Schistosomal liver fibrosis and hepatocellular carcinoma - case series of patients submitted to liver transplantation

ABSTRACT Schistosomiasis affects approximately 207 million people in 76 countries. The association between hepatocellular carcinoma and Schistosoma mansoni infection has been investigated. Studies using animal models suggest that the parasite may accelerate the oncogenic process when combined with other factors, such as hepatitis C virus infection or exposure to a carcinogen. Herein, we report a case series of six hepatocellular carcinoma patients from Northeast Brazil, with negative serology for both hepatitis B and C virus, submitted to liver transplantation, whose explant showed evidence of schistosomal liver fibrosis. Since all patients enrolled in this study were submitted to liver transplantation, we were able to access the whole explanted liver and perform histopathological analysis, which is often not possible in other situations. Although 50% of them showed signs of liver failure, no cirrhosis or any liver disease other than schistosomal fibrosis had been detected. These uncommon findings suggest that Schistosoma mansoni infection might predispose to hepatocellular carcinoma development, regardless of the absence of other risk factors.

Low transformation growth factor-β1 production and collagen synthesis correlate with the lack of hepatic periportal fibrosis development in undernourished mice infected with Schistosoma mansoni

Undernourished mice infected (UI) submitted to low and long-lasting infections by Schistosoma mansoni are unable to develop the hepatic periportal fibrosis that is equivalent to Symmers’ fibrosis in humans. In this report, the effects of the host’s nutritional status on parasite (worm load, egg viability and maturation) and host (growth curves, biology, collagen synthesis and characteristics of the immunological response) were studied and these are considered as interdependent factors influencing the amount and distribution of fibrous tissue in hepatic periovular granulomas and portal spaces. The nutritional status of the host influenced the low body weight and low parasite burden detected in UI mice as well as the number, viability and maturation of released eggs. The reduced oviposition and increased number of degenerated or dead eggs were associated with low protein synthesis detected in deficient hosts, which likely induced the observed decrease in transformation growth factor (TGF)-β1 and liver collagen. Despite the reduced number of mature eggs in UI mice, the activation of TGF-β1 and hepatic stellate cells occurred regardless of the unviability of most miracidia, due to stimulation by fibrogenic proteins and eggshell glycoproteins. However, changes in the repair mechanisms influenced by the nutritional status in deficient animals may account for the decreased liver collagen detected in the present study.

Schistosoma mansoni granuloma in late evolutive phase, in a case of tumoral form in man / Granuloma equistossomótico em fase evolutiva tardia, em um caso de forma tumoral no homem

INTRODUCTION: Authors describe human schistosomal granuloma in late chronic phase, from the morphological and evolutionary viewpoints. METHODS: The study was based on a histological analysis of two fragments obtained from a surgical biopsy of peritoneum and large intestine of a 42-year-old patient, with a pseudotumoral form mimicking a peritoneal carcinomatosis associated to the schistosomiasis hepatointestinal form. RESULTS: Two hundred and three granulomas were identified in the pseudotumor and 27 in the intestinal biopsy, with similar morphological features, most in the late chronic phase, in fibrotic healing. A new structural classification was suggested for granulomas: zone 1 (internal), 2 (intermediate) and 3 (external). CONCLUSIONS: Regarding granuloma as a whole, we may conclude that fibrosis is likely to be controlled by different and independent mechanisms in the three zones of the granuloma. Lamellar fibrosis in zone 3 seems to be controlled by matrix mesenchymal cells (fibroblasts and myoepithelial cells) and by inflammatory exudate cells (lymphocytes, plasmocytes, neutrophils, eosinophils). Annular fibrosis in zone 2, comprising a dense fibrous connective tissue, with few cells in the advanced phase, would be controlled by epithelioid cells involving zone 1 in recent granulomas. In zone 1, replacing periovular necrosis, an initialy loose and tracery connective neoformation, housing stellate cells or with fusiform nuclei, a dense paucicellular nodular connctive tissue emerges, probably induced by fibroblasts. In several granulomas, one of the zones is missing and granuloma is represented by two of them: Z3 and Z2, Z3 and Z1 or Z2 and Z1 and, ultimately, by a scar.

INTRODUÇÃO: Os autores descrevem o granuloma esquistossomótico no homem, na fase crônica tardia, do ponto de vista morfológico e evolutivo. MÉTODOS: O estudo baseou-se na análise histológica de dois fragmentos obtidos de biópsia cirúrgica do peritônio e do intestino grosso de um paciente de 42 anos de idade, com a forma pseudotumoral mimetizando carcinomatose peritoneal associada à forma hepatointestinal da esquistossomose. RESULTADOS: Foram identificados 203 granulomas no pseudotumor e 27 na biópsia intestinal, com aspectos morfológicos semelhantes, a maioria na fase crônica tardia, em cura por fibrose. Foi sugerida nova classificação estrutural para os granulomas: zona 1 (interna), zona 2 (intermediária) e zona 3 (externa). CONCLUSÕES: Considerando o granuloma como um todo, concluímos que, provavelmente, a fibrose é comandada por mecanismos diferentes e independentes nas três zonas do granuloma. A fibrose lamelar na zona 3 parece ser comandada pelas células mesenquimais da matriz (fibroblastos e células mioepiteliais) e pelas células do exsudato inflamatório (linfócitos, plasmócitos, neutrófilos, eosinófilos). A fibrose anular na zona 2, composta por conjuntivo fibroso denso, pouco celular na fase avançada, seria comandada pelas células epitelioides que envolvem a zona 1 nos granulomas recentes. Na zona 1, substituindo a necrose periovular, a neoformação conjuntiva inicialmente frouxa, rendilhada, albergando células estreladas ou com núcleos fusiformes, surge um conjuntivo denso, paucicelular, nodular, provavelmente induzido pelos fibroblastos. Em muitos granulomas falta uma das zonas descritas e o granuloma é representado apenas por duas delas: Z3 e Z2, Z3 e Z1 ou Z2 e Z1 e, no final, por uma cicatriz.