AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD. METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 hea...AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD. METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing high-performance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP. RESULTS: NOD2/CARD15 mutations were found in 185 patients (35.1%) and in 33 controls (16.5%,P<0.0001). SNP8/R702W (10.8% vs 6%, P= 0.02), SNP13/3020insC (19.4% vs 5%, P<0.0001) and exon4 R703C (2.1% vs 0%, P= 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vs controls: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (ORhet=1.71, 95%CI=1.12-2.6, P= 0.0001, ORtwo-risk alleles = 25.2, 95%CI =4.37- ,P<0.0001), early disease onset (carrier: 26.4 years vs non-carrier: 29.8 years, P=0.0006), ileal disease (81.9% (?) 69.5%, OR = 1.99, 95%CI = 1.29-3.08, P= 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs 64.8%), stricturing behavior (OR = 1.69,95%CI = 1.13-2.55, P= 0.026) and increased need for resection (OR=1.71, 95%CI: 1.13-2.62, P= 0.01), but not with duration, extra-intestinal manifestations, familial disease or smoking. TLR4 exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P = 0.06), in NOD2mut/wt: 26.7 years. CONCLUSION: These results confirm that variant NOD2/ CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease, stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4 mutation carriers tended to present at earlier age.展开更多
AIM： To analyze our Wilson disease patient cohort （n = 106） for alterations in the gene coding for MURR1. METHODS： Patients with an established diagnosis of Wilson disease but normal ceruloplasmin blood levels wer...AIM： To analyze our Wilson disease patient cohort （n = 106） for alterations in the gene coding for MURR1. METHODS： Patients with an established diagnosis of Wilson disease but normal ceruloplasmin blood levels were chosen for our study （n = 14）. Patients with two known disease-causing mutations in the ATPTB gene were not included. The three exons of the human MURR1 gene were sequenced after amplification of the genomic DNA by polymerase chain reaction. RESULTS： Our study did not reveal any mutations leading to an amino acid change in the MURR1 sequence of Wilson disease patients. A polymorphism at 472 bp of the coding sequence could be confirmed. CONCLUSION： The MURRI gene plays no role in the pathogenesis of Wilson disease patients with normal serum ceruloplasmin levels.展开更多
AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin(peg IFN/RBV), in treatment-naive hepatitis C virus(HCV) genotype(GT) 1-infected patients.METHODS: In this phase 3, randomi...AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin(peg IFN/RBV), in treatment-naive hepatitis C virus(HCV) genotype(GT) 1-infected patients.METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned(2:1) to daclatasvir vs telaprevir, stratified by IL28 B rs12979860 host genotype(CC vs non-CC), cirrhosis status(compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype(GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus peg IFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus peg IFN/RBV; those without an extended rapid virologic response(e RVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of peg IFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus peg IFN/RBV followed by 12(with e RVR) or 36(no e RVR) wk of peg IFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12(SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia(hemoglobin < 10 g/d L) and rashrelated events, through week 12, were lower with daclatasvir + peg IFN/RBV than with telaprevir + peg IFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5 A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/m L, to investigate any link between NS5 A polymorphisms associated with daclatasvir resistance and virologic outcome. RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups(6.0% and 8.2% in the GT1 b and GT1 a groups, respectively) than in the telaprevir groups(2.2% and 3.0%). Among GT1 binfected patients, daclatasvir plus peg IFN/RBV was noninferior to telaprevir plus peg IFN/RBV for SVR12 [85%(228/268) vs 81%(109/134); difference, 4.3%(95%CI:-3.3% to 11.9%)]. Anemia(hemoglobin < 10 g/d L) was significantly less frequent with daclatasvir than with telaprevir [difference,-29.1%(95%CI:-38.8% to-19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1 ainfected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28 B non-CC and cirrhosis- factors known to affect response to peg IFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients d e m o n s t ra t e d t h a t S V R 1 2 wa s a s s o c i a t e d w i t h IL28 B host genotype(CC vs non-CC, P = 0.011) and cirrhosis status(absent vs present, P = 0.031). NS5 A polymorphisms associated with daclatasvir resistance(at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4%(229/268) in the daclatasvir group, and by 85.1%(114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2%(90/134) and 69.7%(46/66), respectively. Discontinuations(of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria. CONCLUSION: Daclatasvir plus peg IFN/RBV demonstrated noninferiority to telaprevir plus peg IFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1 binfected patients, supporting the use of daclatasvir with other direct-acting antivirals.展开更多
BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear geno...BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear genotype-phenotype correlations exist in WD.Protein-truncating nonsense,frame-shift,or splice-site variants may be associated with more severe disease.In contrast,missense variants may be associated with late-onset,less severe disease,and more neurological manifestations.Recently,a gene variant(HSD17B13:TA,rs72613567)with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed.The clinical manifestations(ALF with non-immune hemolytic anemia or other less severe forms),laboratory parameters,copper metabolism,ATP7B variants,and the HSD17B13:TA(rs72613567)variant were reviewed to analyze the possible genotype-phenotype correlations.RESULTS We analyzed the data of 51 patients with WD,26 females(50.98%),with the mean age at the diagnosis of 12.36±3.74 years.ALF and Coombs-negative hemolytic anemia was present in 8 children(15.67%),all adolescent girls.The Kayser-Fleisher ring was present in 9 children(17.65%).The most frequent variants of the ATP7B gene were p.His1069Gln(c.3207A>G)in 38.24% of all alleles,p.Gly1341Asp(c.4021G>A)in 26.47%,p.Trp939Cys(c.2817G>T)in 9.80%,and p.Lys844Ter(c.2530A>T)in 4.90%.In ALF with hemolytic anemia,p.Trp939Cys(c.2817G>T)and p.Lys844Ter(c.2530A>T)variants were more frequent than in other less severe forms,in which p.His1069Gln(c.3207A>G)was more frequent.p.Gly1341Asp(c.4021G>A)has a similar frequency in all hepatic forms.For 33 of the patients,the HSD17B13 genotype was evaluated.The overall HSD17B13:TA allele frequency was 24.24%.Its frequency was higher in patients with less severe liver disease(26.92%)than those with ALF and hemolytic anemia(14.28%).CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients.In children with ALF and hemolytic anemia,the missense variants other than p.His1069Gln(c.3207A>G)and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants.As genetic analysis is usually time-consuming and the results are late,the importance at the onset of the ALF is questionable.If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease,this could be essential to predict a possible severe evolution.展开更多
Hepatic encephalopathy(HE)is a reversible syndrome of impaired brain function occurring in patients with advanced liver diseases.The precise pathophysiology of HE is still under discussion;the leading hypothesis focus...Hepatic encephalopathy(HE)is a reversible syndrome of impaired brain function occurring in patients with advanced liver diseases.The precise pathophysiology of HE is still under discussion;the leading hypothesis focus on the role of neurotoxins,impaired neurotransmission due to metabolic changes in liver failure,changes in brain energy metabolism,systemic inflammatory response and alterations of the blood brain barrier.HE produces a wide spectrum of nonspecific neurological and psychiatric manifestations.Minimal HE is diagnosed by abnormal psychometric tests.Clinically overt HE includes personality changes,alterations in consciousness progressive disorientation in time and space,somnolence,stupor and,finally,coma.Except for clinical studies,no specific tests are required for diagnosis.HE is classified according to the underlying disease,the severity of manifestations,its time course and the existence of precipitating factors.Treatment of overt HE includes supportive therapies,treatment of precipitating factors,lactulose and/or rifaximin.Routine treatment for minimal HE is only recommended for selected patients.展开更多
文摘AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD. METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing high-performance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP. RESULTS: NOD2/CARD15 mutations were found in 185 patients (35.1%) and in 33 controls (16.5%,P<0.0001). SNP8/R702W (10.8% vs 6%, P= 0.02), SNP13/3020insC (19.4% vs 5%, P<0.0001) and exon4 R703C (2.1% vs 0%, P= 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vs controls: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (ORhet=1.71, 95%CI=1.12-2.6, P= 0.0001, ORtwo-risk alleles = 25.2, 95%CI =4.37- ,P<0.0001), early disease onset (carrier: 26.4 years vs non-carrier: 29.8 years, P=0.0006), ileal disease (81.9% (?) 69.5%, OR = 1.99, 95%CI = 1.29-3.08, P= 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs 64.8%), stricturing behavior (OR = 1.69,95%CI = 1.13-2.55, P= 0.026) and increased need for resection (OR=1.71, 95%CI: 1.13-2.62, P= 0.01), but not with duration, extra-intestinal manifestations, familial disease or smoking. TLR4 exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P = 0.06), in NOD2mut/wt: 26.7 years. CONCLUSION: These results confirm that variant NOD2/ CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease, stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4 mutation carriers tended to present at earlier age.
文摘AIM： To analyze our Wilson disease patient cohort （n = 106） for alterations in the gene coding for MURR1. METHODS： Patients with an established diagnosis of Wilson disease but normal ceruloplasmin blood levels were chosen for our study （n = 14）. Patients with two known disease-causing mutations in the ATPTB gene were not included. The three exons of the human MURR1 gene were sequenced after amplification of the genomic DNA by polymerase chain reaction. RESULTS： Our study did not reveal any mutations leading to an amino acid change in the MURR1 sequence of Wilson disease patients. A polymorphism at 472 bp of the coding sequence could be confirmed. CONCLUSION： The MURRI gene plays no role in the pathogenesis of Wilson disease patients with normal serum ceruloplasmin levels.
文摘AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin(peg IFN/RBV), in treatment-naive hepatitis C virus(HCV) genotype(GT) 1-infected patients.METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned(2:1) to daclatasvir vs telaprevir, stratified by IL28 B rs12979860 host genotype(CC vs non-CC), cirrhosis status(compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype(GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus peg IFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus peg IFN/RBV; those without an extended rapid virologic response(e RVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of peg IFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus peg IFN/RBV followed by 12(with e RVR) or 36(no e RVR) wk of peg IFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12(SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia(hemoglobin < 10 g/d L) and rashrelated events, through week 12, were lower with daclatasvir + peg IFN/RBV than with telaprevir + peg IFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5 A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/m L, to investigate any link between NS5 A polymorphisms associated with daclatasvir resistance and virologic outcome. RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups(6.0% and 8.2% in the GT1 b and GT1 a groups, respectively) than in the telaprevir groups(2.2% and 3.0%). Among GT1 binfected patients, daclatasvir plus peg IFN/RBV was noninferior to telaprevir plus peg IFN/RBV for SVR12 [85%(228/268) vs 81%(109/134); difference, 4.3%(95%CI:-3.3% to 11.9%)]. Anemia(hemoglobin < 10 g/d L) was significantly less frequent with daclatasvir than with telaprevir [difference,-29.1%(95%CI:-38.8% to-19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1 ainfected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28 B non-CC and cirrhosis- factors known to affect response to peg IFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients d e m o n s t ra t e d t h a t S V R 1 2 wa s a s s o c i a t e d w i t h IL28 B host genotype(CC vs non-CC, P = 0.011) and cirrhosis status(absent vs present, P = 0.031). NS5 A polymorphisms associated with daclatasvir resistance(at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4%(229/268) in the daclatasvir group, and by 85.1%(114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2%(90/134) and 69.7%(46/66), respectively. Discontinuations(of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria. CONCLUSION: Daclatasvir plus peg IFN/RBV demonstrated noninferiority to telaprevir plus peg IFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1 binfected patients, supporting the use of daclatasvir with other direct-acting antivirals.
文摘BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear genotype-phenotype correlations exist in WD.Protein-truncating nonsense,frame-shift,or splice-site variants may be associated with more severe disease.In contrast,missense variants may be associated with late-onset,less severe disease,and more neurological manifestations.Recently,a gene variant(HSD17B13:TA,rs72613567)with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed.The clinical manifestations(ALF with non-immune hemolytic anemia or other less severe forms),laboratory parameters,copper metabolism,ATP7B variants,and the HSD17B13:TA(rs72613567)variant were reviewed to analyze the possible genotype-phenotype correlations.RESULTS We analyzed the data of 51 patients with WD,26 females(50.98%),with the mean age at the diagnosis of 12.36±3.74 years.ALF and Coombs-negative hemolytic anemia was present in 8 children(15.67%),all adolescent girls.The Kayser-Fleisher ring was present in 9 children(17.65%).The most frequent variants of the ATP7B gene were p.His1069Gln(c.3207A>G)in 38.24% of all alleles,p.Gly1341Asp(c.4021G>A)in 26.47%,p.Trp939Cys(c.2817G>T)in 9.80%,and p.Lys844Ter(c.2530A>T)in 4.90%.In ALF with hemolytic anemia,p.Trp939Cys(c.2817G>T)and p.Lys844Ter(c.2530A>T)variants were more frequent than in other less severe forms,in which p.His1069Gln(c.3207A>G)was more frequent.p.Gly1341Asp(c.4021G>A)has a similar frequency in all hepatic forms.For 33 of the patients,the HSD17B13 genotype was evaluated.The overall HSD17B13:TA allele frequency was 24.24%.Its frequency was higher in patients with less severe liver disease(26.92%)than those with ALF and hemolytic anemia(14.28%).CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients.In children with ALF and hemolytic anemia,the missense variants other than p.His1069Gln(c.3207A>G)and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants.As genetic analysis is usually time-consuming and the results are late,the importance at the onset of the ALF is questionable.If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease,this could be essential to predict a possible severe evolution.
文摘Hepatic encephalopathy(HE)is a reversible syndrome of impaired brain function occurring in patients with advanced liver diseases.The precise pathophysiology of HE is still under discussion;the leading hypothesis focus on the role of neurotoxins,impaired neurotransmission due to metabolic changes in liver failure,changes in brain energy metabolism,systemic inflammatory response and alterations of the blood brain barrier.HE produces a wide spectrum of nonspecific neurological and psychiatric manifestations.Minimal HE is diagnosed by abnormal psychometric tests.Clinically overt HE includes personality changes,alterations in consciousness progressive disorientation in time and space,somnolence,stupor and,finally,coma.Except for clinical studies,no specific tests are required for diagnosis.HE is classified according to the underlying disease,the severity of manifestations,its time course and the existence of precipitating factors.Treatment of overt HE includes supportive therapies,treatment of precipitating factors,lactulose and/or rifaximin.Routine treatment for minimal HE is only recommended for selected patients.
