Hepatic schistosomiasis as a determining factor in the development of hepatic granulomas and liver fibrosis: a review of the current literature

Abstract

Hepatic schistosomiasis is a neglected parasitosis that affects millions of people each year worldwide and leads to high healthcare costs and increased morbidity and mortality in infected humans. It is a disease that has been widely studied in terms of its pathophysiology; therefore, the signaling pathways that lead to liver damage, with the consequent development of liver fibrosis, are now better understood. Research has elucidated the role of soluble egg antigen in the development of hepatic granulomas and liver fibrosis, the signal transducer and activator of transcription 3 and its participation in liver damage, the role of heat shock protein 47 and its involvement in liver fibrosis, the anti-inflammatory effects caused by interleukin-37, and the role of natural killer and natural killer T cells in the development of the disease. Hepatic schistosomiasis can range from simple hepatomegaly to the development of portal hypertension combined with hepatic fibrosis. For diagnostic purposes, a microscopic examination of excreta remains the gold standard; however, abdominal ultrasound has recently taken on an important role in the assessment of liver lesions produced by the parasite. Praziquantel is considered the management drug of choice, and has been associated with a potential preventive antifibrotic effect.

Keywords: Inflammation; hepatic granuloma and liver fibrosis; hepatic schistosomiasis; schistosome.

Graphical abstract

Figure 1.

The geographic distribution of the different species of Schistosoma. The geographical distribution of schistosoma species is shown as follows: S. mansoni is widely distributed in South America, the Caribbean and Africa; S. japonicum is distributed in China, the Philippines, Indonesia and Thailand; S. haematobium is distributed in Africa and the Middle East; S. mekongi predominates in Cambodia and Laos; and S. intercalatum predominates in central and Western Africa.

Figure 2.

Biological cycle of schistosoma spp. The eggs of the three schistosoma species that frequently parasitize humans are excreted in feces—(a) S. japonicum and (B) S. mansoni—or in urine—(c) S. haematobium. [1] the eggs hatch and release the miracidium [2]; this penetrates the soft parts of the freshwater snail—(a) bulinus spp. For S. japonicum, (B) biomphalaria spp. For S. mansoni, and (C) oncomelania spp. For S. haematobium— [3] two generations of sporocysts (primary and secondary) develop within the freshwater snail [4]; cercariae, which leave the freshwater snail and swim freely in the water, develop [5]; they penetrate human skin [6]; they then lose their tail and become schistosomula, which are introduced into the bloodstream [7]; they subsequently migrate through the portal system to the liver, where they become adults [8]; the adult male and female parasites, after sexually reproducing, migrate to the mesenteric venules or the venules of the bladder plexus, where they deposit their eggs so that they are excreted [12]; subsequently, the cycle is restarted.

Figure 3.

Signaling pathways for the development of fibrosis and hepatic granulomas in hepatic schistosomiasis. (a) The soluble egg antigen (SEA) induces the activation of macrophages. These macrophages produce extracellular vesicles that cause an increase in miRNA-33, which is responsible for the activation of hepatic stellate cells (HSCs), and these cells produce an increase in transforming growth factor β1 (tgf-β1). In turn, this induces the formation of fibrosis and hepatic granulomas [1]. The signal transducer and activator of the transcription 3 (STAT3) signaling pathway in the liver is characterized by an increase in cell proliferation and growth, meaning that it is directly involved in the formation of fibrosis and hepatic granulomas; however, if STAT3 is phosphorylated (p-STAT3), it has the opposite effect, inhibiting these last two processes. In turn, S. japonicum antigen 40 (Sjp40) induces the expression of the STAT3/P53/P21 signaling pathway, which favors senescence and the detection of the growth of HSCs, thus preventing the development of fibrosis and hepatic granulomas [2]. Heat shock protein 47 (HSP47) has a key role in the maturation of procollagen, since this protein participates in the production of collagen types I and III, which favor the development of liver fibrosis [3]. (b) Interleukin-37 (IL-37) can suppress the inflammatory process through the intracellular mothers against decapentaplegic homolog 3 protein (SMAD3) and the extracellular interleukin-18 receptor alpha (IL-18 Rα) signaling pathway, since it is able to promote the polarization of macrophages to the M2 phenotype and produce an decrease in proinflammatory cytokines such as tgf-β1 and interleukin-10 (IL-10), a decrease in type I collagen, and an increase in anti-inflammatory cytokines such as interferon-y (inf-y) [4]. Natural killer (NK) cells and natural killer T cells, through the natural killer group 2 member D (NKG2D) receptor and the production of the murine UL16-binding protein-like transcript 1 (MULT1) ligand, produce a decrease in proinflammatory cytokines and type I collagen and an increase in anti-inflammatory cytokines [5]. These two pathways converge to reduce the development of fibrosis and hepatic granulomas. Praziquantel has a potentially direct preventive effect against the onset of liver fibrosis [6].