ABSTRACT
BACKGROUND: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. METHODS: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. FINDINGS: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. INTERPRETATION: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. FUNDING: The Wellcome Trust, the MRC.
ABSTRACT
BACKGROUND: Cerebral small-vessel disease (cSVD) is the leading monogenic cause of stroke. Despite genetic screening in routine diagnosis, many cases remain without a known causative variant. Using a cohort with suspected familial cSVD and whole-genome sequencing, we screened for variants in genes associated with monogenic cSVD and searched for novel variants associated with the disease. METHODS AND RESULTS: Rare variants were identified in whole-genome sequencing data from the NBR (National Institute for Health Research BioResource Rare Disease) study. Pathogenic variants in known monogenic cSVD genes were identified. Gene-based burden tests and family analysis were performed to identify novel variants associated with familial cSVD. A total of 257 suspected cSVD cases (mean ± SD age, 56.2 ± 16.1 years), and 13 086 controls with other nonstroke diseases (5874 [44.9%] men) were studied. A total of 8.9% of the cases carried a variant in known cSVD genes. Excluding these known causes, 23.6% of unrelated subjects with cSVD carried predicted deleterious variants in the Genomics England gene panel, but no association was found with cSVD in burden tests. We identified potential associations with cSVD in noncoding genes, including RP4-568F9.3 (adjusted P = 7.1 × 10-25), RP3-466I7.1 (adjusted P = 8.9 × 10-16), and ZNF209P (adjusted P = 1.0 × 10-15), and matrisomal genes (adjusted P = 5.1 × 10-6), including FAM20C, INHA, LAMC1, and VWA5B2. CONCLUSIONS: Predicted deleterious variants in known cSVD genes were present in 23.6% of unrelated cases with cSVD, but none of the genes were associated with the disease. Rare variants in noncoding and matrisomal genes could potentially contribute to cSVD development. These genes could play a role in tissue development and brain endothelial cell function. However, further studies are needed to confirm their pathophysiological roles.
Subject(s)
Cerebral Small Vessel Diseases , Genetic Predisposition to Disease , Whole Genome Sequencing , Humans , Cerebral Small Vessel Diseases/genetics , Male , Female , Middle Aged , Aged , Adult , Genetic Variation , Pedigree , Case-Control Studies , Phenotype , Mutation , Risk FactorsABSTRACT
Importance: It is uncertain whether typical variants causing monogenic stroke are associated with cerebrovascular disease in the general population and why the phenotype of these variants varies so widely. Objective: To determine the frequency of pathogenic variants in the 3 most common monogenic cerebral small vessel diseases (cSVD) and their associations with prevalent and incident stroke and dementia. Design, Setting, and Participants: This cohort study is a multicenter population-based study of data from UK Biobank participants recruited in 2006 through 2010, with the latest follow-up in September 2021. A total of 9.2 million individuals aged 40 to 69 years who lived in the United Kingdom were invited to join UK Biobank, of whom 5.5% participated in the baseline assessment. Participants eligible for our study (n = 454â¯756, excluding 48â¯569 with incomplete data) had whole-exome sequencing and available data pertaining to lacunar stroke-related diseases, namely stroke, dementia, migraine, and epilepsy. Exposures: NOTCH3, HTRA1, and COL4A1/2 pathogenic variants in monogenic stroke; Framingham cardiovascular risk; and ischemic stroke polygenic risk. Main Outcomes and Measures: Primary outcomes were prevalent and incident stroke and dementia. Odds ratios (ORs) and hazard ratios (HRs) were adjusted for age, sex, ethnicity, exome sequencing batch, and top 10 genetic principal components. Results: Of the 454â¯756 participants (208â¯027 [45.8%] men; mean [SD] age, 56.5 [8.1] years), 973 participants carried NOTCH3 variants, 546 carried HTRA1 variants, and 336 carried COL4A1/2 variants. Variant carriers were at least 66% more likely to have had stroke. NOTCH3 carriers had increased vascular dementia risk (OR, 5.42; 95% CI, 3.11-8.74), HTRA1 carriers an increased all-cause dementia risk (OR, 2.17; 95% CI, 1.28-3.41), and COL4A1/2 carriers an increased intracerebral hemorrhage risk (OR, 3.56; 95% CI, 1.34-7.53). NOTCH3 variants were associated with incident ischemic stroke and vascular dementia. NOTCH3 and HTRA1 variants were associated with magnetic resonance imaging markers of cSVD. Cardiovascular risk burden was associated with increased stroke risk in NOTCH3 and HTRA1 carriers. Variant location was also associated with risk. Conclusions and Relevance: In this cohort study, pathogenic variants associated with rare monogenic stroke were more common than expected in the general population and associated with stroke and dementia. Cardiovascular risk burden is associated with the penetrance of such variants. Our results support the hypothesis that cardiovascular risk factor control may improve disease prognosis in individuals with monogenic cSVD variants. This lays the foundation for future studies to evaluate the effect of early identification before symptom onset on mitigating stroke and dementia risk.
Subject(s)
Cerebral Small Vessel Diseases , Dementia, Vascular , Stroke, Lacunar , Stroke , Humans , Cohort Studies , Cerebral Small Vessel Diseases/epidemiology , Cerebral Small Vessel Diseases/genetics , Stroke/epidemiology , Stroke/genetics , Stroke, Lacunar/genetics , Risk Factors , High-Temperature Requirement A Serine Peptidase 1ABSTRACT
BACKGROUND AND OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by a cysteine-altering mutation in one of the thirty-four epidermal growth factor-like repeat (EGFR) domains of the NOTCH3 protein. CADASIL has a variable phenotypic presentation and NOTCH3 mutations in EGFRs 1-6 have been found correlated with greater disease severity. We examined clinical and radiological features and performed bioinformatic annotation of mutations in a large CADASIL cohort to further understand these associations. METHODS: We examined the association of NOTCH3 variant position on stroke onset and other clinical features among patients with CADASIL from the United Kingdom. We also explored how in-silico predicted protein aggregation differed by variant position and the extent to which this affected stroke risk. RESULTS: We identified 76 different cysteine-altering NOTCH3 variants in our cohort of 485 patients (mean age: 50.1 years; % male: 57.5). After controlling for cardiovascular risk factors, variants in EGFRs 1-6 were associated with earlier onset of stroke (hazard ratio [HR]: 2.05, 95% CI: 1.43-2.94) and encephalopathy (HR: 2.70, 95% CI: 1.15-6.37), than variants in EGFRs 7-34. Although the risk of stroke was higher in the patients with predicted protein aggregation (HR: 1.50, 95% CI: 1.05-2.14), this association was no longer significant after controlling for variant site. Further analysis suggested lower stroke risk was observed for variants in EGFRs 10-17 compared to variants in the other EGFR domains. DISCUSSION: NOTCH3 variant position is a predictor of stroke and encephalopathy in CADASIL independent of cardiovascular risk factors. Lower stroke risk was found for variants in EGFRs 10-17. Molecular factors that influence CADASIL disease severity remain to be determined.
ABSTRACT
BACKGROUND: Cysteine-altering NOTCH3 variants identical to those causing the rare monogenic form of stroke, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), have been reported more common than expected in the general population, but their clinical significance and contribution to stroke and dementia risk in the community remain unclear. METHODS: Cysteine-altering NOTCH3 variants were identified in UK Biobank whole-exome sequencing data (N=200 632). Frequency of stroke, vascular dementia and other clinical features of CADASIL, and MRI white matter hyperintensity volume were compared between variant carriers and non-carriers. MRIs from those with variants were visually rated, each matched with three controls. RESULTS: Of 200 632 participants with exome sequencing data available, 443 (~1 in 450) carried 67 different cysteine-altering NOTCH3 variants. After adjustment for various covariates, NOTCH3 variant carriers had increased risk of stroke (OR: 2.33, p=0.0004) and vascular dementia (OR: 5.00, p=0.007), and increased white matter hyperintensity volume (standardised difference: 0.52, p<0.001) and white matter ultrastructural damage on diffusion MRI (standardised difference: 0.72, p<0.001). On visual analysis of MRIs from 47 carriers and 148 matched controls, variants were associated with presence of lacunes (OR: 5.97, p<0.001) and cerebral microbleeds (OR: 4.38, p<0.001). White matter hyperintensity prevalence was most increased in the anterior temporal lobes (OR: 7.65, p<0.001) and external capsule (OR: 13.32, p<0.001). CONCLUSIONS: Cysteine-changing NOTCH3 variants are more common in the general population than expected from CADASIL prevalence and are risk factors for apparently 'sporadic' stroke and vascular dementia. They are associated with MRI changes of small vessel disease, in a distribution similar to that seen in CADASIL.
Subject(s)
CADASIL/genetics , Dementia, Vascular/genetics , Genetic Predisposition to Disease , Receptor, Notch3/genetics , Stroke/genetics , Adult , Aged , Brain/diagnostic imaging , Dementia, Vascular/diagnostic imaging , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Stroke/diagnostic imagingABSTRACT
Peer aggression and victimization are ubiquitous phenomena in schools which warrant the attention of educators and researchers. The high connection between aggression and victimization behooves researchers to look into how the comorbidity of them develops over time. The present study investigated the associations between aggression and victimization over 3 years in early adolescence and whether these associations are moderated by gender and teacher support. Participants were 567 Grade 7, 8 and 9 students (49.38% girls) from 3 schools in Hong Kong. Over the course of study, they were asked to fill in a set of questionnaires that consisted of items related to peer aggression, victimization, and teacher support at 5 time points. Four models of cross-lagged relations between peer aggression and victimization were tested. The results supported a reciprocal model of peer aggression and victimization for both boys and girls although girls engaged in less peer aggression and victimization than boys. Further analyses also revealed that teacher support acted as a suppressor of the reciprocal relations. The present study sheds lights on intervention strategies that may remediate peer aggression and victimization in schools.
Subject(s)
Adolescent Behavior/psychology , Aggression/psychology , Bullying/psychology , Crime Victims/psychology , Interpersonal Relations , Peer Group , School Teachers , Schools , Adolescent , Female , Hong Kong , Humans , Male , Sex FactorsABSTRACT
Polyaxial screw head dislocation in the absence of a manufacture defect is extremely rare and represents a biomechanical overload of the screw, leading to early failure. A 58-year-old gentleman underwent instrumented fusion using polyaxial pedicle screws-titanium rod construct with interbody cage for spondylolytic spondylolisthesis at the L5/S1 level. He attempted to bend forward ten days after the surgery which resulted in a dislocation of the right S1 polyaxial screw head from the screw shank with recurrence of symptoms. He underwent revision surgery uneventfully. This case highlights the need to pay particular attention to the strength of fixation and the amount of release to avoid such a complication.
ABSTRACT
BACKGROUND: A comprehensive understanding of the contextual factors that are linked to student engagement requires research that includes cross-cultural perspectives. AIMS: This study investigated how student engagement in school is associated with grade, gender, and contextual factors across 12 countries. It also investigated whether these associations vary across countries with different levels of individualism and socio-economic development. SAMPLES: The participants were 3,420 7th, 8th, and 9th grade students from Austria, Canada, China, Cyprus, Estonia, Greece, Malta, Portugal, Romania, South Korea, the United Kingdom, and the United States. METHODS: The participants completed a questionnaire to report their engagement in school, the instructional practices they experienced, and the support they received from teachers, peers, and parents. Hierarchical linear modelling was used to examine the effects at both student and country levels. RESULTS: The results across countries revealed a decline in student engagement from Grade 7 to Grade 9, with girls reporting higher engagement than boys. These trends did not vary across the 12 countries according to the Human Development Index and Hofstede's Individualism Index. Most of the contextual factors (instructional practices, teacher support, and parent support) were positively associated with student engagement. With the exception that parent support had a stronger association with student engagement in countries with higher collectivism, most of the associations between the contextual factors and student engagement did not vary across countries. CONCLUSIONS: The results indicate both cultural universality and specificity regarding contextual factors associated with student engagement in school. They illustrate the advantages of integrating etic and emic approaches in cross-cultural investigations.
Subject(s)
Individuality , Schools , Students , Adolescent , Child , Cross-Cultural Comparison , Faculty , Female , Humans , Male , Peer Group , Surveys and Questionnaires , United StatesSubject(s)
Antiviral Agents/adverse effects , Drug Eruptions/diagnosis , Hepatitis C/drug therapy , Interferons/adverse effects , Oligopeptides/adverse effects , Ribavirin/adverse effects , Aged , Antiviral Agents/therapeutic use , Biopsy , Female , Humans , Interferons/therapeutic use , Male , Middle Aged , Oligopeptides/therapeutic use , Prospective Studies , Ribavirin/therapeutic use , Risk FactorsABSTRACT
The contribution of social context to school bullying was examined from the self-determination theory perspective in this longitudinal study of 536 adolescents from 3 secondary schools in Hong Kong. Latent class growth analysis of the student-reported data at 5 time points from grade 7 to grade 9 identified 4 groups of students: bullies (9.8%), victims (3.0%), bully-victims (9.4%), and typical students (77.8%). There was a significant association between academic tracking and group membership. Students from the school with the lowest academic performance had a greater chance of being victims and bully-victims. Longitudinal data showed that all 4 groups tended to report less victimization over the years. The victims and the typical students also had a tendency to report less bullying over the years, but this tendency was reversed for bullies and bully-victims. Perceived support from teachers for relatedness significantly predicted membership of the groups of bullies and victims. Students with higher perceived support for relatedness from their teachers had a significantly lower likelihood of being bullies or victims. The findings have implications for the theory and practice of preventive interventions in school bullying.
Subject(s)
Bullying , Crime Victims , Schools , Social Environment , Adolescent , Faculty , Female , Hong Kong , Humans , Longitudinal Studies , Male , Psychoanalytic Theory , Social Support , Statistics as TopicABSTRACT
The objective of the present study was to develop a scale that is appropriate for use internationally to measure affective, behavioral, and cognitive dimensions of student engagement. Psychometric properties of this scale were examined with data of 3,420 students (7th, 8th, and 9th grade) from 12 countries (Austria, Canada, China, Cyprus, Estonia, Greece, Malta, Portugal, Romania, South Korea, the United Kingdom, and the United States). The intraclass correlation of the full-scale scores of student engagement between countries revealed that it was appropriate to aggregate the data from the 12 countries for further analyses. Coefficient alphas revealed good internal consistency. Test-retest reliability coefficients were also acceptable. Confirmatory factor analyses indicated that the data fit well to a second-order model with affective, behavioral, and cognitive engagement as the first-order factors and student engagement as the second-order factor. The results support the use of this scale to measure student engagement as a metaconstruct. Furthermore, the significant correlations of the scale with instructional practices, teacher support, peer support, parent support, emotions, academic performance, and school conduct indicated good concurrent validity of the scale. Considerations and implications regarding the international use of this student engagement in school measure are discussed.
Subject(s)
Achievement , Cognition , Learning , Schools , Students/psychology , Adolescent , Child , Emotions , Factor Analysis, Statistical , Female , Humans , Male , Psychometrics , Reproducibility of ResultsABSTRACT
BACKGROUND: Liver stiffness and non-invasive tests predict overall survival in chronic hepatitis C. However, in patients chronically infected with hepatitis B virus (HBV), only the association between liver stiffness and the risk of hepatocellular carcinoma has been published. AIM: To evaluate the 5-year prognostic value of liver stiffness, non-invasive tests of liver fibrosis, and liver biopsy, to predict overall survival in chronic hepatitis B. METHODS: In a consecutive cohort, we prospectively assessed fibrosis, with liver stiffness, FibroTest, APRI, FIB-4 and liver biopsy (if indicated). We examined death and liver transplantation during a 5-year follow-up, and factors associated with overall survival. RESULTS: A total of 600 patients (men 64%, mean age 42 years, inactive carriers 36%) with chronic hepatitis B were included. At 5 years, 25 patients were dead (13 liver-related deaths) and four patients had liver transplantation. Overall survival was 94.1% and survival without liver-related death 96.3%. No liver-related death was observed in inactive carriers. Survival was significantly decreased in patients diagnosed with severe fibrosis, whatever the non-invasive method used (P < 0.0001), or liver biopsy (P = 0.02). Patients' prognosis decreased as liver stiffness and FibroTest increased. In multivariate analysis, FibroTest and liver stiffness had the highest hazard ratio with survival. The association persisted after adjustment on age, necro-inflammatory histological activity presumed by ActiTest and treatment. CONCLUSIONS: Liver stiffness measurement or FibroTest can predict survival in chronic HBV infection. Thus, these tools may help physicians to early assess prognosis and discuss specific treatments, such as liver transplantation.
Subject(s)
Elasticity Imaging Techniques , Hepatitis B, Chronic/mortality , Liver Cirrhosis/diagnosis , Liver/pathology , Adult , Biomarkers , Biopsy , DNA, Viral/analysis , Female , Hepatitis B Antigens/immunology , Hepatitis B virus/genetics , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/immunology , Humans , Liver Function Tests , Liver Transplantation , Male , Middle Aged , Predictive Value of Tests , Prognosis , Prospective Studies , Survival Rate , Time FactorsSubject(s)
Acute Kidney Injury/chemically induced , Anti-Bacterial Agents/adverse effects , Arthroplasty, Replacement, Knee , Bone Cements/adverse effects , Drug-Related Side Effects and Adverse Reactions/complications , Aged , Anti-Bacterial Agents/administration & dosage , Female , Humans , Surgical Wound Infection/prevention & control , Treatment OutcomeABSTRACT
This study examined gender differences in student engagement and academic performance in school. Participants included 3420 students (7th, 8th, and 9th graders) from Austria, Canada, China, Cyprus, Estonia, Greece, Malta, Portugal, Romania, South Korea, the United Kingdom, and the United States. The results indicated that, compared to boys, girls reported higher levels of engagement in school and were rated higher by their teachers in academic performance. Student engagement accounted for gender differences in academic performance, but gender did not moderate the associations among student engagement, academic performance, or contextual supports. Analysis of multiple-group structural equation modeling revealed that perceptions of teacher support and parent support, but not peer support, were related indirectly to academic performance through student engagement. This partial mediation model was invariant across gender. The findings from this study enhance the understanding about the contextual and personal factors associated with girls' and boys' academic performance around the world.
Subject(s)
Achievement , Perception , Schools , Social Environment , Students/psychology , Adolescent , Canada , Child , China , Cross-Cultural Comparison , Educational Status , Europe , Female , Humans , Male , Models, Psychological , Peer Group , Sex Factors , Surveys and Questionnaires , United StatesABSTRACT
BACKGROUND: Non invasive methods for fibrosis evaluation remain to be validated longitudinally in hepatitis B. AIM: To evaluate longitudinally transient elastography (TE) and biomarkers for liver fibrosis assessment and follow-up of hepatitis B virus (HBV) inactive carriers. METHODS: Three hundred and twenty-nine consecutive HBeAg-negative HBV patients (201 inactive carriers) who underwent TE, Fibrotest and aspartate to platelet ratio index (APRI) the same day were studied. RESULTS: TE (median 4.8 vs. 6.8 kPa, P < 0.0001), Fibrotest (0.16 vs. 0.35, P < 0.0001) and APRI values (0.28 vs. 0.43, P < 0.0001) were significantly lower in inactive carriers than in the remaining patients whereas they did not differ among inactive carriers according to HBV DNA levels. In 82 inactive carriers with repeated examinations, although differences were observed among individual patients, TE values did not differ significantly over time (median intra-patient changes at end of follow-up relative to baseline: -0.2 kPa, P = 0.12). Conversely, significant fluctuations were observed for Fibrotest (+0.03, P = 0.012) and APRI (-0.01, P < 0.05). Eleven inactive carriers (5.5%) had initial elevated TE values (>7.2 kPa) confirmed during follow-up in two with significant fibrosis (F2 and F3) on liver biopsy. CONCLUSION: Non-invasive tools, particularly TE, could be useful, in addition to HBV DNA and transaminase levels, for follow-up of HBV inactive carriers as well as better selection of patients who require a liver biopsy.
Subject(s)
Biomarkers/blood , Elasticity Imaging Techniques/methods , Hepatitis B/complications , Liver Cirrhosis/diagnosis , Adult , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Carrier State , Cross-Sectional Studies , Female , Hepatitis B/diagnostic imaging , Hepatitis B virus , Humans , Liver Cirrhosis/diagnostic imaging , Liver Cirrhosis/physiopathology , Longitudinal Studies , Male , Middle Aged , Predictive Value of Tests , Severity of Illness Index , Statistics as TopicABSTRACT
The present study compared how parents of preschoolers with and without Autism Spectrum Disorders (ASD) perceived and felt about participation in community activities. A questionnaire survey was conducted with 380 Hong Kong parents of preschoolers with ASD and 214 Hong Kong parents of preschoolers without ASD. The two groups were not different in their willingness and frequency of participation in community activities. However, the psychological processes underneath their willingness were very different. Among the parents of preschoolers with ASD, their willingness was associated with how they perceived the difficulty and importance of the participation and what emotions they experienced during the activities. This pattern of association was not evident among the parents of preschoolers without ASD.
Subject(s)
Child Development Disorders, Pervasive/psychology , Interpersonal Relations , Parents/psychology , Activities of Daily Living , Adult , Attitude , Child , Child, Preschool , Emotions , Female , Hong Kong , Humans , Male , Marital Status , Middle Aged , Residence Characteristics , Surveys and QuestionnairesABSTRACT
We prospectively assessed contrast-enhanced sonography for evaluating the degree of liver fibrosis as diagnosed via biopsy in 99 patients. The transit time of microbubbles between the portal and hepatic veins was calculated from the difference between the arrival time of the microbubbles in each vein. Liver biopsy was obtained for each patient within 6 months of the contrast-enhanced sonography. Histological fibrosis was categorized into two classes: (1) no or moderate fibrosis (F0, F1, and F2 according to the METAVIR staging) or (2) severe fibrosis (F3 and F4). At a cutoff of 13 s for the transit time, the diagnosis of severe fibrosis was made with a specificity of 78.57%, a sensitivity of 78.95%, a positive predictive value of 78.33%, a negative predictive value of 83.33%, and a performance accuracy of 78.79%. Therefore, contrast-enhanced ultrasound can help with differentiation between moderate and severe fibrosis.
Subject(s)
Algorithms , Biopsy , Image Enhancement/methods , Image Interpretation, Computer-Assisted/methods , Liver Cirrhosis/diagnosis , Phospholipids , Sulfur Hexafluoride , Ultrasonography/methods , Adult , Aged , Aged, 80 and over , Contrast Media , Female , France , Humans , Liver Cirrhosis/classification , Male , Middle Aged , Observer Variation , Reproducibility of Results , Sensitivity and Specificity , Young AdultABSTRACT
The recent advent of non-invasive methods for assessment of fibrosis allows serial assessments in all patients with hepatitis C. The aim of this prospective study was to evaluate changes in liver fibrosis, as measured with non-invasive methods, in a large cohort of HCV-infected patients with and without treatment. From May 2003 through March 2006, all previously untreated HCV-infected patients were enrolled in this study. Liver fibrosis was staged with FibroScan and Fibrotest at inclusion, then every year in untreated patients, and at the end of treatment and 6 months later in treated patients. The study population consisted of 416 patients, of whom 112 started treatment after enrolment. In the treatment group, FibroScan and Fibrotest values were significantly higher before and after treatment than in untreated patients at baseline and after 1 year. However, there was no significant difference between treated and untreated patients at the end of follow-up. FibroScan and Fibrotest values fell in all treated patients, whatever their virological response. In multivariate analysis, treatment was the only factor independently associated with a fall in the FibroScan value. In conclusion, whatever the virological response, treatment for HCV infection is associated with an improvement of FibroScan and Fibrotest values. Further studies are needed to compare these non-invasive methods with liver biopsy. These non-invasive methods, and especially FibroScan, should be useful for assessing treatment efficacy in clinical trials of new drugs.
Subject(s)
Biomarkers/blood , Elasticity Imaging Techniques/methods , Hepatitis C/drug therapy , Liver Cirrhosis/pathology , Liver/pathology , Adult , Aged , Antiviral Agents/therapeutic use , Cohort Studies , Female , Humans , Interferon alpha-2 , Interferon-alpha/therapeutic use , Male , Middle Aged , Prospective Studies , RNA, Viral/blood , Recombinant Proteins , Ribavirin/therapeutic use , Severity of Illness Index , Treatment OutcomeABSTRACT
The recent availability of non-invasive tools to measure liver fibrosis has allowed examination of its extent and determination of predictors in all patients with chronic hepatitis C virus (HCV) infection. On the other hand, most information on hepatic fibrosis in HCV/human immunodeficiency virus (HIV)-coinfected patients has been derived from liver biopsies taken before highly active antiretroviral therapy (HAART) was widely available. All consecutive HCV patients with elevated aminotransferases seen during the last 3 years were evaluated and liver fibrosis measured using transient elastography (FibroScan) and biochemical indexes. Patients were split according to their HIV serostatus. A total of 656 (69.6%) HCV-monoinfected and 287 (30.4%) HIV/HCV-coinfected patients were assessed. Mean CD4 count of coinfected patients was 493 cells/muL and 88% were under HAART (mean time, 4.2 +/- 2.4 years). Advanced liver fibrosis or cirrhosis was recognized in 39% of the coinfected and 18% of the monoinfected patients (P < 0.005). A good correlation was found between FibroScan) and biochemical indexes [AST to platelet ratio index (r = 0.405, P < 0.0001), FIB-4 (r = 0.393, P < 0.0001) and Forns (r = 0.407, P < 0.0001)], regardless of the HIV status. In the multivariate analysis, age >45 years, body mass index (BMI) >25 kg/m(2), and HIV infection were independently associated with advanced liver fibrosis or cirrhosis. HIV/HCV-coinfected patients have more advanced liver fibrosis than HCV-monoinfected patients despite the immunologic benefit of HAART.