Parasites of the liver - epidemiology, diagnosis and clinical management in the European context.

Parasites in the liver cause significant global morbidity and mortality, as they can lead to recurrent cholangitis, cirrhosis, liver failure and cancer. Due to climate change and globalisation, their incidence is increasing, especially in Europe. The correct diagnosis of a hepatic parasite is often delayed because clinicians are unfamiliar with respective entities. Therefore, in this review, we aim to provide clinicians with a comprehensive clinical picture of hepatic parasites and to bring these neglected parasitic liver diseases to the wider attention of hepatology stakeholders in Europe and around the world.

Prophylactic versus therapeutic role of the transplanted CD34+ Umbilical Cord Blood Stem Cells and Wharton Jelly Mesenchymal Stem Cells in early / acute hepatic S. mansoni granulomas reversal in mice; a novel approach.

PURPOSE: Praziquantel (PZQ) is the conventional antibilharzial agent. Nevertheless, no antibilharzial prophylactic agents or 100% curable therapy approved and no reported data about use of human CD34+ Umbilical Cord Blood Stem Cells (CD34+UCBSCs) or Wharton Jelly Mesenchymal Stem Cells (WJMSCs) in prevention and/or complete eradication of acute S.mansoni granulomas in liver. We aimed to study possible prophylactic vs therapeutic role of human CD34+UCBSCs and WJMSCs in acute hepatic bilharzial granulomas in pre vs post-infected mice. METHODS: Seventy mice were divided into 7 groups (10 mice each): Normal, S.mansoni-infected, post-infected PZQ-treated, CD34+UCBSCs pre and post-infected, WJMSCs pre and post-infected. Serological, parasitological, histopathological evaluation using OCT4 & TGFB immunohistochemistry and quantitative image analysis assessment of TGFB-stained fibrogenesis in liver granulomas performed. RESULTS: Histopathologically, surprisingly and significantly, the prophylactic pre-infection stem cells (CD34+UCBSCs and WJMSCs) & similarly the post-infection CD34+UCBSCs treatment revealed eradication/reversal of the entire granulomas and no fibrosis. Moreover, post-infection PZQ treatment showed fewer and significantly smaller granulomas than post-infection WJMSCs treatment. Nevertheless, post-infection WJMSCs exhibited non-significant less TGFB-stained fibrogenesis. CONCLUSION: CD34+UCBSCs exerted the best prophylactic and therapeutic roles in prevention and complete cure of acute hepatic S.mansoni granulomas over WJMSCs and PZQ. In contrast, only pre-infection WJMSCs exhibited similar preventive (prophylactic) effect. On the contrary, post-infection WJMSCs were the worst (incompletely reversed granulomas). Post-infection Praziquantel was overall better therapeutically than WJMSCs in this regard. Accordingly, when it comes to WJMSCs application, WJMSCs are better used as a pre-infection prophylactic and preventive tool rather than a post-infection therapy. Further studies are needed.

Angiostrongylus vasorum Causing Severe Granulomatous Hepatitis with Concurrent Multiple Acquired PSS.

A 14 mo old female Jack Russell terrier presented with a 12 hr history of vomiting and inappetence. She was subsequently diagnosed with multiple acquired portosystemic shunts during an exploratory celiotomy. Gross and histopathological hepatic abnormalities were consistent with chronic disease, including features suggestive of portal hypertension that was potentially caused by migrating and resident Angiostrongylus vasorum larvae. Fecal analysis and polymerase chain reaction of hepatic tissue confirmed the presence of Angiostrongylus vasorum . The dog recovered clinically following empirical treatment and supportive care. A lack of parasite burden was confirmed 9 wk postdiagnosis; however, serum biochemical analysis at that time was suggestive of ongoing hepatic dysfunction.

Severe pentasomide Armillifer armillatus infestation complicated by hepatic encephalopathy.

BACKGROUND: Diagnosis of Armillifer armillatus infestation is usually incidental, commonly via autopsy or radiography. Affected individual are usually asymptomatic. The case presented here, however, had severe thoracic and abdominal involvement with clinical manifestations. AIM: To report a case of heavy A. armillatus infestation in an adult female Nigerian rural dweller complicated by hepatic parenchyma damage. SETTING: Case report from semi-urban southern Nigeria, using clinical records and imaging findings. MATERIALS AND METHODS: Clinical case records, including laboratory results and radiographic /computed tomography images. CONCLUSION: Parenchymal damage with organ dysfunction can be seen with severe A. armillatus infestation. Thus, there is a need for regular health education regarding the risk of A. armillatus infestation for individuals who consume snake meat.

Abdominal angiostrongyliasis: report of two cases with different clinical presentations / Angiostrongilíase abdominal: relato de dois casos com diferentes apresentações clínicas

Abdominal angiostrongyliasis is a sporadic infectious disease caused by the nematode Angiostrongylus costaricensis. It usually presents as acute abdomen, secondary to mesenteric ischemia, and pronounced eosinophilia. In some cases its course is insidious and transient, and the diagnosis is suspicious. The disease is confirmed by the detection of A. costaricensis elements in surgical specimen. The treatment is supportive, with avoidance of antihelminthic administration due to a possible erratic migration followed by worsening of the disease. We report two cases, both with intense eosinophilia and serum IgG-ELISA positive to A. costaricensis. The first case presented ileal perforation and was surgically treated. The second one showed hepatic nodules at ultrasound and was only symptomatically treated, evolving to an apparent protracted resolution. These two cases exemplify different clinical forms of the disease, one of them with liver involvement.

A angiostrongilíase abdominal é doença esporádica decorrente da infecção pelo nematódeo Angiostrongylus costaricensis. Costuma manifestar-se como abdome agudo secundário a isquemia mesentérica, além de marcada eosinofilia. Pode também apresentar-se de forma insidiosa e transitória, exigindo alta suspeita clínica para o diagnóstico. A doença é confirmada pela identificação de elementos do A. costaricensis em peças cirúrgicas. O tratamento é apenas de suporte, devendo-se evitar o uso de anti-helmínticos pela possibilidade de migração errática do verme com piora do quadro. Aqui foram apresentados dois casos, ambos com acentuada eosinofilia e ELISA-IgG sérico positivo para A. costaricencis. O primeiro caso cursou com perfuração ileal e foi tratado cirurgicamente. O segundo caso apresentou nódulos hepáticos ao ultrassom e foi tratado sintomaticamente, evoluindo para lenta resolução. Estes dois casos exemplificam diferentes formas de apresentação clínica da doença, uma delas com envolvimento hepático.

Capillaria hepatica infestation.

Capillaria hepatica is a very rare zoonotic infestation which primarily infests rodents and is rarely found in humans. The presenting features are fever of unknown origin, hepatomegaly and peripheral eosinophilia. Liver biopsy remains the cornerstone of diagnosis. Treatment of choice is Albendazole and outcome is generally good.

Characterization and clinical application of human CD34+ stem/progenitor cell populations mobilized into the blood by granulocyte colony-stimulating factor.

A phase I study was performed to determine the safety and tolerability of injecting autologous CD34(+) cells into five patients with liver insufficiency. The study was based on the hypothesis that the CD34(+) cell population in granulocyte colony-stimulating factor (G-CSF)-mobilized blood contains a subpopulation of cells with the potential for regenerating damaged tissue. We separated a candidate CD34(+) stem cell population from the majority of the CD34(+) cells (99%) by adherence to tissue culture plastic. The adherent and nonadherent CD34(+) cells were distinct in morphology, immunophenotype, and gene expression profile. Reverse transcription-polymerase chain reaction-based gene expression analysis indicated that the adherent CD34(+) cells had the potential to express determinants consistent with liver, pancreas, heart, muscle, and nerve cell differentiation as well as hematopoiesis. Overall, the characteristics of the adherent CD34(+) cells identify them as a separate putative stem/progenitor cell population. In culture, they produced a population of cells exhibiting diverse morphologies and expressing genes corresponding to multiple tissue types. Encouraged by this evidence that the CD34(+) cell population contains cells with the potential to form hepatocyte-like cells, we gave G-CSF to five patients with liver insufficiency to mobilize their stem cells for collection by leukapheresis. Between 1 x 10(6) and 2 x 10(8) CD34(+) cells were injected into the portal vein (three patients) or hepatic artery (two patients). No complications or specific side effects related to the procedure were observed. Three of the five patients showed improvement in serum bilirubin and four of five in serum albumin. These observations warrant further clinical trials.

Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice.

Schistosomiasis mansoni, a tropical helminthic disease, is caused by disseminated worm eggs that induce CD4(+) T-cell mediated granulomatous inflammation and fibrosis. T suppressor cell activity has been proposed as one of the mechanisms active in the down-modulation of the murine disease during the chronic stage (16-20 weeks of the infection). In recent years a new category of the CD4(+) CD25(+) T regulatory (Treg) lymphocyte has been identified that maintains immune tolerance to self, and also functions in the regulation of parasite-induced immunopathology. The Foxp3 gene which encodes the transcription factor Scurfin was found to be expressed by and required for the generation of CD4(+) CD25(+) T reg. At 8 weeks of the infection Foxp3 gene expression of splenocytes was similar to that of naive mice, but increased fourfold by 16 weeks. In contrast, granulomatous livers at 8 and 16 weeks showed 10- and 30-fold increases, respectively, in gene expression compared with normal liver. The percentage of granuloma CD4(+) CD25(+) T cells rose from 12% at 8 weeks to 88% at 16 weeks of the infection. Foxp3 expression was 3.5-fold higher in the CD4(+) CD25(+) versus the CD4(+) CD25(-) T cells in the 8 week infection granulomas. As a novel observation neuropilin-1 membrane expression, a recently identified marker for Treg, was correlated with Foxp3 expression in the granuloma CD4(+) CD25(+) but not the CD25(-) cells. Co-incubation with polyclonal stimulation of CD4(+) CD25(+) splenic cells with CD4(+) CD25(-) cells suppressed proliferation of the latter. Retroviral transfer of the Foxp3 gene at the onset of granuloma formation enhanced fourfold Foxp3 expression in the granuloma CD4(+) CD25(+) T cells and strongly suppressed full granuloma development. Gene transfer also significantly enhanced transforming growth factor-beta, interferon-gamma and interleukin-4 but not interleukin-10 expression. It is concluded, that CD4(+) CD25(+), Foxp3(+) Treg cells also regulate schistosome egg-induced immunopathology.

Hepatosplenic schistosomiasis: a review.

BACKGROUND: Schistosomiasis is a granulomatous disease that is caused by infection with schistosomes. It is a major health threat in tropical and subtropical countries. Due to increased movement, all residents of the universe are at risk of contracting this infection. The infection goes through several stages, but the most life-threatening form and leading cause of mortality is hepatosplenic schistosomiasis (HSS). It is a chronic complication, which develops as a consequence of inflammatory response. This complication has not been adequately addressed or attended the and as a consequence most of patients presenting with this complication in our settings die. OBJECTIVES: To review literature on hepatosplenic schistosomiasis, to give the state-of-the-art management of HSS, to give our own experience on management of this complication and hence impart knowledge to medical personnel on HSS. DATA SOURCE: Literature is from Medline database and experience from gastroenterology clinics. Our own experience has been blended on top. STUDY SELECTION AND DATA EXTRACTION: We have selected material, which have been verified and can be applicable in resource poor-countries, where this problem is a major health threat. DATA SYNTHESIS: Based on published studies and meta-analyses and our own experience we have been able to draw conclusions on the current understanding of the subject. CONCLUSION: Hepatosplenic schistosomiasis is a deadly complication and occurs mainly in poor countries. Regular reviews and updates of our knowledge is important to enable stakeholders of health sector understand the problem and develop strategies on its management.

[Prevention and treatment of opisthorchiasis of the liver]. / Profilaktika i lechenie oslozhnenii opistorkhoza pecheni.

Rare cases of lethal outcomes after surgical operations on the liver were analyzed which were caused by invasion of helminth Opisthorchis felineus. It was shown that prolonged and massive invasion, in the absence of specific treatment, can result in failure of the compensatory potencies of the liver. It occurs mainly due to activation of the pathogenic flora in the bile tree against the background of the intraductal hypertension characteristic of opisthorchiasis. Destructive purulent cholangitis, cholangitic abscesses in the liver and suppuration of opisthorchiasis cysts can develop. The direct cause of death was progressing hepatic insufficiency. The postoperative lethality among patients with opisthorchiasis cysts of the liver was 5.7%, with liver abscesses--12.5%. The external drainage of the biliary tree in patients with this pathology and intraportal infusions reduce lethality and the number of specific postoperative complications.

Intrasplenic transplantation of IL-18 gene-modified hepatocytes: an effective approach to reverse hepatic fibrosis in schistosomiasis through induction of dominant Th1 response.

Hepatic fibrosis is a common outcome of chronic liver diseases. In schistosomiasis, chronic parasite egg-induced granuloma formation can lead to fibrosis, which is immunologically characterized by the dominant Th2 response. Recently, it has been shown that gene therapy is an attractive approach for the treatment of hepatic fibrosis. To investigate the antifibrotic effects of IL-18 gene transfer, a normal murine liver cell line BNL.CL2 was transfected with recombinant adenovirus encoding mouse IL-18, and then intrasplenically transplanted into mice infected with Schistosoma japonicum (S. japonicum). Our data show that IL-18 gene-modified hepatocytes intrasplenically transplanted into mice can effectively express IL-18 in the liver and in peripheral blood. Intrasplenic transplantation of IL-18 gene-modified hepatocytes into S. japonicum-infected mice could result in a significantly increased IFN-gamma and IL-2 but decreased IL-4 and IL-10 concentration both in the liver and in the serum, suggesting that the dominant Th2 response in mice with schistosomiasis could be reversed by this intervention. Consistent with the changes in Th1 and Th2 cytokine production, mice intrasplenically transplanted with IL-18 gene-modified hepatocytes developed much less hepatic fibrosis at 20 weeks after infection, which was evaluated by liver content of hydroxyproline, collagens, and hepatic mRNA expression of procollagens. These data indicate that intrasplenic transplantation of IL-18 gene-modified hepatocytes can be a candidate for therapeutic intervention in hepatic fibrosis through induction of a dominant Th1 response.

Hepatic schistosomiasis.

Schistosomiasis is a major, worldwide cause of morbidity and mortality. Disease from the organism Schistosoma mansoni results from egg deposition in the liver, intestines, and other organs and is associated with an intense, granulomatous response from the human host. Clinical manifestations range from mild to severe intestinal forms, and hepatosplenic schistosomiasis, which is associated with hepatic fibrosis, portal hypertension, esophageal varices, and splenomegaly. This article presents information about the epidemiology, immunopathogenesis and clinical aspects of the disease, the relationship between hepatic schistosomiasis and viral infections, diagnosis, therapy, and control strategies for schistosomiasis.

Dynamic analysis of T-lymphocyte function in relation to hepatopathologic changes and effect of interleukin-12 treatment in mice infected with Schistosoma japonicum.

We analyzed the dynamics of splenic T-lymphocyte function in relation to hepatopathologic changes in C3H/Hc mice, experimentally infected with Schistosoma japonicum. Vigorous granuloma formation was observed at 7 wk postinfection. At 10 wk postinfection, granuloma formation entered into the down-modulation stage, as represented by the diminished granuloma size. The Th2 response was activated when eggs appeared in the liver, whereas Th1 responses were depressed and the proliferation of T lymphocytes was decreased. The level of IgG antibodies to the worm and egg antigens rose continually after infection. Interleukin-12 treatment of infected mice inhibited Th2 responses and T-cell proliferation, decreased granuloma formation and fibrosis, but had no effect on the fecundity of the worms. These data suggest that egg deposition is the major factor driving Th2 responses, depressing Th1 cytokine expression as well as T-cell proliferation in S. japonicum-infected mice.

[Sclerotherapy of single non-parasitic liver cyst]. / Leczenie obliteracyjne pojedynczych niepasozytniczych torbieli watroby.

Single, non-parasitic liver cysts, usually asymptomatic, accidental finding during ultrasound examination require treatment only if they attain larger diameter and upper right quadrant symptoms could not be explained by other pathology. Treatment options include surgical enucleation, open or laparoscopic unroofing or percutaneous emptying usually associated with injection of sclerotising agent. From May 1995 to June 1997 10 patients with single, symptomatic, non-parasitic cysts of the liver were treated at the 2nd Department of General Surgery, Collegium Medicum of Jagiellonian University. Ultrasound and gastroscopy excluded other pathology of upper GI tract that might be responsible for the symptoms. Under ultrasound guidance samples of cysts content were collected for cytology, bilirubin concentration and bacteriology. Injection of the contrast medium revealed no contact of the cyst's cavity with the biliary tree. 5 patients were excluded from the protocol due to leakage of contrast in to fee peritoneal cavity. Other 5 were submitted to sclerotherapy by injection of 95% ethanol after introduction of fine drain into the cyst's cavity under ultrasound guidance; in two patients procedure was performed once, in two twice and in one tree times. In 4 patients complete or nearly complete resolution of symptoms was achieved, in one with big cyst treatment failed. We observed no complication. Owing to satisfying results we may conclude that this minimally invasive method might be attempted before more aggressive treatment would be employed.

Distribution of hepatic glycosaminoglycans during acute schistosomiasis: modulation by IFN gamma treatment.

An important pathological outcome of schistosomiasis is hepatic fibrosis, with a significant deposit of collagens and proteoglycans. In this study, hepatic and granuloma-associated glycosaminoglycans (GAGs) were analyzed both quantitatively and qualitatively at the acute stage of murine infection with Schistosoma mansoni. The effects of IFN gamma, which has been successfully used for reducing collagen deposition in the liver during schistosomiasis, were also analyzed in granulomas and the surrounding liver parenchyma. Acute schistosomiasis resulted in a 4.4-fold increase in total hepatic GAG content, from which granulomatous GAGs--mainly chondroitin sulfates A/C and B--represented only one sixth of total GAGs amount. Therefore, the increase was found predominantly in the parenchyma. In this compartment, qualitative changes were also induced with a marked increase in the proportion of chondroitin sulfates A/C balanced by a decrease in the proportion of heparan sulfate and dermatan sulfate. IFN gamma reduced parenchymal GAG content by 47%. Qualitatively, the cytokine increased the proportion of heparan sulfate and reduced the quantity of chondroitin sulfates A/C by half in this compartment. By contrast, IFN gamma had neither quantitative nor qualitative effect on fibroinflammatory granulomas. In these structures, the absence of heparan sulfate--which is suspected to mediate IFN gamma activity--might explain these observations.

Suppression of immunopathology in schistosomiasis by interleukin-2-targeted fusion toxin, DAB389IL-2. I. Studies of in vitro and in vivo efficacy.

Schistosomiasis causes pathology in an estimated 200 million individuals. Clinical disease is caused by a complex immunopathologic response to the parasite ova, which are deposited in the host tissues. This immunopathologic response is caused by T lymphocytes which express the high-affinity IL-2 receptor (IL-2R). DAB389IL-2 is a diphtheria toxin-IL-2 fusion toxin protein which functionally inactivates or kills cells which bear the high-affinity IL-2R. DAB389IL-2 has been used in man to suppress IL-2R-dependent immune reactivity. Therefore, we reasoned that DAB389IL-2 might suppress immunopathology in schistosomiasis. In these studies we assessed the in vitro and in vivo effects of DAB389IL-2 on the development of immunopathology in murine schistosomiasis. DAB389IL-2 suppressed IL-2, lectin mitogen (Con A), and soluble Schistosoma mansoni egg antigen-induced lymphocyte proliferation and in vitro granuloma formation. In addition, DA-B389IL-2 suppressed in vitro IL-2R expression. DA-B389IL-2 also suppressed the development of granulomas and collagen deposition in vivo in the livers of infected animals. Therefore, DAB389IL-2 may have potential for the targeted reduction of immunopathology due to schistosomiasis in man.

Schistosomiasis as an important determining factor for the response of Egyptian patients with chronic hepatitis C to therapy with recombinant human alpha-2 interferon.

The aim of the present study was to compare the response to recombinant human alpha-2 interferon therapy in 2 groups of Egyptian patients having chronic hepatitis C with or without associated schistosomiasis. Group 1 included 36 patients with associated intestinal schistosomiasis, and group 2 included 24 patients without schistosomiasis. All patients had abnormal serum aminotransferase levels and were negative for hepatitis B surface antigen and anti-hepatitis core antibody, but positive for hepatitis C virus antibody in serum. All patients received interferon at a dose of 3 million units subcutaneously 3 times a week for 6 months and were followed up clinically, biochemically and haematologically during this treatment period and for 6 months thereafter. A second liver biopsy was obtained from every patient after the completion of interferon therapy. Both the percentage of complete response with return to normal of alanine aminotransferase levels during therapy and the overall response rate at 6 months (when patients with a partial response were also included as responders) were significantly lower (P < 0.001) in group 1 (14% and 33% respectively) than in group 2 (63% and 71% respectively). The liver histology also improved significantly in group 2 (46%) compared with group 1 (14%) after completion of therapy (P < 0.05). On the other hand the overall relapse rate in responders, by 6 months after cessation of therapy, was significantly higher (P < 0.05) in group 1 (92%) than in group 2 (59%). These results show that the presence of associated schistosomiasis has to be considered as an important factor in determining the response of Egyptian patients with chronic hepatitis C to therapy with interferon.

Tratamento cirurgico da hipertensao portal na esquistossomose: estado atual da questao / Surgery treatment of the portal hypertension in mansonic schistosomiasis

A esquistossomose hepatesplenica e uma das principais causas de hipertensao portal no Brasil, estimando-se a existencia de cerca de 1 milhao de pessoas com esta forma de doenca em nosso pais. A hemorragia por varizes gastresofagianas e a principal manifestacao da doenca e a indicacao do tratamento. A preservacao da funcao hepatica e a ineficacia do tratamento endoscopico justificam a opcao pelo tratamento cirurgico. Estudo prospectivo randomizado realizado em nosso Grupo levou a escolha da desconexao azigo-portal associada a esplenectomia como a opcao preferencial no tratamento da hipertensao portal na esquistossomose mansonica