Schistosomal Hepatic Fibrosis Research Articles

Stem cell-derived exosomes as a potential therapy for schistosomal hepatic fibrosis in experimental animals

ABSTRACT Schistosomiasis is a neglected tropical disease. Egg-induced granuloma formation and tissue fibrosis are the main causes of the high morbidity and mortality of schistosomiasis. Mesenchymal stem cells (MSCs)-derived exosomes play an important role with a superior safety profile than MSCs in the treatment of liver fibrosis. Therefore, the aim of this study was to investigate the potential therapeutic effect of MSCs-derived exosomes on schistosomal hepatic fibrosis. Exosomes were isolated from bone marrow MSCs and characterized. A total of 85 mice were divided into four groups: group I (control group), group II (PZQ group) infected and treated with PZQ, group III (EXO group) infected and treated with MSCs-derived exosomes and group IV (PZQ+EXO group) infected and treated with both PZQ and MSCs-derived exosomes. Assessment of treatment efficacy was evaluated by histopathological and immunohistochemical examination of liver sections by proliferating cell nuclear antigen (PCNA) and nuclear factor-κB (NF-κB). The results showed significant reduction of the number and diameter of hepatic granulomas, hepatic fibrosis, upregulation of PCNA expression and reduction of NF-κB expression in EXO and PZQ+EXO groups as compared to other groups at all durations post infection. Additionally, more improvement was observed in PZQ+EXO group. In conclusion, MSCs-derived exosomes are a promising agent for the treatment of schistosomal hepatic fibrosis, and their combination with PZQ shows a synergistic action including antifibrotic and anti-inflammatory effects. However, further studies are required to establish their functional components and their mechanisms of action.

Human umbilical cord blood mesenchymal stem cells as a potential therapy for schistosomal hepatic fibrosis: an experimental study

ABSTRACT The objective of our study was to assess the effect of human umbilical cord blood (HUCB) mesenchymal stem cells (MSCs) transplantation on schistosomal hepatic fibrosis in mice. The study animals were divided into three groups. Group I is a control group, where the mice were infected with Schistosoma mansoni cercariae and remained untreated. The mice of the other two groups were infected and treated with either praziquantel (Group II) or HUCB-MSCs (Group III). Liver function tests, as well as histopathological evaluation of liver fibrosis using hematoxylin and eosin and Masson's trichrome stains, were performed. Additionally, an immunohistochemical study was carried out using anti-glial fibrillary acidic protein (GFAP) in hepatic stellate cells. Compared to the control group, the treated (praziquantel and MSCs) groups showed a substantial improvement, with a significant difference regarding the histopathological evaluation of liver fibrosis in the MSCs-treated group. In conclusion, MSCs could be a promising and efficient cell therapy for liver fibrosis.

Gastric mucosal function in portal hypertensive gastropathy secondary to schistosomal hepatic fibrosis: effect of sclerotherapy

Gastric mucosal function in portal hypertensive gastropathy secondary to schistosomal hepatic fibrosis [SHF] was evaluated. Group I comprised 20 patients with no bleeding;10 had portal hypertensive gastropathy [PHG]. Group II comprised 20 patients with bleeding. Free acidity, total acidity, basal acid output, serum pepsinogen I, gastric mucosal blood flow [GMBF] and gastrin were significantly lower in group II, whereas serum gastrin and somatostatin staining were significantly higher. No histopathological changes were noted between both groups, In conclusion, bleeding caused by SHF results in hypoacidity, hypergastrinaemia and hypopepsinogenaemia. Estimated GMBF distinguishes patients with PHG and those who are bleeders

Dendritic cell subsets and serum interleukin-12 in schistosomal hepatic fibrosis: relation to severity of liver disease and renal injury.

Dendritic cell subsets and serum interleukin-12 in schistosomal hepatic fibrosis: relation to severity of liver disease and renal injury.

Human umbilical cord mononuclear cells could ameliorate schistosomal hepatic fibrosis. An experimental study

Hepatic fibrosis is considered a worldwide public health problem. Liver transplantation is the treatment of choice. Rejection, post-operative complications and unavailability of donors are major obstacles. Recent treatment modalities include cell therapy but more researches are still needed. Human umbilical cord blood is a rich source for mononuclear cells which recently have shown promising anti-fibrotic results. The present study aimed to evaluate the potential effect of human umbilical cord blood mononuclear cells infusion on an experimental model of hepatic fibrosis caused by Schistosoma mansoni. Assessment of liver fibrosis was done by haematoxylin, eosin and Masson's trichrome staining. Homing to injured liver was assessed by staining of human specific nuclear antigen. Liver functions, collagen and hepatic stellate cells staining were done. Our results revealed marked improvement of liver fibrosis raising the possibility for the mononuclear cells clinical use in patients with hepatic fibrosis.

Effectiveness of vinpocetine and isosorbide-5-mononitrate on experimental schistosomiasis mansoni: Biochemical and immunohistochemical study

Schistosomiasis is one of the most important tropical and subtropical devastating diseases, where praziquantel is the sole drug of choice. Praziquantel effectively kills the adult worms, however, drug resistance has been repeatedly reported. Moreover, there is currently no efficient anti-fibrotic therapy available for chronic schistosomiasis. So, novel drugs which exert anti-fibrotic efficacy are urgently needed. This research is complementary to our previous work that evaluated the anti-schistosomal effects of the anti-inflammatory vinpocetine, as well as the vasodilator and the anti-oxidant isosorbide-5-mononitrate. In the present study, we assessed the therapeutic efficacies of drugs in Swiss albino female mice experimentally infected with an Egyptian strain of Schistosoma mansoni, using some biochemical and immunohistochemical parameters. Our results revealed that both vinpocetine and isosorbide-5-mononitrate monotherapy significantly decreased hepatic nuclear factor-kappaB, 10 weeks post infection. The best effects were seen in mice administered praziquantel combined with isosorbide-5-mononitrate, as detected by reduction in hydroxyproline and collagen contents of the liver, and significant increase in the hepatic nitric oxide content. The data provides insight into the potential effects of the assessed drugs with isosorbide-5-mononitrate being more superior to vinpocetine, hence it can be used as novel adjuvant to praziquantel to alleviate schistosomal hepatic fibrosis. However, molecular mechanism/s and clinical trials are worthy to be scrutinized.

The comparative efficacy of renin-angiotensin system blockers in schistosomal hepatic fibrosis

Schistosomiasis mansoni is involved in hepatic fibrogenesis and portal hypertension. Previous studies proved that blockade of some components of the renin-angiotensin system (RAS) reduce liver fibrogenesis. However, the effects of inhibition of early stages of RAS pathway in schistosomal fibrosis have not been studied yet. Thus, the aim of this study was to compare the role of different antihypertensive drugs on hepatic fibrosis in murine schistosomiasis. BALB/c mice (n = 50) weighing 20g were subjected to inoculation of 50 cercariae and submitted to different treatments: aliskiren, 50 mg/kg (n = 10); bradykinin, 2 μg/kg (n = 5); losartan, 10 mg/kg (n = 10); lisinopril 10 mg/kg (n = 5) and control, proportional volume vehicle (n = 5); daily for 14 weeks. Six animals were not subjected to cercariae inoculation or any type of treatment. Ultrasound, histological, immunohistochemical and proteomic analyzes were performed to evaluate markers associated with hepatic fibrogenesis. The hepatic areas stained with Sirius red and thenumber of cells marked by α-SMA in animals treated with aliskiren, bradykinin, lisinopril and losartan were diminished when compared to control group, demonstrating reduced hepatic fibrosis after RAS blockade. These results were reinforced by ultrasonography analysis and protein expression of TGFβ. These findings demonstrated the effect of RAS inhibition on hepatic fibrosis in murine schistosomiasis, with the most evident results being observed in the losartan and aliskiren treated groups. The main mechanisms underlying this process appear to involve anti-fibrogenic activity through the inhibition of collagen and TGFβ synthesis.

Endothelial Injury and Oxidative Stress in Patients with Schistosomal Hepatic Fibrosis: Relation to Renal Dysfunction and Hemodynamics

Background Schistosomiasis mansoni is associated with immune-mediated glomerulopathy; however, the mechanism of renal involvement is not well established. Endothelial injury plays an important role in the pathogenesis of chronic renal diseases and may be related to oxidative stress. The present work was designed to study markers of endothelial injury and oxidative stress in patients with schistosomal hepatic fibrosis (SHF) in relation to renal dysfunction and hemodynamics.Methods Forty-five patients with SHF (15 without albuminuria, 15 with mild/moderate albuminuria, and 15 with severe albuminuria) and 15 healthy subjects were included in the study. Endothelial injury was assessed by plasma von Willibrand factor (vWF) activity and serum angiotensin converting enzyme (ACE) levels. Serum malondialdehyde (MDA) levels and 24-hour urinary levels of leucine aminopeptidase (LAP) were measured as markers for oxidative stress and tubular damage respectively. Renal hemodynamics were assessed using Duplex-Doppler ultrasonography by calculating the diastolic/systolic renal flow velocity ratio (d/s), intrarenal resistive index (RI), and hilar renal blood flow (RBF).ResultsPatients with SHF showed significant increases in plasma vWF activity, serum levels of ACE and MDA, urinary LAP levels and RI and significant decreases in d/s and RBF compared with healthy subjects (P < 0.05). The increase in plasma vWF activity and the changes in renal hemodynamics were positively correlated but were not related to the severity of glomerular injury (P > 0.05). Serum MDA and urinary LAP levels were significantly higher in patients with albuminuria than in patients without albuminuria while serum ACE level was significantly higher in patients with severe albuminuria than in other patients (P < 0.05). There was a significant positive correlation between serum MDA levels and severity of liver disease in patients with SHF (P < 0.05).Conclusion Endothelial injury, possibly due to oxidative stress, may play an important role in the pathogenesis of renal dysfunction and increased renovascular impedence in SHF and in the initiation of schistosomal nephropathy in this disease.Disclosures All authors: No reported disclosures.

Transient elastography (FibroScan) is not useful in the diagnosis of schistosomal hepatic fibrosis

Transient Elastography (TE) is a widely-used noninvasive measure of liver stiffness. This study aimed to evaluate the diagnostic accuracy of TE in the diagnosis of schistosomal hepatic fibrosis (SHF). A total of 30 patients (Mean±SD age 42.1±8.8 years) with pure schistosomiasis were included. Abdominal ultrasound (US) and upper gastrointestinal endoscopy were performed to all patients to assess for signs of portal hypertension and the presence of varices as sequels of SHF. TE (FibroScan) was done to determine liver stiffness. A cutoff value of ≥10.1 Kpa indicates advanced fibrosis (F3-4). Splenomegaly was detected in 27(90 %) patients and was moderate to marked (≥15cm) in 19 (63.3 %). Esophageal and gastric varices were found in 25 (83.3 %) and 4 (13.3 %) cases respectively. TE was successful in all patients, and the mean ± SD liver stiffness was 9.4 ± 5.5 Kpa (Range: 3.5-30 Kpa).F3-4 by FibroScan was detected in 8/25 (32.0 %) and 9/27 (33.3 %) of patients with EV and splenomegaly respectively. Similarly, F3-4 was absent in 4/5(80.0 %) and3/3 (100 %) of those without EV and splenomegaly advanced fibrosis respectively (p=0.71 and p=0.27 respectively). To our knowledge, this study shows for the first time that TE is not useful in diagnosis of SHF and EV in patients with pure schistosomiasis. Whether this is applicable to other cases of prehepatic portal hypertension, such as portal vein thrombosis and congenital hepatic fibrosis, needs further investigation.

Assessment of the nutritional status and serum leptin level of hepatitis C virus-infected Egyptian patients with and without schistosomal hepatic periportal fibrosis

Background Schistosomiasis has been a major public health problem in Egypt. Moreover, Egypt has been widely regarded as having the highest recorded prevalence of hepatitis C virus (HCV) in the world. Malnutrition is prevalent in all forms of liver disease. Objective The aim of the work was to assess the nutritional status of HCV-infected patients with and without schistosomal hepatic periportal fibrosis. Patients and methods This study was carried out on 93 men. A total sample size of 93 patients was taken. The patients were divided into three groups of 31 each: group I included 31 patients having HCV; group II included 31 patients having mixed schistosomal hepatic periportal fibrosis and HCV; and group III included 31 healthy controls. Serum leptin was measured. Abdominal ultrasonography was performed to all participants to detect the degree of fibrosis according to the WHO scoring system. Nutritional assessment was carried out using anthropometric measurements. Body fat content was measured using bioelectrical impedance analysis. Results This study showed that the fat content was higher in group I than in group II and was higher in controls than in patients. Serum leptin level was significantly higher in group II than in group I. Conclusion Affection with HCV and/or schistosomal hepatic periportal fibrosis affects the nutritional status of the individuals affected, with more pronounced nutritional derangement in patients with both diseases.

Expression of heat shock protein 47, transforming growth factor-beta 1, and connective tissue growth factor in liver tissue of patients with Schistosoma japonicum-induced hepatic fibrosis.

SUMMARY To detect the expression of pro-fibrotic molecules, such as heat shock protein 47 (Hsp47), transforming growth factor-beta 1 (TGF-β1) and connective tissue growth factor (CTGF) in liver specimens, and analyse their correlations with the progression of schistosomal hepatic fibrosis, liver biopsy was performed in 42 chronic schistosomiasis (CS) patients, 16 chronic hepatitis B (CHB) patients and five healthy individuals (HI). Immunohistochemistry (IHC) analyses displayed that the expression of Hsp47, TGF-β1 and CTGF was increased in CS and CHB patients compared with HI. Using real-time PCR, the mRNA levels of Hsp47, TGF-β1 and CTGF were higher in CS patients compared with HI. In CS patients, the mRNA levels of these genes were correlated with the stage of fibrosis, and TGF-β1 mRNA expression was associated with the grade of inflammation. Additional analyses indicated that the mRNA levels of Hsp47 and CTGF were highly correlated with liver stiffness value and spleen thickness diameter, both of which represented the severity of fibrosis. In conclusion, the three molecules are involved in the pathogenesis of hepatic fibrosis infected by Schistosoma japonicum. TGF-β1 participates not only in the inflammatory process, but also in the fibrotic process in which Hsp47 and CTGF probably play a key role.

Efficacy of pentoxifylline as an antifibrotic drug in experimental murine schistosomal hepatic fibrosis.

This study evaluated the possible antifibrotic effect of pentoxifylline on experimentally induced schistosomal hepatic fibrosis and its effect on serum leptin and transforming growth factor-β1 levels as possible antifibrotic mechanisms in correlation with the hepatic fibrosis indices. A total of ninety clean laboratories bred, males Swiss, albino mice were included, of which ten mice served as a control non-infected, non-treated group and sacrificed at one time. Eighty mice, each was subcutaneously infected with 50 Schistosoma mansoni cercariae and classified into groups: GI (infected & non-treated), GII (infected & treated with Mirazid), GIII (infected & treated with Pentoxifylline) and GIV (infected & treated with a combination of Mirazid and Pentoxifylline). Each group was further subdivided into 2 subgroups; subgroup 'a' which started treatment at 6th week post-infection (P.I.) and sacrificed at the end of 9th week P.I and subgroup 'b' which started treatment at 14th week P.I and sacrificed at the end of 17th week P.I. The efficacy of the treatment was assessed by histopathological examination of the liver with measurement of granuloma sizes, estimation of hydroxyproline content in the liver, and assessment of serum levels of leptin and transforming growth factor- β1 (TGF-β1).Mirazid (MZD) caused significant reductions in granuloma sizes and hepatic hydroxyproline content and caused non-significant reductions in serum levels of leptinand transforming growth factor- β1 t 9th & 17t hweeks P.II(GIII. Pentoxifylline (PTX) caused significant reductions in granuloma sizes, hepatic hydroxyproline, and serum levels of leptin and transforming growth factor- β1 t the 9"th& 17kt weeks P.II (GIII. While combined therapy of both MZD & PTX in GIIVcaused more reductions in granuloma sizes, hepatic hydroxyproline, and serum levels of leptin and TGF- β1 t the 9th & 17th weeks P.IIwhen compared to the other groups.

Exogenous bone morphogenetic protein-7 reduces hepatic fibrosis inSchistosoma japonicum-infected miceviatransforming growth factor-β/Smad signaling

To investigate the antifibrotic effects of bone morphogenetic protein-7 (BMP-7) on Schistosoma japonicum (S. japonicum)-induced hepatic fibrosis in BALB/C mice. Sixty BALB/C mice were randomly divided into three groups, including a control group (group A, n = 20), model group (group B, n = 20) and BMP-7 treated group (group C, n = 20). The mice in group B and group C were abdominally infected with S. japonicum cercariae to induce a schistosomal hepatic fibrosis model. The mice in group C were administered human recombinant BMP-7. Liver samples were extracted from mice sacrificed at 9 and 15 wk after modeling. Hepatic histopathological changes were assessed using Masson's staining. Transforming growth factor-beta 1 (TGF-β1), alpha-smooth muscle actin (α-SMA), phosphorylated Smad2/3 (pSmad2/3) and Smad7 protein levels and localization were measured by Western blotting and immunohistochemistry, respectively, and their mRNA expressions were detected by reverse transcription-polymerase chain reaction (RT-PCR). The schistosomal hepatic fibrosis mouse model was successfully established, as the livers of mice in group B and group C showed varying degrees of typical schistosomal hepatopathologic changes such as egg granuloma and collagen deposition. The degree of collagen deposition in group C was higher than that in group A (week 9: 22.95 ± 6.66 vs 2.02 ± 0.76; week 15: 12.84 ± 4.36 vs 1.74 ± 0.80; P < 0.05), but significantly lower than that in group B (week 9: 22.95 ± 6.66 vs 34.43 ± 6.96; week 15: 12.84 ± 4.36 vs 18.90 ± 5.07; P < 0.05) at both time points. According to immunohistochemistry data, the expressions of α-SMA, TGF-β1 and pSmad2/3 protein in group C were higher than those in group A (α-SMA: week 9: 21.24 ± 5.73 vs 0.33 ± 0.20; week 15: 12.42 ± 4.88 vs 0.34 ± 0.27; TGF-β1: week 9: 37.00 ± 13.74 vs 3.73 ± 2.14; week 15: 16.71 ± 9.80 vs 3.08 ± 2.35; pSmad2/3: week 9: 12.92 ± 4.81 vs 0.83 ± 0.48; week 15: 7.87 ± 4.09 vs 0.90 ± 0.45; P < 0.05), but significantly lower than those in group B (α-SMA: week 9: 21.24 ± 5.73 vs 34.39 ± 5.74; week 15: 12.42 ± 4.88 vs 25.90 ± 7.01; TGF-β1: week 9: 37.00 ± 13.74 vs 55.66 ± 14.88; week 15: 16.71 ± 9.80 vs 37.10 ± 12.51; pSmad2/3: week 9: 12.92 ± 4.81 vs 19.41 ± 6.87; week 15: 7.87 ± 4.09 vs 13.00 ± 4.98; P < 0.05) at both time points; the expression of Smad7 protein in group B was higher than that in group A and group C at week 9 (8.46 ± 3.95 vs 1.00 ± 0.40 and 8.46 ± 3.95 vs 0.77 ± 0.42; P < 0.05), while there were no differences in Smad7 expression between the three groups at week 15 (1.09 ± 0.38 vs 0.97 ± 0.42 vs 0.89 ± 0.39; P > 0.05). Although minor discrepancies were observed, the results of RT-PCR and Western blotting were mainly consistent with the immunohistochemical results. Exogenous BMP-7 significantly decreased the degree of hepatic fibrosis in both the acute and chronic stages of hepato-schistosomiasis, and the regulatory mechanism may involve the TGF-β/Smad signaling pathway.

Laparoendoscopic Transgastric Histoacryl Injection of Gastric Varices: A New Surgical Approach

Gastric varices (GVs) are a common finding in Egyptian patients with portal hypertension due to cirrhosis or schistosomal hepatic fibrosis. These patients present with an acute attack or history of hematemesis. Endoscopic histoacryl injection is the standard treatment in Egypt; however, because of technical difficulties it is possible to inject only a little amount of this material, as it may endanger the channels of the flexible endoscope. We thought of a new surgical laparoendoscopic technique to obviate the need for repeated endoscopies and complete obliteration of GVs. This study was conducted on 20 patients with portal hypertension and GVs. After the patient was placed under general anesthesia, a small gastrostomy was done in the anterior gastric wall through which a 10-mm trocar was inserted for the laparoscopic camera. Injection of GVs was done via a spinal needle or a central venous line needle inserted directly. Injection of an adequate amount of histoacryl was done under direct vision. This study was conducted from July 2009 to August 2011 on 20 patients with GVs. The age range was from 22 to 56 years, with a mean age of 39.8±7.85 years. There were 14 men (70%) and 6 women (30%). Fourteen patients (70%) showed complete obliteration of GVs after one session of treatment, whereas 6 patients (30%) had unsatisfactory results and were subjected to another session. GVs were completely obliterated after the second session in 4 patients. Two cases of recurrence of GVs were operated on. This new technique enabled us to inject GVs with a suitable amount of glue material under direct vision without harming the endoscope. Use of this procedure is recommended in patients fit for surgery and those who had failed endoscopic injection sclerotherapy.

PTU-037 Endothelial injury and oxidative stress in patients with schistosomal hepatic fibrosis: relation to renal dysfunction and haemodynamics

IntroductionEndothelial injury plays an important role in the pathogenesis of chronic renal diseases and may be related to oxidative stress. The present work was designed to study markers of endothelial...

Potential antifibrotic effects of AT1 receptor antagonist, losartan, and/or praziquantel on acute and chronic experimental liver fibrosis induced by Schistosoma mansoni

1. This study investigates the potential antifibrotic effect of losartan, AT-1 receptor antagonist, and/or praziquantel (PZQ) on acute and chronic hepatic fibrosis induced by Schistosoma mansoni (S. mansoni). 2. Schistosoma mansoni-infected mice were in two batches (I & II), each in four groups: (i) Infected untreated; (ii) treated with losartan, starting from the 4th or 12th weeks post-infection (PI); (iii) treated with PZQ in the 7th week PI; and (iv) treated with losartan, as group (ii) plus PZQ as group (iii). Comparable groups of uninfected mice were run in parallel with infected groups. Mice of batches I and II were killed 10 and 18 weeks PI, respectively. Hepatic content of hydroxyproline (HYP), serum levels and tissue expression of matrix metalloproteinase-2 (MMP-2), and transforming growth factor-β1 (TGF-β1) were determined. Parasitological, biochemical and histological parameters, which reflect disease severity and morbidity, were examined. 3. Losartan alone caused a considerable decrease in worm burden, hepatic tissue egg load with an increase in percentage of dead eggs, modulation of granuloma size and regression of inflammatory reactions, which was less obvious in the chronic stage. The best results were obtained when losartan was co-administered with PZQ, especially in the acute stage. This was revealed by a remarkable reduction in serum levels and tissue expression of MMP-2, TGF-β1 and HYP content, accompanied by conservation of hepatic reduced glutathione (GSH) versus the PZQ-treated group. 4. In conclusion, losartan has a promising antifibrotic action and could be introduced as a therapeutic tool with PZQ especially in acute schistosomal hepatic fibrosis.

PP-108 Prevalence of transfusion-transmitted virus in patients with viral liver disease

Introduction: Primary liver cancer accounts for only 1 2% of malignant tumors found at autopsy in western countries. However, in some parts of Africa and Asia it may account for up to 20 30% of all types of malignancy. The high frequency of HBsAg positivity in individuals with Hepatocellular Carcinoma (HCC) strongly suggests that chronic HBV infection may contribute in some way towards the development of 1ry liver cell carcinoma. Although HCC is probably caused by one or more environmental carcinogens, a hereditary predisposition to the tumor has not been excluded. Aim: Determine the incidence of HBsAg carriers patients suffering from primary HCC and detect the association between primary HCC and HLA. Subjects and Methods: The material consisted of twenty patients diagnosed as HCC based on Ultrasonographic examination and by Histopathology. Laboratory investigations; liver biopsy, HBsAg, Anti-HBcAg (IgM) and HLA typing using lymphocyte microcytotoxicity technique. Results: The 20 studied cases were negative for HBcAb IgM and 10 patients were positive for HBsAg. HLA typing revealed significant rise of HLA-A9, HLA-B5 among HCC patients. HLAA9 was significantly increased in HBsAg positive and negative cases. HLA-B5 was significantly increased in HBsAg positive cases only while HLA-B8 was significantly increased in HBsAg negative cases only. In cases with mixed hepatic cirrhosis and Schistosomal hepatic fibrosis which were negative for HBsAg showed significant increase in HLA-A9. Conclusions: 1. Significant association of HBsAg positivity in patients with HCC. 2. Significant association of HLA-A9 and HLA-B5 with HCC. 3. HLA-A9 in patients mixed cirrhosis and Schistosomal hepatic fibrosis may be predisposing to HCC.

PP-110 A study of the carriers of hepatitis B surface antigen among patients with schistosomal hepatic fibrosis

Objectives: We determined whether serum concentration of TIMP-1 and TIMP-2 are related to the progress of liver fibrosis in patients with chronic hepatitis B (CHB). Methods: Commercially available ELISA were used to study circulating values of TIMP-1 and TIMP-2 in CHB patients (n = 159) and 20 healthy controls. TIMP-1 and TIMP-2 expressions in the liver were detected by immunohistochemical staining, then analyzed the correlation between the levels of hepatic expression and serum concentration of them. Hepatic histology was evaluated, and quantified the stage of fibrosis by using the Hepatitis-Activity-Index (HAI) according to Ishak et al. Results: The serum concentration of TIMP-1 or TMIP-2 positively correlated with their expression in the liver of CHB patients, and both of them were higher in the patients than those in the healthy controls, and which had a significant difference (P < 0.05). The serum concentrations of TIMP-1 and TIMP-2 increased significantly with development of fibrosis and had positive correlations with HAI (r = 0.51, P < 0.01; r = 0.42, P < 0.01), whereas serum ALT wasn’t related to fibrosis or HAI. Conclusions: Regular determinations of both TIMP-1 and TIMP-2 in CHB patients may be used as indicators of increasing fibrosis.

In Egyptians, a mutation in the lymphotoxin-α gene may increase susceptibility to hepatitis C virus but not that to schistosomal infection

In Egypt, human schistosomiasis is a chronic endemic disease that can produce portal hypertension and occasionally death. Curiously, most Egyptian cases of the disease are complicated by co-infection with hepatitis C virus (HCV), the co-infection generally resulting in more severe liver disease than seen in those only infected with HCV. The high frequency of co-infection may be the result of transmission of the virus during parental schistosomal therapy or schistosomiasis-related surgery but it also seems possible that certain individuals are particularly susceptible to both schistosome and HCV infection. Lymphotoxin-alpha (LTalpha) participates in inflammatory responses, and single-nucleotide polymorphisms (SNP) in the human LTalpha gene have recently been found to have profound effects on individual susceptibility to various diseases, including some of those caused by parasitic infection. The possibility that the SNP that create an NcoI restriction site in the gene are associated with increased susceptibility to schistosomal and/or HCV infection has now been investigated in the Egyptian city of Alexandria. The subjects investigated were 22 patients infected only with HCV, 44 cases of schistosomal hepatic fibrosis (SHF) who were either co-infected with HCV (22) or HCV-free (22), and 22 apparently healthy, schistosome-free and HCV-free controls. When each of these subjects was tested for the NcoI polymorphism in their LTalpha gene, by PCR-RFLP, those with isolated HCV infection and those co-infected with Schistosoma and HCV (but not those infected with Schistosoma alone) were found significantly more likely to carry the mutation than the control subjects (P<0.05). When the cases of SHF were pooled together (irrespective of HCV-infection status), they were not found significantly more likely to have the mutation than the controls. At least in Egypt, therefore, the LTalpha mutation may have a role in susceptibility to HCV infection (and the subsequent development of clinical manifestations) but appears to have little if any effect on susceptibility to schistosome infection. Larger studies are now needed to confirm these results.

IL‐4 and reactive oxygen species are elevated in Egyptian patients affected with schistosomal liver disease

Schistosomiasis is a chronic liver disease that is endemic in rural areas of Egypt. Some patients may acquire infection and develop minimal complications while others may develop severe complications and progress to portal hypertension and cirrhosis especially if co-infected with hepatitis C virus (HCV). The reasons for this are poorly understood. Previous studies suggested an independent role for Th2-biased cytokine responses to schistosomal antigens in persistent hepatic fibrosis and development of complications. Studies in murine schistosomiasis demonstrated that the development of fibrosis requires the production of the profibrotic cytokines such as IL-4. On the other hand, previous studies have suggested that reactive oxygen species may play an important role in schistosomal granuloma formation and disease progression To investigate the status of the profibrotic IL-4 cytokine, oxidative stress (as indicated by thiobarbituric acid reactive substances), the antioxidants enzymes catalase and red blood cells glutathione content in a cohort of Egyptian patients affected with schistosomal hepatic disease and or hepatitis C infection. The current study included four groups: patients with isolated HCV infection (HCV), comprised of 22 patients aged (mean +/- SD) 51.3 +/- 4.7 years; patients with HCV and schistosomal hepatic fibrosis (SHF) (Co-infected patients), comprised of 22 patients aged 49.6 +/- 4.0 years, patients with pure chronic schistosomiasis comprised of 22 patients with chronic schistosomiasis aged 53.7 +/- 5.6 years and a control group, comprised of 22 control subjects aged 48.5 +/- 5.4 years. Thiobarbituric acid reactive substances (TBARS), Catalase activity and red blood cells glutathione contents were determined using chemical methods while plasma IL-4 was determined using a commercially available ELISA kit. A significant reduction in erythrocyte catalase activity in patients with isolated HCV infection, isolated SHF and those co-infected with SHF and HCV compared with the control group was found (P < 0.05). A similar pattern was found regarding erythrocyte glutathione content. Conversely TBARS level were significantly increased in patients with HCV, SHF and mixed groups compared with the control group (P < 0.05). Plasma IL-4-values were significantly increased in the three groups compared to the control subjects group. Furthermore, plasma IL-4 was significantly higher in patients with isolated SHF and those with SHF + HCV compared to the HCV alone patient group. Plasma IL-4 also correlated positively with portal vein diameter in SHF and SHF . HCV groups. (r = 0.54 and P < 0.05). Furthermore when all patients were analysed collectively, there was a positive correlation between plasma IL-4 and right lobe of the liver and plasma TBARS concentration. Schistosomal infection triggers a Th2 type immune response as indicated by the high plasma IL-4. It also triggers an increase in reactive oxygen species levels. These effects especially IL-4 lead to more reduction in the level of antioxidants enzymes (that may be already compromised in malnourished schistosomal patients) with the resultant disease progression and development of complications.