Long-term outcome after liver transplantation for hepatic schistosomiasis: a single-center experience over 15 years.

Our objective was to study the long-term outcomes of patients who had undergone liver transplantation because of schistosomiasis at our institute over the last 15 years. Four hundred forty-one patients underwent liver transplantation at our institute, and 14 did so for schistosomiasis. The survival of patients who underwent transplantation for schistosomiasis was compared with that of patients who underwent transplantation for other liver diseases. Survival curves were drawn via the Kaplan-Meier method and were compared with the log-rank test. P < 0.05 was considered significant. All 14 patients were male, and the average age was 56.8 ± 8.4 years. The average Model for End-Stage Liver Disease score was 18.2 ± 5.6, and the average Child-Pugh score was 10.6 ± 1.2. All patients had splenomegaly; pretransplant variceal bleeding occurred in 7 patients (50%), and portal vein thrombosis was diagnosed in 5 patients (36%). Patient survival was 75% 1 year after transplantation and 75% at the end of follow-up because no patients were lost after the first year. Patients who underwent transplantation for other causes achieved survival rates of 86% and 76% 1 and 10 years after transplantation, respectively. There was no significant survival difference between the 2 groups (P = 0.66). All patients who survived the early posttransplant period had functioning liver grafts with no reported diagnoses of schistosomiasis in the new grafts. In conclusion, liver transplantation for patients with schistosomiasis has a favorable outcome with no risk of reactivation.

Gastrointestinal nematode infection exacerbates malaria-induced liver pathology.

Mixed parasite infections are common in many parts of the world, but little is known of the effects of concomitant parasite infections on the immune response or severity of clinical disease. We have used the nonlethal malaria infection model of Plasmodium chabaudi AS in combination with the gastrointestinal nematode Heligmosomoides bakeri polygyrus to investigate the impact of nematode infections on malarial morbidity and antimalarial immunity. The data demonstrate that wild-type C57BL/6 mice coinfected with both parasites simultaneously exhibit a striking increase in mortality, while mice deficient in IFN-gamma or IL-23 survive coinfection. The increase in mortality in wild-type mice was associated with severe liver pathology characterized by extensive coagulative necrosis and an increase in hepatic IFN-gamma, IL-17, and IL-22 mRNA expression. This is the first demonstration of increased malaria-associated pathology associated with a switch toward a proinflammatory environment, involving not only IFN-gamma but also the IL-17/IL-23 axis, as a result of coinfection with a gastrointestinal helminth.

Liver morbidity due to Schistosoma mekongi in Cambodia after seven rounds of mass drug administration.

Severe liver disease due to Schistosoma mekongi was frequent in northern Cambodia. Between 1995 and 2002, seven rounds of mass chemotherapy (praziquantel) reduced infection from 50% to below 3%. In 2002, we assessed hepatosplenic morbidity by historical, clinical and ultrasonographic investigations in adults (older than 14 years) from endemic (n=342) and non-endemic (n=103) areas (Kratie province). Clinical hepatomegaly (25 vs. 0%), splenomegaly (55 vs. 0%), reported blood in stool (41 vs. 20%) and abdominal pain (78 vs. 57%) were significantly higher in the endemic area. In this area, significantly more subjects reported a family history of death due to schistosomiasis (12 vs. 0%); 63% (vs. 0%) reported having at least three treatments of praziquantel in previous years; and only 11% (vs. 99%) had normal liver ultrasonographic examination. Periportal fibrosis with portal hypertension was diagnosed in 46% (vs. 0%) of people in this area; 18% (vs. 0%) and 5% (vs. 0%) of portal hypertension was classified as moderate and severe, respectively. People aged between 24 and 35 years were mostly affected. There was no gender difference. The pathology in the endemic district is most probably residual morbidity of S. mekongi infections. Contributions of co-infections (hepatitis) cannot be excluded. Careful monitoring of the affected communities is required.

Parasite-associated morbidity: liver fluke infection and bile duct cancer in northeast Thailand.

Infection with the liver fluke, Opisthorchis viverrini, remains a major public health problem in Northeast Thailand, where approximately one-third of the population is infected. The northeast region is largely populated by Laos-descendent Thais who enjoy eating raw fish, which harbour the infective stage of the fluke. The parasite has maintained its presence in the population despite the widespread use of praziquantel and dissemination of health education material throughout the region by vigorous government-sponsored programs in recent years. The most severe consequence of liver fluke infection is cholangiocarcinoma, i.e. cancer of the bile duct epithelium. Although mortality due to the parasites alone appears to be uncommon, cholangiocarcinoma arising as a result of infection is one of the leading causes of death in the region. This paper reviews the pathogenesis of infection and the geographic, hospital-based and community studies which demonstrate the close relationship between infection and cancer. In addition, data from the Cancer Registry of Khon Kaen, Northeast Thailand and population-based studies using ultrasonography to visualize early tumours which illuminate the very high frequency of the cancer among heavily infected individuals and communities are discussed. Finally, the paper will close with a brief commentary on the prospects for control of the parasite and its likely impact on the frequency of cancer given the current epidemiological situation of liver fluke infection.

Hepatopathy in complicated falciparum malaria: report from eastern India.

A prospective study done in 216 children with complicated falciparum malaria showed hepatopathy in 33.3% of cases with a higher incidence in children aged above five years. Bilirubin and alanine aminotransferase were moderately raised in most cases. No significant association with other common complications and no higher risk of mortality was observed.

Long-term follow-up after liver transplantation in Egyptians transplanted abroad.

OBJECTIVE: To study the long-term outcome after liver transplantation (LT) in Egyptian patients who underwent LT outside Egypt. METHODS: Between May 1993 and February 2004, over 150 Egyptians underwent LT outside Egypt. Data of 67 recipients were collected in Egypt through personal communications with the Overseas Liver Transplant Centers and through the records of the Egyptian Liver Transplant Association. RESULTS: Most patients underwent LT in Europe (73.1%), few in the United State of America (17.9%) and in Japan (9%). Sixty-one patients underwent cadaveric LT and the remaining 6 patients underwent living related liver transplantation (LDLT). The male to female ratio was 58:9. Median age was 45 (3-63 years). Hepatitis C virus (HCV) cirrhosis whether alone or mixed with schistosomiasis was the main indication for LT. Out of those 67 recipients, 52 (77.6%) survived after a median follow-up period of 4.6 years (rang 1-10.5 years). Deaths were due to primary non-function in 3 patients, postoperative bleeding in one patient, recurrent hepatitis C virus (HCV) in 10 patients, and chronic rejection in one patient. CONCLUSION: Egyptians underwent LT abroad showed a good long-term outcome. Due to the high prevalence of HCV, we expect a growing need for LT in Egypt. Although LDLT has been introduced recently in Egypt, cadaveric liver donation is still not legalized by the government. Efforts should be directed to expanding LDLT, legalizing cadaveric LT and also to the prevention and control of HCV infection in Egypt in order to avoid its devastating effect on the society as well as its enormous negative impact on Egypt's economy and future development.

[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.

Hepatic changes in fatal malaria: an emerging problem.

Over the last few years there has been a rise in the incidence of fatal malaria in urban areas of India, and this worrying trend is a major cause of concern for the national health authorities. The spectrum of histopathological changes that occur in the livers of Indian subjects with fatal malaria has recently been investigated, in a retrospective autopsy-based study. This investigation involved the 151 fatal cases of malaria seen at a tertiary-care hospital in Mumbai between January 2001 and December 2007. The diagnosis of malaria was made on the basis of the examination of a smear of peripheral blood (81 cases) or a histopathological examination (70 cases). For each subject of the present study, at least two blocks were prepared, using routine histological methods, from a liver sample collected at autopsy. The sections produced from these blocks were stained with various compounds, including Prussian Blue (which was used to distinguish malarial pigment from non-malarial). The pattern of liver necrosis seen in the malaria cases was compared with that seen in 11 cases of acute viral hepatitis, and with the liver histology seen in 50 control subjects, who had died of causes other than malaria or liver disease. The most common clinical presentation of the subjects who died of malaria was fever (85%), followed by jaundice (68%). The presence of jaundice often led to an initial misdiagnosis of acute viral hepatitis. In the livers of the fatal malaria cases, Kupffer-cell hyperplasia and the retention of haemozoin pigment were the two most common histological features. Necrosis was seen in 63 (41%) of these cases, with predominant centrilobular haemorrhagic necrosis in 16 (10%). The inflammation in the sections of liver from the malaria cases with hepatic necrosis was sparse compared with that in the corresponding sections from patients with acute viral hepatitis, although mixed portal inflammation was frequently noted in the malaria cases. None of the liver sections from the 50 control subjects showed evidence of pigment, necrosis or any other pathology. In conclusion, jaundice was one of the commonest clinical presentations of the fatal cases of malaria and could mimic viral hepatitis on clinical examination. The characteristic histopathological features of the livers of those with fatal malaria were Kupffer-cell hyperplasia, malarial pigment within the Kupffer cells, and liver-cell necrosis, with portal inflammation, steatosis and cholestasis also observed.

NK cell responses to Plasmodium infection and control of intrahepatic parasite development.

Various components of innate and adaptive immunity contribute to host defenses against Plasmodium infection. We investigated the contribution of NK cells to the immune response to primary infection with Plasmodium yoelii sporozoites in C57BL/6 mice. We found that hepatic and splenic NK cells were activated during infection and displayed different phenotypic and functional properties. The number of hepatic NK cells increased whereas the number of splenic NK cells decreased. Expression of the Ly49 repertoire was modified in the spleen but not in the liver. Splenic and hepatic NK cells have a different inflammatory cytokines profile production. In addition, liver NK cells were cytotoxic to YAC-1 cells and P. yoelii liver stages in vitro but not to erythrocytic stages. No such activity was observed with splenic NK cells from infected mice. These in vitro results were confirmed by the in vivo observation that Rag2(-/-) mice were more resistant to sporozoite infection than Rag2(-/-) gamma c(-/-) mice, whereas survival rates were similar for the two strains following blood-stage infection. Thus, NK cells are involved in early immune mechanisms controlling Plasmodium infection, mostly at the pre-erythrocytic stage.

Survival and causes of death among patients with Yersinia enterocolitica infection. A Norwegian 10-year follow-up study on 458 hospitalized patients.

The aim of the present study was to elucidate the possible influence of the Yersinia enterocolitica infection on long-time survival, and to describe clinical conditions associated with a fatal issue. During the period 1974-83, Y. enterocolitica infection was diagnosed in 458 hospitalized patients by antibody response or isolation of the microorganism. The patients were followed for 4-14 years (until 1987). The observed cumulative survival rates for female patients, and for the whole material, deviated significantly from the expected rates for 10 and 8 years. Two patients died in association with the acute infection, and 2 died from malignant mesothelioma during the first year of observation. 4/42 other patients died during the follow-up period from chronic multiorgan disease, 9 from malignant disease, and 2 died from hematological disorders. A very high mortality (10/22) was observed among patients who had developed chronic liver disease subsequently to the infection. We conclude that chronic conditions associated with the Y. enterocolitica infection may exert a substantial impact on long-time survival.

Cholangiocarcinoma in patients with opisthorchiasis.

Cholangiocarcinoma is very common in areas endemic for the liver fluke Opisthorchis viverrini. Survival after surgical treatment of cholangiocarcinoma associated with opisthorchiasis was studied prospectively in 30 patients, all of whom resided in an endemic area. The median age was 52 (range 32-69) years and twenty-five patients were men. Seven patients had their tumours removed, four with concomitant liver resection. Twenty-two patients underwent palliative biliary bypass procedures to a segmental duct. Laparotomy with biopsy of metastatic lesions was undertaken in one patient with multiple lymph node metastases and peritoneal seedlings. No patient received postoperative chemotherapy or radiation treatment. Patients were followed for 2 years or until death. The 1-year survival rate after tumour resection was 86 per cent and the 2-year survival rate 43 per cent. After palliative procedures the 1-year survival rate was 26 per cent; no patient reached 2 years and the median survival time was 8 months. Survival after surgical treatment of cholangiocarcinoma in patients with opisthorchiasis is broadly similar to that reported for cholangiocarcinoma without liver fluke infestation.

Toxoplasma gondii and Schistosoma mansoni synergize to promote hepatocyte dysfunction associated with high levels of plasma TNF-alpha and early death in C57BL/6 mice.

To address the question of how the murine host responds to a prototypic type 1 cytokine inducer while concurrently undergoing a helminth-induced type 2 cytokine response, C57BL/6 strain animals with patent schistosomiasis mansoni were orally infected with the cystogenic Toxoplasma gondii strain ME49. Schistosoma mansoni infection resulted in a significantly higher mortality rate when mice were subsequently orally infected with ME49, and these animals displayed a defective IFN-gamma and NO response relative to animals infected with T. gondii alone. Plasma levels of TNF-alpha and aspartate transaminase in double-infected mice were greatly elevated relative to mice infected with either parasite alone. Consistent with the latter observation, these animals exhibited severe liver pathology, with regions of coagulative necrosis and hepatocyte vacuolization unapparent in mice carrying either infection alone. Interestingly, mean egg granuloma size was approximately 50% of that in mice with S. mansoni infection alone. The exacerbated liver pathology in coinfected mice did not appear to be a result of uncontrolled tachyzoite replication, because both parasite-specific RT-PCR analysis and immunohistochemical staining demonstrated a low number of tachyzoites in the liver. We hypothesize that mortality in these animals results from the high level of systemic TNF-alpha, which mediates a severe liver pathology culminating in death of the animal.

Should both schistosomal and nonschistosomal variceal bleeders be disconnected?

Splenopancreatic disconnection (SPD) was conceived and implemented as a technical addition to distal splenorenal shunt (DSRS) to maintain its selectivity and preserve portal perfusion. The proposed hemodynamic and metabolic stability of hepatocytes after DSRS-SPD should improve survival. In this nonrandomized study, 145 consecutive (Child A/B) variceal bleeders were electively subjected to selective shunt with DSRS in 93 and DSRS-SPD in 52 patients. The 2 groups were similar before surgery with a mean follow up of 24 +/- 12 (DSRS) and 27 +/- 14 (DSRS-SPD) months. DSRS-SPD had an operative mortality of 3.8%. Postoperative pancreatitis occurred in 7.7% after DSRS-SPD and 3.2% after DSRS alone, with schistosomal hepatic fibrosis representing 86% of morbid cases. Shunt patency was high and recurrent variceal hemorrhage was low in both groups. Clinical encephalopathy was significantly reduced after DSRS-SPD (p less than 0.05). The addition of SPD significantly reduced both the incidence of chronic hyperbilirubinemia in the schistosomal patients (p less than 0.05) and the difference between the changes in total serum bilirubin in all patients (p = 0.001). Portal perfusion was preserved after DSRS-SPD in all of the angiographically-studied patients. The overall survival was 84% after DSRS and 88% after DSRS-SPD. The schistosomal patients showed an incidence of 95% and 96% survival after DSRS and DSRS-SPD, respectively. DSRS-SPD was able to improve survival (92%) better than DSRS (77%) among well-matched nonschistosomal patients. These data show: (1) DSRS-SPD still has low operative mortality and a high patency rate with a low incidence of recurrent variceal hemorrhage, (2) DSRS-SPD maintains portal perfusion, achieves better survival, and reduces the incidence of encephalopathy, especially in patients with nonalcoholic cirrhosis and mixed liver disease, (3) in the schistosomal population, DSRS-SPD reduces the incidence of chronic hyperbilirubinemia but increases the risk of postoperative pancreatitis.

Intranasal administration of a Schistosoma mansoni glutathione S-transferase-cholera toxoid conjugate vaccine evokes antiparasitic and antipathological immunity in mice.

Mucosal administration of Ags linked to cholera toxin B subunit (CTB) can induce both strong mucosal secretory IgA immune responses and peripheral T cell hyporeactivity. In this study, intranasal (i.n. ) administration of CTB-conjugated Schistosoma mansoni 28-kDa GST (CTB-Sm28GST) was found to protect infected animals from schistosomiasis, especially from immunopathological complications associated with chronic inflammation. Worm burden and liver egg counts were reduced in infected animals treated with the CTB-Sm28GST conjugate as compared with mice infected only, or with mice treated with a control (CTB-OVA) conjugate. However, a more striking and consistent effect was that granuloma formations in liver and lungs of mice treated with CTB-Sm28GST were markedly suppressed. Such treatment was associated with reduced systemic delayed-type hypersensitivity and lymphocyte proliferative responses to Sm28GST. Production of IFN-gamma, IL-3, and IL-5 by liver cells was also markedly reduced after i.n. treatment of CTB-Sm28GST, whereas IL-4 production was not impaired. Intranasal treatment of infected mice with CTB-Sm28GST increased IgG1-, IgG2a-, IgA-, and IgE-Ab-forming cell responses in liver in comparison with treatment with CTB-OVA, or free Sm28GST. Most importantly, mucosal treatment with CTB-Sm28GST significantly reduced animal mortality when administered to chronically infected mice. Our results suggest that it may be possible to design a therapeutic vaccine against schistosomiasis that both limits infection and suppresses parasite-induced pathology.