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Chi H, Gan C, Jiang Y, Chen D, Qiu J, Yang Q, Chen Y, Wang M, Yang H, Jiang W, Li Q. The compound heterozygous mutations of c.607G>a and c.657delC in the FAH gene are associated with renal damage with hereditary tyrosinemia type 1 (HT1). Mol Genet Genomic Med 2022; 11:e2090. [PMID: 36369907 PMCID: PMC9834193 DOI: 10.1002/mgg3.2090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/22/2022] [Accepted: 10/27/2022] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Hereditary tyrosinemia type 1 (HT1) is a rare inherited metabolic disease characterized by severe liver and renal dysfunction. Early identification in affected children is critical for improved treatment options and prognosis. METHODS In this study, we identified novel compound heterozygous mutations (NM_000137: c.657delC (p.K220Rfs*12) and c.607G>A (p.A203T)) in the fumarylacetoacetate hydrolase (FAH) gene in a family. We also characterized the clinical phenotype of the proband and verified the pathogenic effects of the mutations. Furthermore, we explored the pathogenic mechanism of renal injury through renal biopsy pathology and cell-based in vitro assays. Our study aims to verify the association between novel fumarylacetoacetate hydrolase (FAH) variants and HT1, confirm the pathogenic effects of the mutations and explore the pathogenic mechanism of renal injury. RESULTS We showed these FAH mutations were inherited in an autosomal recessive manner and resulted in abnormal FAH protein expression and dysfunction, leading to fumarylacetoacetate (FAA) accumulation. The proband also showed apparent renal injury, including glomerular filtration barrier dysfunction and abnormal tubular protein reabsorption. CONCLUSIONS These observations may provide deeper insights on disease pathogenesis and identify potential therapeutic approaches for HT1 from a genetic perspective. Similarly, we hope to provide valuable information for genetic counseling and prenatal diagnostics.
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Affiliation(s)
- Huan Chi
- Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of PediatricsChildren's Hospital of Chongqing Medical UniversityChongqingP.R. China
| | - Chun Gan
- Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of PediatricsChildren's Hospital of Chongqing Medical UniversityChongqingP.R. China
| | - Yaru Jiang
- Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of PediatricsChildren's Hospital of Chongqing Medical UniversityChongqingP.R. China
| | - Dan Chen
- Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of PediatricsChildren's Hospital of Chongqing Medical UniversityChongqingP.R. China
| | - Jiawen Qiu
- Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of PediatricsChildren's Hospital of Chongqing Medical UniversityChongqingP.R. China
| | - Qing Yang
- Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of PediatricsChildren's Hospital of Chongqing Medical UniversityChongqingP.R. China
| | - Yaxi Chen
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious DiseasesThe Second Affiliated Hospital, Chongqing Medical UniversityChongqingP.R. China
| | - Mo Wang
- Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of PediatricsChildren's Hospital of Chongqing Medical UniversityChongqingP.R. China
| | - Haiping Yang
- Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of PediatricsChildren's Hospital of Chongqing Medical UniversityChongqingP.R. China
| | - Wei Jiang
- Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of PediatricsChildren's Hospital of Chongqing Medical UniversityChongqingP.R. China
| | - Qiu Li
- Pediatric Research Institute, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child development and Critical Disorders, Chongqing Key Laboratory of PediatricsChildren's Hospital of Chongqing Medical UniversityChongqingP.R. China
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Wang F, Li Y, Zhao S, Chen Z, Xu Z, Wang L, Zhang TJ, Yan J, Cao L, Wang P, Li A, Zhong Y, Wu Z, Qi X, Zhang M, Wu N. The utility of hierarchical genetic testing in paediatric liver disease. Liver Int 2022; 42:1097-1108. [PMID: 35257483 DOI: 10.1111/liv.15235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/20/2021] [Accepted: 11/01/2021] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Genetic factors underlie a substantial proportion of paediatric liver diseases. Hereditary liver diseases have considerable genetic heterogeneity and variable clinical manifestations, which bring great challenges to clinical and molecular diagnoses. In this study, we investigated a group of paediatric patients with varying degrees of liver dysfunction using a hierarchical genetic testing strategy. METHODS We first applied a panel encompassing 166 known causal genes of liver disease. We then used exome sequencing (ES) in those patients whose cases remained undiagnosed to identify the genetic aetiology of their symptoms. RESULTS In total, we enrolled 131 unrelated paediatric patients with liver disease of Chinese Han ethnicity. We first applied targeted gene sequencing of 166 genes to all patients and yielded a diagnostic rate of 35.9% (47 of 131). Eighty-four patients who remained undiagnosed after target gene sequencing were subjected to ES. As a result, eight (8/84, 9.5%) of them obtained molecular diagnoses, including four patients suspected of abnormal bilirubin metabolism and four idiopathic cases. Non-typical genetic findings, including digenic inheritance and dual molecular diagnosis, were also identified. Through a comprehensive assessment of novel candidate variants of uncertain disease association, 11 patients of the remaining undiagnosed patients were able to obtain likely molecular diagnoses. CONCLUSIONS Our study presents evidence for the diagnostic utility of sequential genetic testing in a cohort of patients with paediatric liver disease. Our findings expand the understanding of the phenotypic and mutational spectrum underlying this heterogeneous group of diseases.
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Affiliation(s)
- Fuchuan Wang
- Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yaqi Li
- Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Sen Zhao
- Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Zefu Chen
- Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Zhiqiang Xu
- Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Lianlei Wang
- Department of Orthopedic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, P. R. China
| | - Terry Jianguo Zhang
- Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Jianguo Yan
- Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Lili Cao
- Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Pu Wang
- Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Aiqin Li
- Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yanwei Zhong
- Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhihong Wu
- Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.,Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaolong Qi
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou, China
| | - Min Zhang
- Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Nan Wu
- Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China.,Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
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Romero‐Cordero S, Noguera‐Julian A, Cardellach F, Fortuny C, Morén C. Mitochondrial changes associated with viral infectious diseases in the paediatric population. Rev Med Virol 2021; 31:e2232. [PMID: 33792105 PMCID: PMC9286481 DOI: 10.1002/rmv.2232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 12/24/2022]
Abstract
Infectious diseases occur worldwide with great frequency in both adults and children, causing 350,000 deaths in 2017, according to the latest World Health Organization reports. Both infections and their treatments trigger mitochondrial interactions at multiple levels: (i) incorporation of damaged or mutated proteins into the complexes of the electron transport chain; (ii) impact on mitochondrial genome (depletion, deletions and point mutations) and mitochondrial dynamics (fusion and fission); (iii) membrane potential impairment; (iv) apoptotic regulation; and (v) generation of reactive oxygen species, among others. Such alterations may result in serious adverse clinical events with considerable impact on the quality of life of the children and could even cause death. Herein, we use a systematic review to explore the association between mitochondrial alterations in paediatric infections including human immunodeficiency virus, cytomegalovirus, herpes viruses, various forms of hepatitis, adenovirus, T-cell lymphotropic virus and influenza. We analyse how these paediatric viral infectious processes may cause mitochondrial deterioration in this especially vulnerable population, with consideration for the principal aspects of research and diagnosis leading to improved disease understanding, management and surveillance.
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Affiliation(s)
- Sonia Romero‐Cordero
- Faculty of MedicinePompeu Fabra UniversityBarcelonaSpain
- Faculty of MedicineUniversitat Autònoma de BarcelonaBellaterraSpain
| | - Antoni Noguera‐Julian
- Malalties Infeccioses i Resposta Inflamatòria Sistèmica en PediatriaUnitat d´InfeccionsServei de PediatriaInstitut de Recerca Pediàtrica Hospital Sant Joan de DéuBarcelonaSpain
- Departament de PediatriaUniversitat de BarcelonaBarcelonaSpain
- CIBER de Epidemiología y Salud Pública, CIBERESP (ISCIII)MadridSpain
- Red de Investigación Translacional en Infectología PediátricaRITIPMadridSpain
| | - Francesc Cardellach
- Faculty of Medicine and Health SciencesMuscle Research and Mitochondrial Function LaboratoryCellex‐IDIBAPSUniversity of BarcelonaBarcelonaSpain
- CIBER de Enfermedades RarasCIBERER (ISCIII)MadridSpain
- Internal Medicine DepartmentHospital Clínic of Barcelona (HCB)BarcelonaSpain
| | - Clàudia Fortuny
- Malalties Infeccioses i Resposta Inflamatòria Sistèmica en PediatriaUnitat d´InfeccionsServei de PediatriaInstitut de Recerca Pediàtrica Hospital Sant Joan de DéuBarcelonaSpain
- Departament de PediatriaUniversitat de BarcelonaBarcelonaSpain
- CIBER de Epidemiología y Salud Pública, CIBERESP (ISCIII)MadridSpain
- Red de Investigación Translacional en Infectología PediátricaRITIPMadridSpain
| | - Constanza Morén
- Faculty of Medicine and Health SciencesMuscle Research and Mitochondrial Function LaboratoryCellex‐IDIBAPSUniversity of BarcelonaBarcelonaSpain
- CIBER de Enfermedades RarasCIBERER (ISCIII)MadridSpain
- Internal Medicine DepartmentHospital Clínic of Barcelona (HCB)BarcelonaSpain
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Utility and accuracy of transient elastography in determining liver fibrosis: a case-control study. Eur J Pediatr 2020; 179:671-677. [PMID: 31960149 DOI: 10.1007/s00431-019-03561-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 12/19/2019] [Accepted: 12/23/2019] [Indexed: 12/15/2022]
Abstract
The objectives of this prospective case-control study were to determine liver stiffness (LSM) by transient elastography (TE) in children with newly diagnosed chronic liver disease (CLD) and to find out normal values in healthy Indian children. Two groups (A: 50 CLD who underwent liver biopsy and B: 50 healthy) aged 5-18 years were recruited prospectively. Liver biopsies were scored as per Metavir scoring and compared with TE. The median age of 100 recruited children was 13.6 years. In group B, normal LSM was 4.9 (2.5-7.3) kPa with significantly higher LSM in adolescent males (5.6 (4.1-7.3) kPa) as compared with females (4.3 (3.7-4.9) kPa), p = 0.001. In group A, TE was excellent in discriminating significant fibrosis (≥ F2) (P = 0.001) at a cut-off value of 10.6 kPa with area under receiver operating characteristic curve of 0.96. Metavir fibrosis stage (β = 0.611; R2 = 0.586) and age (β = 0.230; R2 = 0.586) were independent variables associated with higher LSM in stepwise multiple logistic regression analysis.Conclusions: TE is an excellent non-invasive tool to assess significant liver fibrosis and can be used as an alternative to liver biopsy. Normative value of TE in adolescent males is higher than in females.What is Known:• Transient elastography is a good non-invasive test for liver fibrosis assessment.• Normal liver stiffness depends on race, gender, and age.What is New:• This is the first study from India to show the normative data of transient elastography in healthy Indian children.• We have documented that liver stiffness measurement by fibroscan in treatment naïve chronic liver disease has excellent correlation in significant fibrosis, severe fibrosis, and cirrhosis.
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Sun PX, Tong YY, Shi J, Zhang H, Liu SJ, Du J. Normal values of shear wave velocity in liver tissue of healthy children measured using the latest acoustic radiation force impulse technology. World J Clin Cases 2019; 7:3463-3473. [PMID: 31750329 PMCID: PMC6854399 DOI: 10.12998/wjcc.v7.i21.3463] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 09/25/2019] [Accepted: 10/15/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Several studies have demonstrated the feasibility and effectiveness of using ultrasound elastography to assess liver tissue stiffness. Virtual touch imaging quantification (VTIQ) based on acoustic radiation force impulse imaging has been developed as a latest and noninvasive method for assessing liver stiffness in children.
AIM To determine the standard value in healthy children, and to identify possible factors that might influence the VTIQ measurement.
METHODS With the ethical approval, 202 children between 1 month and 15 years old were included in this study. None of them had any liver or systematic diseases. All children had a normal ultrasound scan and normal body mass index (BMI) range. The subjects were divided into four age and BMI groups. The effects of gender, age, liver lobe, measurement depth, and BMI on liver elasticity were investigated.
RESULTS A significant correlation was found between age and shear wave velocity (SWV) value. At measurement depths of 1.5 cm and 2.0 cm in the left lobe, there were significant differences among the age groups. SWV values were significantly negatively correlated with the measurement depth. Gender, liver lobe, and BMI showed no significant effect on the SWV values. Age and BMI may influence the quality of the elastogram.
CONCLUSION VTIQ is a noninvasive technique that is feasible to measure liver stiffness in children. The afore-mentioned velocity value obtained utilizing VTIQ method could be used as reference value for normal liver stiffness in children.
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Affiliation(s)
- Pei-Xuan Sun
- Diagnostic Imaging Center, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yu-Yang Tong
- Department of Ultrasound, Shanghai Cancer Center, Fudan University, Shanghai 200032, China
| | - Jing Shi
- Diagnostic Imaging Center, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Huan Zhang
- Diagnostic Imaging Center, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Shi-Jian Liu
- Department of Clinical Epidemiology and Biostatistics, Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Jun Du
- Diagnostic Imaging Center, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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Engelmann G, Quader J, Teufel U, Schenk JP. Limitations and opportunities of non-invasive liver stiffness measurement in children. World J Hepatol 2017; 9:409-417. [PMID: 28357028 PMCID: PMC5355763 DOI: 10.4254/wjh.v9.i8.409] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 11/29/2016] [Accepted: 01/14/2017] [Indexed: 02/06/2023] Open
Abstract
Changes in liver structure are an important issue in chronic hepatopathies. Until the end of the 20th century, these changes could only be determined by histological analyses of a liver specimen obtained via biopsy. The well-known limitations of this technique (i.e., pain, bleeding and the need for sedation) have precluded its routine use in follow-up of patients with liver diseases. However, the introduction of non-invasive technologies, such as ultrasound and magnetic resonance imaging, for measurement of liver stiffness as an indirect marker of fibroses has changed this situation. Today, several non-invasive tools are available to physicians to estimate the degree of liver fibrosis by analysing liver stiffness. This review describes the currently available tools for liver stiffness determination that are applicable to follow-up of liver fibrosis/cirrhosis with established clinical use in children, and discusses their features in comparison to the “historical” tools.
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Elevation of Alanine Aminotransferase Activity Occurs after Activation of the Cell-Death Signaling Initiated by Pattern-Recognition Receptors but before Activation of Cytolytic Effectors in NK or CD8+ T Cells in the Liver During Acute HCV Infection. PLoS One 2016; 11:e0165533. [PMID: 27788241 PMCID: PMC5082795 DOI: 10.1371/journal.pone.0165533] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 10/13/2016] [Indexed: 02/06/2023] Open
Abstract
Pattern-recognition receptors (PRRs) promote host defenses against HCV infection by binding to their corresponding adapter molecules leading to the initiation of innate immune responses including cell death. We investigated the expression of PRR genes, biomarkers of liver cell-death, and T cell and NK cell activation/inhibition-related genes in liver and serum obtained from three experimentally infected chimpanzees with acute HCV infection, and analyzed the correlation between gene expression levels and clinical profiles. Our results showed that expression of hepatic RIG-I, TLR3, TLR7, 2OAS1, and CXCL10 mRNAs was upregulated as early as 7 days post-inoculation and peaked 12 to 83 days post-inoculation. All of the three HCV infected chimpanzees exhibited significant elevations of serum alanine aminotransferase (ALT) activity between 70 and 95 days after inoculation. Elevated levels of serum cytokeratin 18 (CK-18) and caspases 3 and 7 activity coincided closely with the rise of ALT activity, and were preceded by significant increases in levels of caspase 3 and caspase 7 mRNAs in the liver. Particularly we found that significant positive auto-correlations were observed between RIG-I, TLR3, CXCL10, 2OAS1, and PD-L1 mRNA and ALT activity at 3 to 12 days before the peak of ALT activity. However, we observed substantial negative auto-correlations between T cell and NK cell activation/inhibition-related genes and ALT activity at 5 to 32 days after the peak of ALT activity. Our results indicated cell death signaling is preceded by early induction of RIG-I, TLR3, 2OAS1, and CXCL10 mRNAs which leads to elevation of ALT activity and this signaling pathway occurs before the activation of NK and T cells during acute HCV infection. Our study suggests that PRRs and type I IFN response may play a critical role in development of liver cell injury related to viral clearance during acute HCV infection.
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Revill PA, Locarnini SA. New perspectives on the hepatitis B virus life cycle in the human liver. J Clin Invest 2016; 126:833-6. [PMID: 26901815 DOI: 10.1172/jci86650] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The central role of the transcriptional template of the hepatitis B virus (HBV), covalently closed circular DNA (cccDNA), has been difficult to study in patients with chronic hepatitis B (CHB) infection. In this issue of the JCI, Zhang and colleagues reveal a mosaic distribution of viral antigens and nucleic acids and a mismatch between HBV cccDNA, RNA, and expression of the hepatitis B surface antigen (HBsAg). These unusual patterns varied over the natural history of CHB, prompting the authors to propose a new three-stage model of the HBV life cycle at the single-cell level.
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Nichtalkoholische Steatohepatitis mit Zirrhose bei jungen Erwachsenen mit hypothalamisch-hypophysärer Dysfunktion. DER PATHOLOGE 2013; 34:318-22. [DOI: 10.1007/s00292-012-1735-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Engelmann G, Gebhardt C, Wenning D, Wühl E, Hoffmann GF, Selmi B, Grulich-Henn J, Schenk JP, Teufel U. Feasibility study and control values of transient elastography in healthy children. Eur J Pediatr 2012; 171:353-60. [PMID: 21861093 DOI: 10.1007/s00431-011-1558-7] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Accepted: 08/10/2011] [Indexed: 12/14/2022]
Abstract
Transient elastography (TE) is a new technique for the non-invasive assessment of liver fibrosis. The degree of fibrosis is equivalent to the liver stiffness measured in kilopascal (kPa). It is frequently used in adult patients with a mean normal stiffness of 4.4-5.5 kPa. Since 2008, liver stiffness can be measured even in small children and infants following the availability of a new probe with a smaller diameter (S-probe 5 mm) than the regular probe (M-probe 7 mm). We report control values for healthy children between 0 and 18 years and investigated the feasibility of this technique in a pediatric population. For control values, TE was performed in infants and children after exclusion of liver disease by medical history, clinical examination, blood investigation, and abdominal ultrasound. For feasibility analyses the results of all TE performed in our clinic were analyzed irrespective of the underlying disease. Liver stiffness was measured with the S-probe (thorax diameter <45 cm (S1) or 45-75 cm (S2)) and the M-probe (thorax diameter >75 cm) according to the manufacturer's recommendations. A total of 240 healthy children were analyzed to establish control values. The median liver stiffness was 4.7 kPa resulting in an upper limit of normal of 6.47 kPa. Median values of stiffness were significantly age dependent with 4.40, 4.73, and 5.1 kPa in children 0-5, 6-11, and 12-18 years (p = 0.001) while the interquartile range decreased with age (0.8, 0.7, and 0.6 kPa). The resulting upper limit of normal (median plus 1.64 times standard deviation) was 5.96, 6.65, and 6.82 kPa. Girls between 11 and 18 years showed a significantly lower median stiffness than boys of the same age (4.7 vs. 5.6 kPa; p < 0.005). Feasibility was tested in 975 consecutive liver stiffness measurements (LSM) in children 0-18 years of age. Patients with invalid LSM were significantly younger than those with valid LSM (5.8 vs. 9.7 years, p < 0.0001), showed a significantly higher stiffness (10.2 vs. 6.17, p < 0.0001), and examinations took significantly longer (202 vs. 160 s, p < 0.0001). TE is technically possible in children of all age groups. The upper limit of normal increases significantly with age. Due to movement artifacts the measurement is reliable from the age of 6 without sedation. In younger children the number of invalid measurements increases significantly. Further studies are needed to asses the value of TE in the diagnosis and follow-up of liver disease in pediatric hepatology.
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Affiliation(s)
- Guido Engelmann
- Department of General Pediatrics, University Hospital, Heidelberg, INF 430, 69120 Heidelberg, Germany.
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Engelmann G, Gebhardt C, Wenning D, Wühl E, Hoffmann GF, Selmi B, Grulich-Henn J, Schenk JP, Teufel U. Feasibility study and control values of transient elastography in healthy children. Eur J Pediatr 2011. [PMID: 21861093 DOI: 10.1007/s00431-012-1778-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Transient elastography (TE) is a new technique for the non-invasive assessment of liver fibrosis. The degree of fibrosis is equivalent to the liver stiffness measured in kilopascal (kPa). It is frequently used in adult patients with a mean normal stiffness of 4.4-5.5 kPa. Since 2008, liver stiffness can be measured even in small children and infants following the availability of a new probe with a smaller diameter (S-probe 5 mm) than the regular probe (M-probe 7 mm). We report control values for healthy children between 0 and 18 years and investigated the feasibility of this technique in a pediatric population. For control values, TE was performed in infants and children after exclusion of liver disease by medical history, clinical examination, blood investigation, and abdominal ultrasound. For feasibility analyses the results of all TE performed in our clinic were analyzed irrespective of the underlying disease. Liver stiffness was measured with the S-probe (thorax diameter <45 cm (S1) or 45-75 cm (S2)) and the M-probe (thorax diameter >75 cm) according to the manufacturer's recommendations. A total of 240 healthy children were analyzed to establish control values. The median liver stiffness was 4.7 kPa resulting in an upper limit of normal of 6.47 kPa. Median values of stiffness were significantly age dependent with 4.40, 4.73, and 5.1 kPa in children 0-5, 6-11, and 12-18 years (p = 0.001) while the interquartile range decreased with age (0.8, 0.7, and 0.6 kPa). The resulting upper limit of normal (median plus 1.64 times standard deviation) was 5.96, 6.65, and 6.82 kPa. Girls between 11 and 18 years showed a significantly lower median stiffness than boys of the same age (4.7 vs. 5.6 kPa; p < 0.005). Feasibility was tested in 975 consecutive liver stiffness measurements (LSM) in children 0-18 years of age. Patients with invalid LSM were significantly younger than those with valid LSM (5.8 vs. 9.7 years, p < 0.0001), showed a significantly higher stiffness (10.2 vs. 6.17, p < 0.0001), and examinations took significantly longer (202 vs. 160 s, p < 0.0001). TE is technically possible in children of all age groups. The upper limit of normal increases significantly with age. Due to movement artifacts the measurement is reliable from the age of 6 without sedation. In younger children the number of invalid measurements increases significantly. Further studies are needed to asses the value of TE in the diagnosis and follow-up of liver disease in pediatric hepatology.
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Affiliation(s)
- Guido Engelmann
- Department of General Pediatrics, University Hospital, Heidelberg, INF 430, 69120 Heidelberg, Germany.
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You J, Sriplung H, Geater A, Chongsuvivatwong V, Zhuang L, Chen HY, Huang JH, Tang BZ. Hepatitis B virus DNA is more powerful than HBeAg in predicting peripheral T-lymphocyte subpopulations in chronic HBV-infected individuals with normal liver function tests. World J Gastroenterol 2008; 14:3710-8. [PMID: 18595137 PMCID: PMC2719233 DOI: 10.3748/wjg.14.3710] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the peripheral T-lymphocyte subpopulation profile, and its correlations with hepatitis B virus (HBV) replication level in chronic HBV-infected (CHI) individuals with normal liver function tests (LFTs).
METHODS: Frequencies of T-lymphocyte subpopu-lations in peripheral blood were measured by flow cytometry in 216 CHI individuals. HBV markers were detected with ELISA. Serum HBV DNA load was assessed with quantitative real-time PCR. Information of age at HBV infection, and maternal HBV infection status was collected. ANOVA linear trend test and linear regression were used in statistical analysis.
RESULTS: CHI individuals had significantly decreased relative frequencies of CD3+, CD4+ subpopulations and CD4+/CD8+ ratio, and increased CD8+ subset percentage compared with uninfected individuals (all P < 0.001). There was a significant linear relationship between the load of HBV DNA and the parameters of T-lymphocyte subpopulations (ANOVA linear trend test P < 0.01). The parameters were also significantly worse among individuals whose mothers were known to be HBV carriers, and those having gained infection before the age of 8 years. In multiple regressions, after adjustment for age at HBV infection and status of maternal HBV infection, log copies of HBV DNA maintained its highly significant predictive coefficient on T-lymphocyte subpopulations, whereas the effect of HBeAg was not significant.
CONCLUSION: HBV DNA correlates with modification in the relative T-lymphocyte subpopulation frequencies. High viral load is more powerful than HBeAg in predicting the impaired balance of T-cell subsets.
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You J, Sriplung H, Geater A, Chongsuvivatwong V, Zhuang L, Chen HY, Yu L, Tang BZ, Huang JH. Effect of viral load on T-lymphocyte failure in patients with chronic hepatitis B. World J Gastroenterol 2008; 14:1112-9. [PMID: 18286696 PMCID: PMC2689417 DOI: 10.3748/wjg.14.1112] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Revised: 10/23/2007] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate peripheral T-lymphocyte sub-population profile and its correlation with hepatitis B virus (HBV) replication in patients with chronic hepatitis B (CHB). METHODS Distribution of T-lymphocyte subpopulations in peripheral blood was measured by flow cytometry in 206 CHB patients. HBV markers were detected with ELISA. Serum HBV DNA load was assessed with quantitative real-time polymerase chain reaction (PCR). The relationship between HBV replication and variation in peripheral T-cell subsets was analyzed. RESULTS CHB patients had significantly decreased CD3+ and CD4+ cells and CD4+/CD8+ ratio, and increased CD8+ cells compared with uninfected controls (55.44 +/- 12.39 vs 71.07 +/- 4.76, 30.92 +/- 7.48 vs 38.94 +/- 3.39, 1.01 +/- 0.49 vs 1.67 +/- 0.33, and 34.39 +/- 9.22 vs 24.02 +/- 4.35; P < 0.001, respectively). Univariate analysis showed a similar pattern of these parameters was significantly associated with high viral load, presence of serum hepatitis B e antigen (HBeAg) expression, liver disease severity, history of maternal HBV infection, and young age at HBV infection, all with P < 0.01. There was a significant linear relationship between viral load and these parameters of T-lymphocyte subpopulations (linear trend test P < 0.001). There was a negative correlation between the levels of CD3+ and CD4+ cells and CD4+/CD8+ ratio and serum level of viral load in CHB patients (r = -0.68, -0.65 and -0.75, all P < 0.0001), and a positive correlation between CD8+ cells and viral load (r = 0.70, P < 0.0001). There was a significant decreasing trend in CD3+ and CD4+ cells and CD4+/CD8+ ratio with increasing severity of hepatocyte damage and decreasing age at HBV infection (linear trend test P < 0.01). In multiple regression (after adjustment for age at HBV infection, maternal HBV infection status and hepatocyte damage severity) log copies of HBV DNA maintained a highly significant predictive coefficient on T-lymphocyte subpopulations, and was the strongest predictor of variation in CD3+, CD4+, CD8+ cells and CD4+/CD8+ ratio. However, the effect of HBeAg was not significant. CONCLUSION T-lymphocyte failure was significantly associated with viral replication level. The substantial linear dose-response relationship and strong independent predictive effect of viral load on T-lymphocyte subpopulations suggests the possibility of a causal relationship between them, and indicates the importance of viral load in the pathogenesis of T cell hyporesponsiveness in these patients.
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Ke CZ, Chen Y, Gong ZJ, Meng ZJ, Liu L, Ren ZJ, Zhou ZH. Dynamic changes of HBV DNA in serum and peripheral blood mononuclear cells of chronic hepatitis patients after lamivudine treatment. World J Gastroenterol 2006; 12:4061-3. [PMID: 16810760 PMCID: PMC4087722 DOI: 10.3748/wjg.v12.i25.4061] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the dynamic changes of hepatits B virus (HBV) DNA in serum and peripheral blood mononuclear cells (PBMCs) of patients after lamivudine therapy.
METHODS: A total of 72 patients with chronic HBV infection were included in this study. All patients were confirmed to have the following conditions: above 16 years of age, elevated serum alanine amonotransferase (ALT), positive hepatitis B e antigen (HBeAg), positive HBV DNA in serum and PBMCs, negative antibodies against HAV, HCV, HDV, HEV. Other possible causes of chronic liver damages, such as drugs, alcohol and autoimmune diseases were excluded. Seventy-two cases were randomly divided into lamivudine treatment group (n = 42) and control group (n = 30). HBV DNA was detected both in serum and in PBMCs by fluorescence quantitative polymerase chain reaction (PCR), during and after lamivudine treatment.
RESULTS: In the treatment group, HBV DNA became negative both in serum and in PBMC, of 38 and 25 out of 42 cases respectively during the 48 wk of lamivudine treatment, the negative rate was 90.5% and 59.5% respectively. In the control group, the negative rate was 23.3% and 16.7% respectively. It was statistically significant at 12, 24 and 48 wk as compared with the control group (P < 0.005). The average conversion period of HBV DNA was 6 wk (2-8 wk) in serum and 16 wk (8-24 wk) in PBMC.
CONCLUSION: Lamivudine has remarkable inhibitory effects on HBV replication both in serum and in PBMCs. The inhibitory effect on HBV DNA in PBMCs is weaker than that in serum.
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Affiliation(s)
- Chang-Zheng Ke
- Department of Infectious Diseases, Taihe Hospital Affiliated to Yunyang Medical College, Shiyan, Hubei Province, China
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Wang KX, Peng JL, Wang XF, Tian Y, Wang J, Li CP. Detection of T lymphocyte subsets and mIL-2R on surface of PBMC in patients with hepatitis B. World J Gastroenterol 2003; 9:2017-20. [PMID: 12970897 PMCID: PMC4656665 DOI: 10.3748/wjg.v9.i9.2017] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the levels of T lymphocyte subsets and membrane interleukin-2 receptor (mIL-2R) on surface of peripheral blood mononuclear cells (PBMCs) of patients with hepatitis B and its role in the pathogenesis of hepatitis B.
METHODS: The levels of T lymphocyte subsets and mIL-2R in PBMC before and after being stimulated with PHA were detected by biotin-streptavidin (BSA) technique in 196 cases of hepatitis B.
RESULTS: In patients with hepatitis B, the levels of CD3+, CD4+ cells, and the ratio of CD4+ cells/CD8+ cells were lower, but the level of CD8+ cells was higher than those in normal controls (42.20 ± 6.01 vs 65.96 ± 6.54, 38.17 ± 5.93 vs 41.73 ± 6.40, 0.91 ± 0.28 vs 1.44 ± 0.31, 39.86 ± 6.36 vs 30.02 ± 4.54, P < 0.01). The total expression level of mIL-2R in PBMC before and after being stimulated with PHA was also lower than those in normal controls (3.47 ± 1.55 vs 4.52 ± 1.49, 34.03 ± 2.94 vs 37.95 ± 3.00, P < 0.01). In all the patients with hepatitis B, the levels of T lymphocyte subsets and mIL-2R in PBMC with HBV-DNA (+) were lower than those with HBV-DNA (-), which were significantly different (39.57 ± 7.11 vs 44.36 ± 5.43, 34.36 ± 7.16 vs 40.75 ± 5.87, 37.82 ± 6.54 vs 41.72 ± 6.21, 0.88 ± 0.33 vs 0.99 ± 0.27, 2.82 ± 1.62 vs 3.85 ± 1.47, 31.56 ± 3.00 vs 35.84 ± 2.83, P < 0.01). In addition, the levels of CD3+, CD4+, CD8+ cells, the ratio of CD4+ cells/CD8+ cells and mIL-2R among different courses of hepatitis B were all significantly different (F = 3723.18, P < 0.01. F = 130.43, P < 0.01. F = 54.01, P < 0.01. F = 2.99, P < 0.05. F = 7.16, P < 0.01).
CONCLUSION: Both cellular and humoral immune functions are obviously in disorder in patients with hepatitis B, which might be closely associated with the chronicity in patients.
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Affiliation(s)
- Ke-Xia Wang
- School of Medicine, Anhui University of Science and Technology, Huainan 232001, Anhui Province, China
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