In the new area of noninvasive markers of hepatocellular carcinoma.
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Antigens, Neoplasm↗
Biomedical subjects
Pierre Bedossa
Publications and source records attributed to Pierre Bedossa.
Liver fibrosis in women with chronic hepatitis C: evidence for the negative role of the menopause and steatosis and the potential benefit of hormone replacement therapy.
BACKGROUND AND AIMS: The rates of fibrosis progression in chronic hepatitis C are significantly different between males and females. The antifibrogenic effect of oestrogen has been proposed, possibly via inhibition of stellate cells. The aim of this study was to evaluate the severity of chronic hepatitis C in women, in relation to the menopause, steatosis and hormone replacement therapy (HRT). METHODS: From November 2003 to October 2004, women with chronic hepatitis C were enrolled prospectively. A questionnaire was completed prospectively and a blood sample was obtained on the day of biopsy. We identified characteristics associated with moderate/severe fibrosis using univariate and multivariate analysis. RESULTS: 251 women were included in the study. 122 women (52%) were menopausal and 65 were receiving HRT. 61 (24%) women with moderate/severe fibrosis (F2-F4, Metavir score) had a longer known duration of infection (>15 years), a higher body mass index and presented with steatosis more frequently than 190 (76%) women with mild fibrosis (F0-F1). Women with F2-F4 were more often menopausal (67% v 47%). The probability of fibrosis F2-F4 was lower for menopausal women receiving HRT (p = 0.012). Steatosis was more frequent and more severe in menopausal women. CONCLUSIONS: Severity of fibrosis was associated with a longer duration of infection (>15 years), a higher body mass index, advanced steatosis and the menopause. Menopausal women receiving HRT presented with a lower stage fibrosis. These results reinforce the hypothesis of a protective role of oestrogens in the progression of fibrosis. Steatosis may be implicated in the progression of fibrosis after the menopause.
Adolescent↗
Direct and indirect evidence for the reversibility of cirrhosis.
The aim of this study was to assess the reversibility of cirrhosis after therapy in a large series of patients with cirrhosis from various etiologies. We performed a retrospective study of 113 patients with biopsy-proven cirrhosis who underwent specific therapy and follow-up biopsies. Two pathologists performed blinded analyses of indirect biochemical and morphological signs of cirrhosis. Fourteen (12.4%) of the 113 cirrhotic patients had biopsy-proven disappearance of cirrhosis, defined as a decrease of 2 or greater in their METAVIR fibrosis score: 8 were related to hepatitis C virus, 3 to hepatitis B virus, and 3 to autoimmune cirrhosis. Necro-inflammatory activity decreased from 2.4 +/- 0.65 to 0.85 +/- 0.9 (P = .004), and fibrosis from 4 to 1.7 +/- 0.61 (P = .001). Prothrombin time (n = 1), platelet count (n = 2), serum albumin level (n = 2), and ultrasound abnormalities (n = 6) normalized in patients who had initial abnormalities. Hyaluronic acid and procollagen type III serum level decreased in all. In the 11 patients with regression of viral cirrhosis, 2 were nonresponders and 9 were responders, including 2 relapsers. The 3 patients with regressive autoimmune cirrhosis were complete responders to immunosupressive therapy. Using repeated liver biopsies, clinicobiochemical, radiologic, and endoscopic tests, we provide evidence for potential reversibility of cirrhosis after long-lasting suppression of the necro-inflammatory activity of liver disease.
Biopsy↗
Identification of potential therapeutic targets by gene-expression profiling in pancreatic endocrine tumors.
BACKGROUND & AIMS: Prediction of biological behavior in pancreatic endocrine tumors (PET) is difficult on histologic criteria alone. The aim of this study was to characterize PET gene expression by complementary DNA (cDNA) microarray and identify specific differences in gene-expression profiles between nonmetastatic and metastatic tumors. METHODS: We studied 24 well-differentiated PETs corresponding to 12 benign tumors and to 12 carcinomas with metastasis. Total RNAs were extracted followed by microarray hybridization, imaging scan procedure, and statistical anaylsis. PET tissue arrays were constructed from 129 archival tumors for immunohistochemical validation of microarray data. RESULTS: A total of 123 transcripts were found to separate nonmetastatic from metastatic PETs (ie, 72 up-regulated and 51 down-regulated genes in malignant tumors). Some of these genes were involved in pathways related to (1) angiogenesis and remodeling (CD34, cadherin-5, E-selectin, semaphorin E, and fibrillin), (2) signal transduction through tyrosine kinases (tyrosine kinase-2, platelet-derived growth factor-Rbeta, MKK4, and discoidin domain receptor-1), (3) calcium-dependent cell signaling (transient receptor potential cation channel-1, calcium channel voltage-dependent beta2, neurocalcin delta, and GABA-A receptor gamma2), and (4) response to drug (MDR1 and carcinoembryonic antigen-related cell adhesion molecule 6). By using tissue arrays, we confirmed the differential expression of CD34 (P = .0008), E-selectin (P = .003), MKK4 (P = .0001), and MDR1 (P = .0003) in metastatic vs nonmetastatic PETs. CONCLUSIONS: This study provides insight into tumorigenic pathways in PET. Some of the genes identified are potentially new molecular markers for the detection and treatment of these tumors.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Glypican-3 expression in hepatocellular tumors: diagnostic value for preneoplastic lesions and hepatocellular carcinomas.
Glypican-3 (GPC3), a member of heparan sulfate proteoglycans, plays a role in cell growth, differentiation, and migration. The objectives of this study were to assess the diagnostic value of GPC3 immunostaining in hepatocellular carcinomas (HCCs) and to analyze its expression profile in preneoplastic lesions. Tissue microarrays were built by sampling 54 HCCs and adjacent liver tissues (21 developing from cirrhosis and 33 from normal liver) and 94 cirrhotic macronodules. Fourteen typical liver cell adenomas and 5 with malignant foci were also included. Sections were assessed for GPC3 expression by immunohistochemistry. GPC3 staining was observed in 19 (90%) of 21 HCC cases with cirrhosis and in 18 (64%) of 28 HCC cases with normal liver (P < .01). When staining was positive, it was both membranous and cytoplasmic. Positive staining was observed in 1 case of nonneoplastic adjacent liver. In cases of adenomas, only malignant foci were positive. Among the 94 macronodules, GPC3 immunostaining was noted in 48% (14/29) of high-grade dysplastic or early HCC and in 3% (2/65, P < .001) of benign or low-grade dysplastic macronodules. This study shows that GPC3 is an efficient diagnostic marker of HCC, potentially useful in the differential diagnosis of liver cell adenomas and well-differentiated HCC. Our results also suggest that GPC3 may be considered as an early marker of liver carcinogenesis because it is able to identify some cirrhotic macronodules with malignant potential.
Adult↗
Global proteomic analysis of microdissected cirrhotic nodules reveals significant biomarkers associated with clonal expansion.
Cirrhosis is a heterogeneous tissue composed of polyclonal regenerative and monoclonal neoplastic, potentially malignant nodules from which hepatocellular carcinoma (HCC) might develop. The aim of this study was to investigate proteomic profile changes associated with clonal expansion of cirrhotic nodules and malignant transformation of monoclonal nodules. Seventy-one cirrhotic nodules from 10 female patients with six HCC were dissected from liver surgical specimen by laser capture microdissection. Clonal status of each nodule was assessed by the study of X-chromosome inactivation pattern using the human androgen receptor. Protein profiles were determined by surface-enhanced laser desorption ionisation-time-of-flight technology using Q10 arrays (Cyphergen ProteinChip). Molecular weight of differentially expressed protein peaks was assessed. An average of 50 protein peaks was obtained for each nodule's profile. Comparison of protein profiles in polyclonal (n=45) and monoclonal cirrhotic nodules (n=26) identified three differentially expressed protein peaks (10,092, 54,025 and 62,133 Da). All were upregulated in monoclonal nodules. Twelve peaks were differentially expressed between monoclonal nodules and HCC with nine proteins upregulated in cancer samples. This study confirms that proteome analysis can be achieved from a limited number of microdissected cells, and provides further insight into the process of clonal expansion and malignant transformation of cirrhotic nodules.
Adult↗
CD10 expression in pancreatic endocrine tumors: correlation with prognostic factors and survival.
CD10 is a cell surface metalloprotease expressed by a variety of hematopoietic and solid tumors. Immunohistochemical expression of CD10 was examined in 91 pancreatic endocrine tumors (PETs) included in tissue microarrays and representing various stages of tumorigenesis as well as in 10 normal pancreas tissues. The results were correlated with histoprognostic factors, namely, Ki-67 index and microvascular density. Thirty PETs (33%) presented positive cytoplasmic staining, and in 7 cases (8%), membranous staining also was observed. Stromal CD10 positivity was observed in 29 PETs (32%). In nontumoral pancreatic tissue, the islets were consistently negative. Epithelial cytoplasmic expression of CD10 increased with World Health Organization classification: CD10 was detected in 12% of benign tumors, 29% of tumors of uncertain prognosis, 38% of well-differentiated carcinomas, and 86% of poorly differentiated carcinomas. Membranous expression of CD10 correlated with poor differentiation (P = .0004). Expression of CD10 also correlated significantly with a high proliferative index (P = .020), low microvascular density (P = .043), large tumor size (P = .023), and presence of metastasis (P = .013). Expression was associated with poorer survival (P = .017). No statistical relation was observed between stromal CD10 expression and any of the histopathologic criteria examined. In conclusion, CD10 is expressed in a subset of PETs and correlates with histopathologic indicators of poor outcome, suggesting a role for this molecule in tumorigenesis and prognostic analysis.
Adult↗
Hepatic steatosis in HIV-HCV coinfected patients: analysis of risk factors.
OBJECTIVE: To evaluate the prevalence and severity of steatosis and possible interactions between steatosis, host factors, viral factors, and treatment for HIV infection in HIV-hepatitis C virus (HCV) coinfected patients. METHODS: Steatosis was assessed among 395 HIV-HCV coinfected patients who were enrolled in the ANRS trial HC02 Ribavic and for whom histological data were available. Steatosis was graded as follows: 0 (none); 1 (< 30% hepatocytes containing fat); 2 (30-70%); 3 (> 70%). RESULTS: Steatosis was present in 241 patients (61%), of whom 149 (38%) had grade 1, 64 (16%) grade 2 and 28 (7%) grade 3. In multivariate analysis, the following five independent risk factors were associated with steatosis: HCV genotype 3 [odds ratio (OR), 3.02; 95% confidence interval (CI), 1.91-4.79; P < 0.0001], the mean METAVIR fibrosis score (OR, 1.43; 95% CI, 1.11-1.84; P = 0.0053), the body mass index (BMI; OR, 1.13; 95% CI, 1.05-1.21; P = 0.0013), HCV viral load (OR. 1.65; 95% CI, 1.22-2.23; P = 0.0012) and ferritin (OR, 1.13; 95% CI, 1.06-1.21; P < 0.0003). As HCV genotype 3 was a risk factor for steatosis, further exploratory analyses were stratified according to the HCV genotype (1 and 3). Factors independently associated with steatosis were BMI and HCV viral load in patients with HCV genotype 3 infection and the mean METAVIR fibrosis score, the BMI and ferritin in patients with HCV genotype 1 infection. CONCLUSION: Steatosis is particularly frequent in HIV-HCV coinfected patients, who appear to have the same risk factors for steatosis as HCV monoinfected patients. None of the characteristics of HIV infection, including antiretroviral therapy, was independently associated with steatosis.
Adult↗
Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C.
The relationship between cryoglobulin and severity of liver lesions is debated. No study has focused on the relationship between cryoglobulin, liver steatosis, and fibrosis. The aim of this study was to determine the relationship between cryoglobulins and liver lesions (necroinflammation, fibrosis, and steatosis) in patients with hepatitis C virus (HCV) infection. Four hundred and thirty-seven consecutive patients with untreated chronic hepatitis C who had been admitted for liver biopsy were included in the study. Risk factors for fibrosis and steatosis were assessed. The mean age was 50.9 +/- 13.8 years, and 49% were male. Cryoglobulin was present in 286 patients, 103 of whom had vasculitis. One hundred and eighty-six patients (43%) had steatosis greater than 10%, and 110 (25%) had advanced fibrosis (Metavir score F3-F4). On multivariate analysis, cryoglobulin increased by nearly threefold the risk of having advanced fibrosis and steatosis greater than 10%. Steatosis greater than 10% was associated with a higher body mass index (P < .001), HCV genotype 3 (P < .001), cryoglobulin (P = .002), and advanced liver fibrosis (P = .009). Advanced fibrosis (F3-F4) was associated with a higher level of gamma-glutamyltransferase (P = .04), cryoglobulin (P < .001), a high grade of necroinflammation (Metavir score A2-A3) (P < .001), and steatosis higher than 10% (P = .04). In conclusion, our study shows an independent association between cryoglobulin and steatosis as well as advanced fibrosis.
Adult↗
Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up.
Hepatitis delta virus (HDV) can cause severe acute and chronic liver disease in patients infected by hepatitis B virus. Interferon alpha at high doses, although poorly efficient, is the only treatment reported to provide some benefit in chronic hepatitis delta. Pegylated interferon alpha (PEG-IFN) has not yet been evaluated. Treatment is usually monitored by the qualitative detection of HDV-RNA in serum. In this study, safety and efficacy of PEG-IFN were assessed in chronic hepatitis delta, and serum HDV-RNA kinetics were determined using quantitative RT-PCR. Fourteen patients with chronic hepatitis delta received subcutaneous PEG-IFN alpha-2b during 12 months (1.5 microg/kg per week). Serum HDV-RNA was quantified at initiation and during the course of therapy, and during the posttreatment follow-up period, which ranged from 6 to 42 months (median 16 months). PEG-IFN alpha-2b was well tolerated, inducing no serious adverse effect. Sustained biochemical response was obtained in 8 patients (57%). At the end of treatment, 8 patients (57%) had achieved virological response (undetectable HDV-RNA). Sustained virological response throughout the posttreatment follow-up period was observed in 6 patients (43%). HDV-RNA kinetics were predictive of the response: after 3 months of PEG-IFN, HDV-RNA levels were significantly lower in the responders than in the nonresponders group (P=.018). After 6 months of therapy, a negative HDV-RNA was predictive of sustained response (P=.021). In conclusion, this preliminary study indicates that PEG-IFN alpha-2b is safe and efficient for treatment of chronic hepatitis delta. The follow-up of HDV-RNA levels during therapy, which allows the differentiation of various profiles of virological responses, improves treatment monitoring.
Adult↗
Serum proteome to predict virologic response in patients with hepatitis C treated by pegylated interferon plus ribavirin.
BACKGROUND & AIMS: Surface-enhanced laser desorption ionization time-of-flight mass spectrometry is a proteomic technique that enables the global profiling of proteins. We used this approach to monitor the kinetics of serum proteome in patients with chronic hepatitis C virus infection receiving a standard bitherapy regimen to predict treatment response. METHODS: Ninety-six patients with chronic hepatitis C were retrospectively selected. All patients received complete treatment with pegylated interferon in combination with ribavirin. Patients had serum sampling before starting treatment and at the end of treatment. Results were validated in an independent cohort of 51 patients. RESULTS: Comparison of protein profiles in pretreatment and after-treatment serum allowed us to characterize 50 protein peaks, the level of which significantly varied. In the group of patients with sustained virologic response, 37 peaks displayed significant variation during treatment, whereas only one peak differed in nonresponders. A logistic regression analysis allowed us to define an algorithm composed of 2 protein peaks (fibrosis stage and genotype) that correctly predicted, in pretreatment serum, response to treatment in 89% of all patients with an area under the receiver operating characteristic curve of 0.92. In the independent testing group, the same difference in proteome kinetics was observed between sustained responders and nonresponders. The algorithm correctly predicted treatment response in 81% of patients in the testing group. CONCLUSIONS: This study suggests that the kinetics of proteome are significantly different in serum of patients according to treatment response. Serum protein profiling allows prediction of response to antiviral treatment in a significant proportion of patients.
Adult↗
Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity.
In human obesity, white adipose tissue (WAT) is enriched in macrophages. How macrophage infiltration in WAT contributes to the complications of obesity is unknown. This study tested the hypothesis that recruitment of macrophages in omental WAT is associated with hepatic damage in obese patients. Paired biopsies of subcutaneous and omental WAT and a liver biopsy were collected during gastric surgery in 46 obese women and 9 obese men (BMI 47.9 +/- 0.93 kg/m(2)). The number of HAM56+ macrophages in WAT was quantified microscopically, and correlations with clinical and biological parameters and histological liver pathology were investigated. There were twice as many macrophages in omental as in subcutaneous WAT (P<0.0001). After adjustment for age, omental WAT macrophage infiltration was correlated to fasting glucose and insulin, quantitative insulin sensitivity check index, triglycerides, aspartate aminotransferase (AST), and gamma-glutamyltranspeptidase. We propose an easy equation to estimate the amount of macrophages in omental WAT. Increased macrophage accumulation specifically in omental WAT was associated with hepatic fibroinflammatory lesions (P=0.01). The best predictive model for the severity of hepatic damage includes adiponectinemia, AST, and omental WAT macrophages. These data suggest that the presence of macrophages in omental WAT participates in the cellular mechanisms favoring hepatic fibroinflammatory lesions in obese patients.
Adipocytes↗
A clear cell malignant gastrinoma of the pancreas with cytoplasmic accumulation of lipid droplets.
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Adenocarcinoma, Clear Cell↗
Molecular profiling of early stage liver fibrosis in patients with chronic hepatitis C virus infection.
The molecular mechanisms of acute hepatitis C virus (HCV) infection, end-stage hepatitis (cirrhosis), and hepatocellular carcinoma have been extensively studied, but little is known of the changes in liver gene expression during the early stages of liver fibrosis associated with chronic HCV infection, that is, the transition from normal liver (NL) of uninfected patients to the first stage of liver fibrosis (F1-CH-C). To obtain insight into the molecular pathogenesis of F1-CH-C, we used real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to study the mRNA expression of 240 selected genes in liver tissue with F1-CH-C, in comparison with NL. The expression of 54 (22.5%) of the 240 genes was significantly different between F1-CH-C and NL; 46 genes were upregulated and 8 were downregulated in F1-CH-C. The most noteworthy changes in gene expression mainly affected the transcriptional network regulated by interferons (IFNs), including both IFN-alpha/beta-inducible genes (STAT1, STAT2, ISGF3G/IRF9, IFI27, G1P3, G1P2, OAS2, MX1) and IFN-gamma-inducible genes (CXCL9, CXCL10, CXCL11). Interesting, upregulation of IFN-alpha/beta-inducible genes (but not IFN-gamma-inducible genes) was independent of histological scores (grade and stage of fibrosis) and HCV characteristics (hepatic HCV mRNA levels and the HCV genotype), and was specific to HCV (as compared to hepatitis B virus (HBV)). Other genes dysregulated in F1-CH-C, albeit less markedly than IFN-alpha/beta- and IFN-gamma-inducible genes, were mainly involved in the activation of lymphocytes infiltrating the liver (IFNG, TNF, CXCL6, IL6, CCL8, CXCR3, CXCR4, CCR2), cell proliferation (p16/CDKN2A, MKI67, p14/ARF), extracellular matrix remodeling (MMP9, ITGA2), lymphangiogenesis (XLKD1/LYVE), oxidative stress (CYP2E1), and cytoskeleton microtubule organization (STMN2/SCG10). Thus, a limited number of signaling pathways, and particularly the transcriptional network regulated by interferons, are dysregulated in the first stage of HCV-induced liver fibrosis. Some of the genes identified here could form the basis for new approaches aimed at refining IFN-based therapies for chronic HCV infection.
Gene Expression↗
Identification of a new marker of hepatocellular carcinoma by serum protein profiling of patients with chronic liver diseases.
Surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS) is a proteomic technique that enables the profiling of proteins present in any biological material studied. We used this approach to identify new biomarkers of hepatocellular carcinoma (HCC) in the sera of patients with cirrhosis. Sera from 82 patients with cirrhosis, either without (n = 38) or with (n = 44) HCC, were analyzed by SELDI-TOF MS, and the results of the two groups were compared. The most efficient protein peaks leading to discrimination of patients with HCC were selected (receiver operative characteristic curves). The highest-scoring peak combination was established in a first group of serum samples (multinomial regression) and was tested in an independent group. The protein corresponding to the highest discrimination was purified and characterized further. The intensity of 30 protein peaks significantly differed between cirrhotic patients with and without HCC. An algorithm including the six highest-scoring peaks allowed correct classification (presence or absence of HCC) of 92.5% of patients in the test sample set and 90% in the validation sample set. The highest discriminating peak (8900 Da) was purified further and was characterized as the C-terminal part of the V10 fragment of vitronectin. An in vitro study suggested that the increase of the 8900-Da fragment in the serum of patients with HCC may proceed from the cleavage of native vitronectin with metalloproteases, a family of enzymes whose activity is enhanced in HCC. In conclusion, global protein profiling is an efficient approach that enabled us to identify a catalytic fragment ofvitronectin as a new serum marker of HCC in patients with chronic liver diseases.
Aged↗
Sources of variability in histological scoring of chronic viral hepatitis.
Inter-observer agreement on activity and fibrosis scores used in chronic viral hepatitis has only been studied under selected conditions. The aim of this study was to identify the sources of variability due to specimen characteristics and observers. This study included 254 liver specimens and 15 pathologists and used the Metavir score. In 44 specimens scored by 4 academic pathologists, agreement of Metavir score was good overall, but better for fibrosis (kappa = 0.59) than for activity (kappa = 0.43) and poor for lobular necrosis (kappa = 0.15). The mean agreement was better for senior (0.60 +/- 0.24) than junior pathologists (0.52 +/- 0.30, P < .05). Mean intrabserver agreement was better than inter-observer agreement (0.77 +/- 0.18 vs. 0.58 +/- 0.26, P < .01). In 157 specimens scored by 2 expert pathologists (one senior, one junior), agreement of Metavir score was only good but greatly improved after consensus reading (fibrosis: kappa = 0.48 and 0.77, activity: kappa = 0.44 and 0.70, respectively, before and after consensus). Several causes of disagreement were identified: specimen length, fibrosis class number, observer bias, and putative causes related to Metavir score or specimen. In an intercenter evaluation involving 59 specimens, 1 expert and 10 nonacademic pathologists, agreement was very poor and did not improve over 5 years for activity (kappa = 0.22-0.25) or fibrosis (kappa = 0.13-0.18). In conclusion, the level of experience (specialization, duration, and location of practice) has more influence on agreement than the characteristics of the specimen (length, fibrosis class number, miscellaneous factors). Agreement can be improved by experienced pathologist or consensus reading.
Academic Medical Centers↗
[Post-cholecystectomy amputation neuroma of the common bile duct with obstructive jaundice].
Amputation neuroma of the common bile duct after surgery is a rare and mostly asymptomatic lesion. A 60-year old patient presented with obstructive jaundice three months after a cholecystectomy for symptomatic gallstones. Imaging investigations showed common extrahepatic bile duct stenosis. Surgical resection of the stricture with biliodigestive anastomosis was performed. Histological examination of the surgical specimen revealed an amputation neuroma. Despite its rarity, amputation neuroma of the common bile duct should be considered in patients with post-cholecystectomy syndrome following liver or extrahepatic bile duct surgical procedures.
Cholecystectomy↗
Liver gene expression signature of mild fibrosis in patients with chronic hepatitis C.
BACKGROUND & AIMS: The molecular mechanisms of hepatocellular carcinoma have been studied, but little is known of the changes in liver gene expression during the different stages of chronic hepatitis C virus (HCV) infection, in particular the transition from mild to moderate fibrosis. METHODS: We used real-time quantitative RT PCR to study the messenger RNA expression of 240 selected genes in 2 pools of liver specimens according to the stages of fibrosis (Metavir score; mild fibrosis = F1 and septal fibrosis = F2). Genes whose expression differed between pools (F2 vs F1) by at least 2-fold were selected. In addition, the expression level of these selected genes then was assessed in each of the 62 individual samples (F4, n = 6; F3, n = 17; F2, n = 21; vs F1, n = 18). RESULTS: The 22 genes that were up-regulated in the 21 F2 samples relative to the 18 F1 samples mainly encoded genes involved in cytoskeleton (KRT 19 and SCG 10), growth factors/cytokines (CXCL6, interleukin 8 [IL8], IL1A, IL2, and CXCL10), or growth factor receptors (CCR2, CXCR3, and CXCR4), or were involved in extracellular matrix production (COL1A1, CHI3L, and SPP1), in extracellular matrix remodeling (TIMP1, MMP7, and MMP9), and in cell junction (ITGA2 and CLDN 4). When hierarchically clustering the F2 and F1 samples according to the expression of the 11 most discriminatory genes (KRT 19, COL1A1, STMN2, CXCL6, CCR2, TIMP1, IL8, IL1A, ITGA2, CLDN 4, and IL2), the patient population was categorized into 2 subgroups: F1 and F2. Specifically, 15 of 18 F1 (83%) and 19 of 21 F2 (90%) were classified correctly (P < 10(-5)). We also studied the messenger RNA expression of these 240 selected genes in normal liver in comparison with F1. Genes dysregulated in the transition from normal liver to F1 mainly were interferon-inducible genes, and therefore were very different from those dysregulated in the transition from F1 to F2. CONCLUSIONS: Genes involved in extracellular matrix turnover and immune response are implicated in the transition from mild to moderate fibrosis. Eleven of the genes could form the basis for the gene expression signature of mild versus moderate fibrosis in patients with chronic hepatitis C.
Adult↗