Plasma tissue inhibitor of metalloproteinases-1 and transforming growth factor beta 1--possible non-invasive biomarkers of hepatic fibrosis in patients with chronic B and C hepatitis

BACKGROUND/AIMS: The role of transforming growth factor-beta 1 (TGF-beta 1) in liver fibrosis is in part related to impairment of extracellular matrix breakdown by stimulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) gene. The aim of the study was to evaluate association between TGF-beta 1 and TIMP-1 in relation to liver injury in chronic viral hepatitis B and C. METHODOLOGY: Association between plasma TGF-beta 1 and TIMP-1 was evaluated in 28 consecutive patients undergoing liver biopsy for chronic viral hepatitis B and C (CH-B, CH-C) and these tests were correlated with hepatic fibrosis, inflammation and liver function tests. Moreover carboxyterminal cross-linked telopeptide of type 1 procollagen (ICTP) and carboxyterminal propeptide of type 1 collagen (PICP) were also measured for assessment of extracellular matrix breakdown or synthesis, respectively. RESULTS: Chronic viral hepatitis B and C resulted in a significant increase in plasma TIMP-1 levels but not TGF-beta 1. Among biochemical markers of liver injury, significant correlation with TGF-beta 1 and TIMP-1 was demonstrated in respect to aminotransferase activities in both groups. TIMP-1 showed significant correlation with ICTP levels in both CH-B (r = 0.59) and CH-C (r = 0.62), whereas TGF-beta 1 was correlated with ICTP only in CH-C patients (r = 0.75). PICP did not demonstrate any correlation with either TGF-beta 1 or TIMP-1. Hepatic fibrosis, but not inflammation, correlated significantly with TGF-beta 1 (CH-B: r = 0.73; CH-C: r = 0.79) and TIMP-1 (CH-B: r = 0.66; CH-C: r = 0.71) in both groups and there was a significant correlation between TIMP-1 and TGF-beta 1 in the CH-B group (r = 0.83) and CH-C group (r = 79). CONCLUSIONS: These results support the role of TIMP-1 in a TGF-beta 1-dependent mechanism for liver fibrosis and suggest their plasma levels can be used as a possible early non-invasive marker of liver fibrosis useful for chronic hepatitis management.     

Liver-infiltrating CD56 positive T lymphocytes in hepatitis C virus infection

AIM: Hepatitis C virus (HCV) is a major cause of post-transfusional and sporadic hepatitis, and leads to chronic liver disease. It has been suggested that virus-specific cytotoxic T lymphocytes are responsible for liver injuries that occur in HCV-infected patients. However, the detailed characteristics of these lymphocytes have not yet been defined. We have previously reported that CD56+ T lymphocytes, as intermediates between natural killer cell and T lymphocytes, predominantly infiltrated the liver and were increased in patients with chronic hepatitis related to HCV (CH-C). MATERIAL AND METHODS: We obtained peripheral blood and liver tissues from 32 patients diagnosed as having CH-C, and 10 other liver disease patients (5 chronic hepatitis related to HBV, 5 alcoholics), and analyzed peripheral blood and liver-infiltrating lymphocytes using flow cytometric and immunohistochemical techniques. RESULTS: The CD56+ T lymphocyte ratio in the liver of patients with a high histology activity index (HAI) score for chronic hepatitis was higher than that of patients with a low HAI score and patients with other liver diseases. In addition, T lymphocytes from patients with chronic hepatitis with a high HAI score carried mostly gamma delta-TCR. There was a correlation between the ratio of CH-C and serum alanine aminotransferase, category I (periportal inflammation and necrosis), and IV (fibrosis) of the HAI scoring system. The ratio was highest in zone 1 of the hepatic lobules. CONCLUSION: The correlation between CD56+ T lymphocyte ratios and hepatocellular damage was examined. These findings suggest strongly that liver-infiltrating CD56+ T lymphocytes play an important pathologic role in hepatocellular injury in CH-C.     

Serum thioredoxin elucidates the significance of serum ferritin as a marker of oxidative stress in chronic liver diseases

BACKGROUND/AIMS: Serum thioredoxin (TRX) levels have recently been established as an indicator of oxidative stress in various diseases. The aim of the present study was to clarify the clinical significance of serum ferritin in chronic liver diseases. METHODS: Levels of ferritin, transferrin saturation (TS), aspartate aminotransferase (AST), and TRX were measured in the sera of patients with chronic hepatitis C (CH-C, n=92), chronic hepatitis B (CH-B, n=28), nonalcoholic fatty liver (FL, n=31), or alcoholic liver diseases (ALD, n=17). Serum TRX levels were evaluated with a recently established sandwich enzyme-linked immunosorbent assay kit. RESULTS: Serum TRX levels were significantly higher in CH-C, FL, and ALD than in healthy volunteers. A larger proportion of patients with CH-C, FL, and ALD had elevated levels of serum ferritin than CH-B. Serum ferritin levels were positively correlated with levels of TS, AST, and TRX in CH-C, but were merely correlated with TS values in CH-B. Ferritin levels were also well correlated with AST and TRX, but not with TS in FL and ALD. CONCLUSION: Oxidative stress, which was evaluated by measuring serum TRX, in addition to storage iron and hepatocyte damage is a cause of increasing serum ferritin levels in chronic liver diseases. An elevated serum ferritin level, which was correlated with TS, indicates that iron-induced oxidative stress contributes to CH-C. Elevated ferritin levels in FL and ALD may be mostly due to iron-unrelated stresses.     

红细胞补体受体1基因多态性与特发性肺纤维化易感性的关系

目的 探讨红细胞补体受体1(CR1)密度基因多态性及CR1基因A3650G位点多态性与特发性肺纤维化(IPF)易感性的关系,CR1的HindⅢ密度相关基因组多态性与红细胞膜上CR1数量表达水平的关系.方法 选择2009年11月至2010年12月在河北医科大学第二医院确诊为特发性肺纤维化汉族患者64例(IPF组)及54名同期河北医科大学第二医院健康汉族体检者作为健康对照组.应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)及聚合酶链反应(PCR)检测两组CR1的HindⅢ密度相关基因组多态性以及CR1基因A3650G多态位点的基因型;采用流式细胞术检测CR1在红细胞膜上的数量表达水平.结果 CR1HindⅢ密度相关基因基因型HH型、HL型和LL型在IPF组的分布频率分别为32.8％(21/64)、46.9％(30/64)和20.3％(13/64),在健康对照组分布频率分别为72.2％(39/54)、25.9％(14/54)和1.9％(1/54),差异有统计学意义(x2=15.516,P＜0.05).IPF组与健康对照组HL+ LL基因型优势比OR值为5.32(x2=18.20,P＜0.05).CR1基因A3650G位点的等位基因频率在IPF患者和健康对照组之间比较,总体分布差异无统计学意义(x2=1.094,P＞0.05).CR1在IPF组红细胞上的平均荧光强度为13.46±3.86,与健康对照组(24.33±3.84)比较,差异有统计学意义(t=15.288,P＜0.05).两组CR1基因HindⅢ-RFLP高表达型的红细胞CR1数量表达水平高于中表达型(t=9.973,P＜0.05),中表达型高于低表达型(t=4.359,P＜0.05).IPF组CR1基因HindⅢ-RFLP高表达型、中表达型、低表达型的红细胞CR1数量表达水平均低于健康对照人群(均P＜0.05).结论 红细胞CR1数量表达水平既受CR1基因HindⅢ密度相关基因组多态性遗传控制又受后天因素的影响.CR1基因HL型和LL型人群可能是特发性肺纤维化的易感人群,携带L等位基因的个体存在对特发性肺纤维化的易感性.     

Intrahepatic status of regulatory T cells in autoimmune liver diseases and chronic viral hepatitis.

Aim: Regulatory T cells (Tregs) maintain immunological tolerance and suppress autoreactive immune responses. We evaluated the intrahepatic status of Tregs in patients with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), chronic hepatitis C (CH-C), or chronic hepatitis B (CH-B). Methods: We analyzed 85 patients (20 AIH, 22 PBC, 27 CH-C, and 16 CH-B) and 14 controls. Using liver tissue samples obtained by needle biopsy or from marginal parts of resected metastatic liver tumors in the controls, immunohistochemical analyses of forkhead box P3(+), which is a specific marker for Tregs, CD4(+), and CD8(+) cells were performed. Results: Intrahepatic Tregs were significantly more infiltrated in patients with liver diseases than in the controls. There were significantly fewer intrahepatic Tregs in the AIH patients than in the PBC patients (P = 0.037). Patients with alow frequency of intrahepatic Tregs were detected significantly more in the AIH and CH-B groups than in the PBC and CH-C groups (P < 0.05). In addition, the frequency of Tregs decreased in the liver of PBC patients as the pathological stage of the disease advanced. We found significantly less infiltration of CD4(+) T cells in AIH than in other diseases (P < 0.05). Liver-infiltrating CD8(+) T cells were detected more frequently in the CH-B group than in other groups (P < 0.003). Conclusion: Intrahepatic Tregs were increased in both patients with autoimmune liver diseases and those with viral hepatitis. In autoimmune liver diseases, intrahepatic Tregs were fewer in the AIH patients than in the PBC patients.     

Changes in lipid metabolism in chronic hepatitis C

AIM: To investigate the relationship between certain biochemical parameters of lipid metabolism in the serum and steatosis in the liver. METHODS: The grade of steatosis (0-3) and histological activity index (HAI, 0-18) in liver biopsy specimens were correlated with serum alanine aminotransferase (ALT), total cholesterol and triglyceride levels in 142 patients with chronic hepatitis C (CH-C), and 28 patients with non-alcoholic fatty liver disease (NAFLD) without hepatitis C virus (HCV) infection. The serum parameters were further correlated with 1 797 age and sex matched control patients without any liver diseases. RESULTS: Steatosis was detected in 90 out of 142 specimens (63%) with CH-C. The ALT levels correlated with the grade of steatosis, both in patients with CH-C and NAFLD (P<0.01). Inserting the score values of steatosis as part of the HAI, correlation with the ALT level (P<0.00001) was found. The triglyceride and cholesterol levels were significantly lower in patients with CH-C (with and without steatosis), compared to the NAFLD group and to the virus-free control groups. CONCLUSION: Our study confirms the importance of liver steatosis in CH-C which correlates with lower lipid levels in the sera. Inclusion of the score of steatosis into HAI, in case of CH-C might reflect the alterations in the liver tissue more precisely, while correlating with the ALT enzyme elevation.     

Increased lipid peroxidation in patients with non-alcoholic fatty liver disease and chronic hepatitis C as measured by the plasma level of 8-isoprostane

BACKGROUND: Oxidative stress plays an important role in the pathogenesis of chronic liver diseases. The plasma level of 8-isoprostane, a product of lipid peroxidation, is a marker of oxidative stress in vivo. The aim of the present study was to clarify whether the degree of lipid peroxidation, as measured by the plasma level of 8-isoprostane, influences the progression of chronic liver diseases and hepatocarcinogenesis. METHODS: Plasma 8-isoprostane levels were investigated in 14 patients with non-alcoholic fatty liver disease (NAFLD), 75 with chronic hepatitis C (CH-C), 14 with cured CH-C, 14 with HCV-positive hepatocellular carcinoma (HCC-C) and 38 healthy volunteers. 8-Isoprostane was measured by enzyme immunoassay after affinity column purification. RESULTS: Plasma 8-isoprostane was significantly elevated in NAFLD (11.9 [3.8-56.8] pg/mL), CH-C (10.1 [4.2-134.5] pg/mL) as compared to controls (6.3 [3.6-11.1] pg/mL). Plasma 8-isoprostane values were positively correlated with body mass index in NAFLD (P < 0.05) and with total cholesterol in cured CH-C (P < 0.01). 8-Isoprostane levels were not significantly related to sex, age, biochemical data or iron metabolism markers in all liver diseases. In addition, after the administration of peg-interferon, the values of 8-isoprostane improved in almost all patients, reaching values of healthy subjects. CONCLUSIONS: 8-Isoprostane values are elevated in patients with NAFLD and CH-C as compared to healthy controls. Oxidative stress caused by increased lipid peroxidation is involved in the pathogenesis of NAFLD and CH-C.     

Hepatocyte proliferation and cell cycle phase fractions in chronic viral hepatitis C by image analysis method

OBJECTIVE: Chronic hepatitis is characterized by necrosis of liver cells, accompanied by an inflammatory reaction and compensatory cell proliferation. The interaction of the core and non-structural proteins of hepatitis C virus (HCV) with several cellular factors suggests that cell proliferation may be influenced by HCV. The aim of this study was to investigate hepatocyte proliferation and DNA ploidy patterns in patients with chronic viral hepatitis C (CH-C) compared with chronic non-viral hepatitis (CH-N), using a TV image analysis method. METHODS: The DNA index (DI) and cell phase fractions (G1, S, G2) were measured by means of digital picture analysis method on nuclear suspensions of Feulgen stained hepatocytes. Cells were taken from the liver biopsy specimens of 71 patients with CH-C and 24 patients with CH-N. Twenty-six normal liver samples were used as controls. RESULTS: Significantly higher G1 (94 +/- 4) and lower S (3.56 +/- 3.16) phase fractions were measured in CH-C compared with CH-N (G1, 90 +/- 6; S, 6.4 +/- 5.99). The DI of moderate (1.12 +/- 0.05) and severe (1.12 +/- 0.05) CH-C showed near-aneuploid DNA content, while diploidy (DI < 1.10) was detected in cases of CH-N. CONCLUSION: The higher G1 and lower S cell cycle phase fractions in CH-C reflect decreased hepatocyte proliferation compared with CH-N. The near-aneuploid DNA content of the HCV-infected liver samples may be a sign of increased genetic instability, which may contribute to the carcinogenic potential of HCV.     

Comparison of hepatic oxidative DNA damage in patients with chronic hepatitis B and C

Summary.  8-Hydroxydeoxyguanosine (8-OHdG) is a promutagenic DNA lesion produced by hydroxyl radicals and is recognized as a useful marker in estimating DNA damage induced by oxidative stress. The aim of this study was to clarify the clinical significance of hepatic 8-OHdG levels in patients with chronic viral hepatitis. Hepatic 8-OHdG accumulation was investigated in patients with chronic hepatitis C (CH-C) ( n  = 77) and chronic hepatitis B (CH-B) ( n  = 34) by immunohistochemical staining of liver biopsy samples. 8-OHdG positive hepatocytes were significantly higher in patients with CH-C compared to CH-B (median 55.0 vs 18.8 cells/10⁵ μm², P  < 0.0001). The number of positive hepatocytes significantly increased with the elevation of serum aminotransferase levels, especially in CH-C patients (8-OHdG vs alanine aminotransferase (ALT)/aspartate aminotrasferase (AST) were r  = 0.738/0.720 in CH-C and 0.506/0.515 in CH-B). 8-OHdG reactivity was strongly correlated with body and hepatic iron storage markers in CH-C ( vs serum ferritin, r  = 0.615; vs hepatic total iron score, r  = 0.520; vs hepatic hepcidin mRNA levels, r  = 0.571), although it was related to serum HBV-DNA titers ( r  = 0.540) and age of patients ( r  = –0.559) in CH-B. These results indicate that hepatic oxidative DNA damage is common in chronic viral hepatitis, in particular chronic HCV-infected patients, suggesting a possible link between chronic hepatic inflammation and hepatocarcinogenesis. The strong positive correlation between hepatic DNA damage and iron overload suggests that iron content is one of the most likely mediators of hepatic oxidative stress and iron reduction may be beneficial to reduce the incidence of hepatic cancer in CH-C patients.     

慢性病毒性肝炎患者红细胞CR1粘附活性的变化

目的研究慢性病毒性肝炎患者红细胞 CR1粘附活性的变化,探讨其临床意义。方法采用红细胞天然免疫粘附肿瘤细胞功能实验,对80例慢性病毒性肝炎患者及30例正常人的红细胞 CR1分子活性进行测定,同时检测 CHE 等肝功能指标。结果慢性病毒性肝炎患者红细胞 CR1粘附活性显著低于正常人群(P<0.01);慢性肝炎患者红细胞 CR1粘附活性的变化与 CHE、ALT/AST 的变化密切相关,并且随患者病情好转其红细胞 CR1粘附活性相应回升。结论慢性病毒性肝炎患者红细胞 CR1粘附活性可有效地反应肝功能损伤的严重程度,该项可作为判断慢性肝病病情变化的重要指标。     

Role of serum soluble Fas/soluble Fas ligand and TNF-alpha on response to interferon-alpha therapy in chronic hepatitis C

AIMS/BACKGROUND: To determine the relationship between host factors and host response to interferon (IFN) therapy, serum soluble Fas (sFas), soluble Fas ligand (sFas ligand), and tumor necrosis factor-alpha (TNF-alpha) were analyzed in 41 patients with chronic hepatitis C (CH-C) treated with IFN-alpha. METHODS: Serum levels of sFas, sFas ligand, and TNF-alpha were measured at 0, 4, and 24 weeks of IFN therapy. RESULTS: Eighteen patients were complete responders (CR) and 23 patients were non-responders (NR). Serum levels of sFas and TNF-alpha in patients with CHC were significantly higher than those in healthy controls (p<0.01 and p<0.01, respectively). Serum sFas ligand levels were significantly lower in CH-C patients than in healthy controls (p<0.01). Before IFN therapy, serum levels of sFas in NR were significantly higher than those in CR (p<0.05). At 4 weeks of IFN therapy, serum levels of sFas of CR were significantly elevated compared with levels before IFN therapy (p<0.05). Serum levels of sFas correlated with the histological activity of the liver (p<0.05) and alanine aminotransferase (p<0.05). None of the three parameters, serum sFas, sFas ligand, or TNF-alpha levels, correlated with each other, with HCV-RNA genotype or with serum HCV-RNA load. Multiple logistic regression analysis showed that serum sFas levels before IFN therapy were a contributive factor to predict efficacy of IFN therapy. CONCLUSIONS: Serum sFas/sFas ligand and TNF-alpha play a possible role in pathogenesis of CH-C and also in IFN therapy. Serum sFas levels before IFN therapy may be one of the host-related factors used for evaluating the response of CH-C patients to IFN therapy.     

Different signaling pathways in the livers of patients with chronic hepatitis B or chronic hepatitis C

The clinical manifestations of chronic hepatitis B (CH-B) and chronic hepatitis C (CH-C) are different. We previously reported differences in the gene expression profiles of liver tissue infected with CH-B or CH-C; however, the signaling pathways underlying each condition have yet to be clarified. Using a newly constructed cDNA microarray consisting of 9614 clones selected from 256,550 tags of hepatic serial analysis of gene expression (SAGE) libraries, we compared the gene expression profiles of liver tissue from 24 CH-B patients with those of 23 CH-C patients. Laser capture microdissection was used to isolate hepatocytes from liver lobules and infiltrating lymphoid cells from the portal area, from 16 patients, for gene expression analysis. Furthermore, the comprehensive gene network was analyzed using SAGE libraries of CH-B and CH-C. Supervised and nonsupervised learning methods revealed that gene expression was correlated more with the infecting virus than any other clinical parameters such as histological stage and disease activity. Pro-apoptotic and DNA repair responses were predominant in CH-B with p53 and 14-3-3 interacting genes having an important role. In contrast, inflammatory and anti-apoptotic phenotypes were predominant in CH-C. These differences would evoke different oncogenic factors in CH-B and CH-C. In conclusion, we describe the different signaling pathways induced in the livers of patients with CH-B or CH-C. The results might be useful in guiding therapeutic strategies to prevent the development of hepatocellular carcinoma in cases of CH-B and CH-C.     

Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C

OBJECTIVES: Hepatic iron deposition has been reported in chronic hepatitis C (CH-C), and iron-induced lipid peroxidation may be involved in the pathogenesis of CH-C. The aims of the present study were: 1) to determine whether patients with CH-C have evidence of enhanced hepatic lipid peroxidation and to evaluate its relation to iron status, compared with that in patients with chronic hepatitis B (CH-B); and 2) to assess the effect of interferon (IFN) therapy on hepatic iron and lipid peroxidation. METHODS: In the liver biopsies of 40 patients with CH-C and 26 patients with CH-B, immunohistochemical detection of 4-hydroxy-2-nonenal (HNE)-protein adducts for evaluation of lipid peroxidation was performed, and hepatic iron status was biochemically and histologically assessed. In 16 CH-C patients with normal serum transaminases and undetectable serum HCV-RNA >6 months after the end of IFN treatment (responders) and in 11 nonresponders, hepatic HNE-protein adducts and siderosis were evaluated in pre- and posttreatment liver biopsies. RESULTS: Hepatocytic HNE-protein adducts and iron deposits were more abundant in the patients with CH-C than in those with CH-B. No correlation was found between the levels of hepatocytic HNE-protein adducts and hepatic iron status in either of the two groups. In the responders to IFN treatment for CH-C, hepatocytic HNE-protein adducts disappeared or attenuated with improvement of hepatic siderosis after the treatment, whereas IFN treatment did not improve hepatocytic expression of HNE-protein adducts and hepatic siderosis in the nonresponders. CONCLUSIONS: Patients with CH-C have evidence of enhanced hepatic iron accumulation and lipid peroxidation compared to those with CH-B. In CH-C, hepatic siderosis and lipid peroxidation are improved with successful IFN treatment. These results suggest that hepatic lipid peroxidation and iron may potentially play contributory roles in the pathogenesis of CH-C.     

Phenotypic analysis of circulating and intrahepatic dendritic cell subsets in patients with chronic liver diseases

BACKGROUND/AIMS: Dendritic cells (DCs) are the most potent professional antigen-presenting cells. Although two subsets of circulating DCs, lineage(-)CD11c(+)CD4(low) (CD11c(+)DCs) and lineage (-)CD11c(-)CD4(+)CD123(+) (CD123(+)DCs) are identified in humans, the role of each DC subset in the immunopathogenesis of liver diseases is unknown.METHODS: We examined the numbers and activation status of each DC subset in the circulation and in the inflamed livers in patients with chronic liver diseases by flow cytometry and immunohistochemistry.RESULTS: The numbers of circulating CD11c(+)DCs were inversely correlated with serum alanine aminotransferase (ALT) levels in patients with chronic viral hepatitis, and that the expression of costimulatory molecules on circulating CD11c(+)DCs in patients with chronic viral hepatitis was significantly up-regulated in patients with high serum levels of ALT. Both DCs are also identified in the livers by flow cytometry, and the expression of costimulatory molecule CD40 on those DCs was significantly higher in liver DCs than that in circulating DCs. Moreover, the ratios of CD11c(+)DCs/CD123(+)DCs were higher in liver DCs (mean+/-SD, 7.2+/-6.0) than those of circulating DCs (4.0+/-4.6). Immunohistochemically, CD11c(+) or CD123(+) cells and CD83(+) activated DCs were observed mostly in portal areas with mononuclear cell infiltration in various liver diseases. These overall data suggest that DCs, especially CD11c(+)DCs, could be associated with the necroinflammatory response in the liver of chronic viral liver diseases.CONCLUSIONS: DCs, especially CD11c(+)DCs, may be involved in the immunopathogenesis of chronic liver diseases.     

Measurement of erythrocyte C4d and complement receptor 1 in systemic lupus erythematosus

OBJECTIVE: C4-derived activation fragments are the only complement ligands present on the surfaces of normal erythrocytes. The significance of this observation is unknown, and the role of erythrocyte-bound C4 (E-C4) in human disease has not been explored. More than any other human disease, the pathogenesis of systemic lupus erythematosus (SLE) has been characterized by defects in clearance of complement-bearing immune complexes via erythrocytes expressing complement receptor 1 (CR1). This study was undertaken to determine whether these functional defects might be reflected by abnormal patterns of E-C4 and E-CR1 expression on erythrocytes of patients with SLE. METHODS: We conducted a cross-sectional study of 100 patients with SLE, 133 patients with other diseases, and 84 healthy controls. Erythrocytes were characterized by indirect immunofluorescence and by flow cytometry for determination of levels of C4d and CR1. RESULTS: Patients with SLE had higher levels of E-C4d and lower levels of E-CR1 than did patients with other diseases (P < or = 0.001) or healthy controls (P < or = 0.001). The test was 81% sensitive and 91% specific for SLE versus healthy controls and 72% sensitive and 79% specific for SLE versus other diseases, and it had an overall negative predictive value of 92%. CONCLUSION: This is the first report of abnormal levels of E-C4d in human disease. We found that abnormally high levels of E-C4d and low levels of E-CR1 are characteristic of SLE, and combined measurement of the 2 molecules has high diagnostic sensitivity and specificity for lupus. Determination of E-C4d/E-CR1 levels may be a useful addition to current tests and criteria for SLE diagnosis.     

Upregulation of transferrin receptor 2 and ferroportin 1 mRNA in the liver of patients with chronic hepatitis C

BACKGROUND: Iron accumulation has been reported to be associated with progression of liver injury. The mechanism of iron accumulation in the liver is not known. In the present study, hepatic messenger RNA (mRNA) expression of transferrin receptor (TfR)1, TfR2, and ferroportin (FP)1 was measured in patients with chronic hepatitis (CH). METHODS: Eleven patients with CH-B and 43 patients with CH-C were enrolled. All patients underwent liver biopsy. Hepatic expression of TfR1, TfR2 and FP1 mRNA was analyzed using a real-time polymerase chain reaction. Total hepatic iron score (THIS) was evaluated by Prussian blue staining. RESULTS: Serum ferritin concentration is significantly higher in CH-C than in CH-B. Values of THIS of >/=5 were observed only in CH-C patients (44% of CH-C patients). The expression level of TfR2 mRNA was 10-26-fold higher than the TfR1 mRNA expression level. The TfR2 and FP1 mRNA expression was significantly higher in CH-C than in CH-B patients. Hepatic expression of TfR2 and FP1 mRNA was well correlated with THIS. CONCLUSIONS: Hepatic iron accumulation is more severe in patients with CH-C. Upregulation of hepatic iron transporters may contribute to the hepatic iron accumulation in CH-C.     

肝病患者血清肉碱水平的临床研究

目的观察肝病患者血清肉碱水平,探讨其临床意义,为肉碱治疗肝病提供依据。方法用酶循环法检测25例急性病毒性肝炎,34例慢性病毒性肝炎,22例肾功能正常及9例肾功能异常的肝炎后肝硬化患者血清游离肉碱水平,并分别与40名正常人的检测值比较。结果血清游离肉碱:正常人为(48．3±10．2)μmol／L;急性病毒性肝炎患者为(35．2±13．2)μmol／L,明显低于正常对照组,P=0．000。慢性病毒性肝炎患者为(36．5±9．9) μmol／L,明显低于正常对照组,P=0．000。肾功能正常的肝炎后肝硬化患者为(45．0±11．0)μmol／L,比正常对照组略有下降,但差异无统计学意义,P=0．232。肾功能异常的肝炎后肝硬化患者为(83．6±50.4)μmol／L,比正常对照组升高,但差异无统计学意义,P=0．069。结论肝病患者可发生肉碱代谢异常,肝脏疾病是导致继发性肉碱缺乏的原因之一。     

Impact of hepatitis B virus (HBV) X gene integration in liver tissue on hepatocellular carcinoma development in serologically HBV-negative chronic hepatitis C patients

BACKGROUND/AIMS: We analyzed hepatitis B virus (HBV) X gene integration in hepatocytes of HBV-negative, chronic hepatitis C (CH-C) patients with mild fibrosis, and prospectively followed these patients for the development of hepatocellular carcinoma (HCC). METHODS: The study included 39 HBV-negative CH-C patients with mild fibrosis. HBV-X integration was determined by Alu-PCR analysis of liver specimens obtained by fine-needle biopsy. RESULTS: Integration of HBV-X gene sequence into liver genome occurred in 9 of the 39 patients. Six of the 39 patients developed HCC during the 12-year follow-up period. No significant difference was found in the incidence of HCC between patients with and without HBV-X integration. However, the two patients with HBV-X integration who developed HCC did not have cirrhosis at the time when HCC was diagnosed, whereas the four patients without HBV-X integration who developed HCC did have cirrhosis. CONCLUSIONS: Our findings suggest that HBV-X integration detected at the mild fibrosis stage might not indicate a high risk for HCC. HBV-X integration may be associated with HCC development in the absence of cirrhosis. However, we did not find evidence that HBV-X integration directly plays a role in hepatocarcinogenesis in CH-C patients. Further studies will be needed to clarify this point.     

Distribution of type V secretory phospholipase A2 expression in human hepatocytes damaged by liver disease

BACKGROUND AND AIM: Type V secretory phospholipase A2 (sPLA2-V) is a key enzyme in the arachidonate cascade. However, the distribution of sPLA2-V in human liver has not yet been investigated. In this study, the significance of sPLA2-V expression in human hepatocytes damaged by liver disease was investigated. METHODS: Samples of liver tissue from patients with chronic hepatitis B and C, hepatitis virus-related liver cirrhosis, and congestive hepatocyte injury were immunostained with antibodies against sPLA2-V, cyclooxygenase (COX)-2, hepatitis viral antigens, transforming growth factor (TGF)-beta1, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. RESULTS: In chronic hepatitis patients, sPLA2-V-positive hepatocytes were scattered in the liver lobules, while cyclooxygenase-2, IL-1beta, and TNF-alpha were diffusely expressed. Hepatocytes around necroinflammatory lesions were strongly positive for sPLA2-V. Some sPLA2-V-positive hepatocytes were also positive for viral antigens. TGF-beta1 was expressed only in fibrotic lesions. The pattern of distribution of these proteins in liver cirrhosis patients was similar to that in chronic hepatitis patients, but sPLA2-V expression tended to be more intense than in chronic hepatitis. In the congestive liver, sPLA2-V, COX-2, and the two cytokines were diffusely expressed in surviving hepatocytes. CONCLUSIONS: sPLA2-V expression in hepatocytes is induced by viral infection, fibrosis, and circulatory disturbance. Immunostaining using sPLA2-V antibody is useful for the detection of injured hepatocytes in patients with liver diseases.