoalbuminemia are common features of hepatic actinomycosis. However, such symptoms are also observed in malignant disorders . As imaging often leads to a suspicion of neoplasms and positive cultures are notoriously difficult to obtain, the pre-operative rate of diagnosis of hepatic actinomycosis is <10%. Therefore, an exploratory laparotomy is usually required for a definitive diagnosis of hepatic actinomycosis . Definitive diagnosis is based on histochemical, macroscopic, and microscopic examination of surgical tissue specimens, which reveal yellow sulfur granules and basophilic filament aggregates . Our patient presented with abdominal pain and prominent weight loss, but the blood test results were all within normal limits. A radiologic examination showed a solid liver mass mimicking a hepatic neoplasm. A hepatic tumor was suspected and surgical resection was performed. Histopathologic examination revealed an abscess containing multiple collections of heavy acute and chronic inflammatory infiltrates with florid fibrosis. A few clusters of filamentous microorganisms consistent with Actinomyces colonies were present, and the diagnosis of hepatic actinomycosis was confirmed.
There is no single tumor marker that can be used to differentiate hepatic actinomycosis from liver tumors. Several studies have shown an association between hepatic actinomycosis and elevated CA19-9 levels. CA19-9 is a carbohydrate epitope that is sialylated on the surface of various tumors. CA19-9 is not organ specific and is clinically used as a marker for pancreatic, hepatobiliary, and gastric malignancies. The CA19-9 level is often elevated in benign diseases of the hepatobiliary system, renal failure, pleural effusion, intestinal pneumonia, and systemic lupus erythematosus. However, the level of elevation in these benign conditions is often lower than that in malignant conditions [9, 10]. Despite these benefits, CA19-9 has inadequate sensitivity and specificity to be used as a marker for differentiating hepatic actinomycosis from liver tumors [11, 12].
HMGB1 is located in the nucleus of most cells. It has been reported that HMGB1 is translocated from the nucleus to the cytosol and then released extracellularly. An increasing number of scientific reports have described the presence of extracellular and cytoplasmic HMGB1 in various inflammatory conditions. With respect to acute inflammation, HMGB1 has been demonstrated to be of pathogenic relevance in sepsis, pneumonia, and endotoxemia. Serum levels of HMGB1 significantly increase 16 to 32 hours following systemic lipopolysaccharide challenge in mice, and a systemic injection of the recombinant HMGB1 in mice is lethal, two findings that provide further support for the pathogenic role of HMGB1 in endotoxemia . Induction of experimental sepsis in mice by cecal ligation and puncture also results in increased serum levels of HMGB1. Sera collected from patients with sepsis demonstrated increased levels of HMGB1 compared with sera from healthy controls, with the highest increase of HMGB1 levels in patients who succumbed to the disease . Intra-tracheal administration of HMGB1 in mice induces acute lung inflammation, with accumulation of neutrophils, edema, and production of pro-inflammatory cytokines . An increase in serum HMGB1 levels has also been reported in patients with hemorrhagic shock . HMGB1 has also been reported to play a possible pathogenic role in chronic inflammatory conditions. The presence of cytoplasmic and extracellular HMGB1 has been reported in experimental arthritis models as well as in rheumatoid arthritis (RA) in humans. HMGB1 has been detected in the majority of investigated synovial fluid samples from patients with RA . In muscle biopsies from patients with chronic myositis, HMGB1 is detected cytoplasmically in muscle fibers, in inflammatory infiltrates, and in small vessel endothelial cells. Biopsies obtained before and after systemic corticosteroid treatment revealed diminished extranuclear HMBG1 expression .
In the current study, we showed that serum HMGB1 levels were increased in patients with HCC in comparison to healthy controls, which is consistent with the report of Cheng et al. . However, the serum HMGB1 level in the patient who had actinomycosis was significantly higher than the level in the patients who had HCC. We also detected HMGB1 mRNA and protein levels in the hepatic tissues. The results showed that the HMGB1 protein content and mRNA levels were higher in the affected tissue than HCC and the control tissues. Although the expression of HMGB1 increased in the patients who had HCC and the patient with actinomycosis, the distribution of HMGB1 was different. Based on immunohistochemistry, we clearly showed that HMGB1 was distributed mainly in the nucleus in the patients who had HCC, but in the patient with actinomycosis the expression of HMGB1 increased in the cytoplasm and nucleus. These differences helped to identify hepatic tumors and hepatic actinomycosis; however, we need more samples of hepatic actinomycosis to verify our findings.
To the best of our knowledge, our report is the first to detect an association between highly elevated HMGB1 expression and hepatic actinomycosis. As a new pro-inflammatory cytokine, HMGB1 may play a pathogenic role in hepatic actinomycosis and might be a useful marker in the differential diagnosis of hepatic actinomycosis, particularly in patients for whom diagnosis is difficult.