慢性乙型病毒性肝炎患者在阿德福韦酯治疗期间血磷浓度的变化

发布时间：2018-02-12 14:54

  本文关键词： 肝炎 乙型 慢性 阿德福韦酯 多态性 单核苷酸 磷 骨密度　出处：《河北医科大学》2014年硕士论文　论文类型：学位论文

【摘要】：目的:抗病毒治疗是治疗慢性乙型病毒性肝炎的根本，阿德福韦酯是常用的口服抗病毒药物之一。近年来相继报道了长期服用阿德福韦酯引起的不良反应，其长期用药的安全性亦是一值得关注的问题。阿德福韦酯的主要不良反应为肾毒性，通常表现为血清肌酐的升高或血磷浓度的降低。本研究旨在探讨长期应用阿德福韦酯患者的低磷血症的发生率及其影响因素；分析磷酸钠协同转运蛋白的基因SLC34A1（rs6420094）和G蛋白信号调节因子14的基因RGS14（rs4074995）单核苷酸多态性和血磷浓度的关系；探讨低磷血症患者的骨密度异常（包括骨量减少和骨质疏松）的发生率及其影响因素。 方法：筛选服用阿德福韦酯（10mg/d）单药或联合治疗2年以上的慢性乙型病毒性肝炎患者198例，收集患者临床资料，分为低磷血症组和血磷正常组，计算低磷血症发生率，并对临床资料行单因素和多因素Logistic回归分析，筛选低磷血症的危险因素，分析的变量包括：性别、年龄、体重、用药时间、诊断、治疗。从中筛选31例低磷血症患者和60例血磷正常患者，采集3ml的外周静脉血，应用聚合酶链式反应-限制性片段长度多态性分析法，测定rs6420094和rs4074995的基因型，分析这两个位点等位基因分布频率与血磷浓度的关系。从中进一步筛选低磷血症患者28例，测量骨密度，分为骨密度正常组和骨密度异常组，计算骨密度异常的发生率，应用卡方检验和多因素Logistic回归分析筛选骨密度异常的危险因素，分析的变量包括：性别、年龄、体重、用药时间、血磷浓度、诊断、治疗、基因型。 应用SPSS17.0软件包进行数据分析，临床资料行单因素和多因素非条件二元Logistic回归分析，计算相对风险度的比值比及95%可信区间，排除标准为0.1，纳入标准为0.05。率的比较采用卡方检验，当出现P≈a或n40时用Fisher精确概率法进行计算，全部检验均为双侧检验，P0.05为差异有统计学意义。应用SHEsis软件进行Hardy-Weinberg遗传平衡分析和遗传连锁关系分析，P0.05为符合遗传平衡定律，r20.33和D’0.7为遗传连锁不平衡的判断标准。 结果： 1在198例长期服用阿德福韦酯的慢性乙型病毒性肝炎患者中，55例（27.8%）发生了低磷血症。多因素Logistic回归分析：用药时间和年龄的比值比和95%可信区间分别为1.316（1.000~1.730）和1.458（1.083~1.963）。 2应用SHEsis软件进行Hardy-Weinberg平衡分析：rs6420094位点的血磷正常组和低磷血症组的P值分别为0.167和0.572；rs4074995位点的血磷正常组和低磷血症组的P值分别为0.316和0.856，说明均符合遗传平衡定律。两位点连锁关系分析：D=0.759，，r2=0.412。说明两位点遗传连锁不平衡。rs4074995的基因表型：低磷血症组：A/A型2例、A/G型11例、G/G型18例，血磷正常组：A/A型1例、A/G型21例、G/G型38例。此位点的等位基因分布频率在低磷血症组和血磷正常组之间没有差别（P=0.429）。rs6420094的基因表型：低磷血症组：A/A型13例、G/A型13例、G/G型5例，血磷正常组：A/A型35例、G/A型24例、G/G型1例。此位点的等位基因A在血磷正常组出现频率（78.3%）高于低磷血症组（62.9%），P=0.026。 328例低磷血症患者中，骨密度正常者11例，骨密度异常者17例（60.7%），其中骨量减少者10例，骨质疏松者7例，低磷酸血症的分度在骨密度正常组和骨密度异常组间的差别有统计学意义（P=0.041），其余影响因素的差异均无统计学意义。 结论： 1长期服用阿德福韦酯的慢性乙型肝炎患者的低磷血症发生率为27.8%，长时间用药和老龄是低磷血症有统计学意义的危险因素。 2rs4074995的等位基因分布频率和患者的血磷浓度无关。rs6420094的等位基因分布频率和服用阿德福韦酯的慢性乙型病毒性肝炎患者的血磷浓度存在关联，此位点等位基因A在血磷浓度正常组出现频率高于低磷血症组。 3低磷血症患者的骨密度异常发生率为60.7%，中度低磷血症是骨密度异常的有统计学意义的危险因素。 4聚合酶链式反应-限制性片段长度多态性分析法较经济、准确，在不存在非特异性内切酶或内切酶价格较高的情况下，可应用引物引入突变位点的方法创造酶切位点，在扩增效率低或存在非特异性扩增片段时，可应用半巢式PCR。
[Abstract]:Objective: antiviral treatment is essential in the treatment of chronic hepatitis B, adefovir dipivoxil is one of the commonly used oral antiviral drugs. In recent years have reported adverse reactions caused by long-term use of adefovir dipivoxil, the long-term medication safety is also a concern. The main adverse reactions of adefovir dipivoxil for renal toxicity, usually in order to reduce the serum creatinine or elevated serum phosphate concentration. The incidence and influential factors of this study is to investigate the application of hypophosphatemia in patients with long-term adefovir dipivoxil; gene SLC34A1 analysis of sodium phosphate cotransporter (rs6420094) and G signal regulated protein gene RGS14 factor 14 (rs4074995) the relationship between single nucleotide polymorphism and serum phosphorus to investigate the concentration of abnormal bone density; hypophosphatemia (including patients with osteopenia and osteoporosis) the incidence and influencing factors.
Methods: screening of adefovir dipivoxil (10mg/d) monotherapy or combination therapy for more than 2 years in patients with chronic hepatitis B in 198 cases, clinical data were collected and divided into hypophosphatemia group and normal group P, calculate the incidence of hypophosphatemia, and the clinical data for univariate and multivariate Logistic regression analysis the risk factors, screening of hypophosphatemia, analysis of variables including gender, age, weight, duration, diagnosis, treatment of 31 cases of normal patients. Screening of hypophosphatemia in patients and 60 cases of blood phosphorus from peripheral venous blood collection, 3ml, restriction fragment length polymorphism analysis using polymerase chain reaction restriction -, rs6420094 and rs4074995 genotypes were determined by the analysis of the relationship between the two allele frequency distribution and serum phosphorus concentration. The further screening of 28 cases of patients with hypophosphatemia, measurement of bone density, bone density is divided into normal group and abnormal bone density In the normal group, the incidence of bone mineral density abnormality was calculated. Chi square test and multivariate Logistic regression analysis were used to screen the risk factors of bone mineral density. The variables included: sex, age, weight, medication time, blood phosphorus concentration, diagnosis, treatment and genotype.
The data were analysed by SPSS17.0 software, the clinical data for univariate and multivariate regression analysis of two yuan Logistic, calculate the odds ratio and 95% confidence interval relative risk, 0.1 exclusion criteria for inclusion criteria were compared with 0.05., the rate of chi square test, when the P is a or N40 with Fisher exact probability method all tests were two-sided test P0.05, the difference was statistically significant. SHEsis software was used for Hardy-Weinberg analysis of genetic equilibrium analysis and genetic linkage between P0.05, to comply with the law of genetic equilibrium, r20.33 and D 0.7 as the standard for judging genetic linkage disequilibrium.
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