新诊断策略与相关基因检测对妊娠期急性脂肪肝的诊断价值和评价
发布时间：2018-08-06 14:43
【摘要】：【目的】1、以诊断妊娠期急性脂肪肝(AFLP)的Swansea标准为标准,进行病例回顾性分析,提出新的诊断策略,探讨新诊断策略的诊断价值。2、通过基因检测27个诊断AFLP的患者、配偶、配偶父母、发病期的新生儿以及再次妊娠未发病分娩的新生儿的9个基因,探讨相关基因检测对于AFLP的诊断意义。【方法】新诊断策略:收集我院以及深圳市第三人民医院2003年至2017年1月收治的AFLP病例资料73份,诊断标准依据肝脏穿刺活检,或英国Swansea大学建立的诊断标准,纳入到病例组。同时,选取同期年龄、孕周相似有上消化道症状同时存在肝功能异常的患者,作为对照组。用新诊断策略(妊娠晚期发病,有上消化道症状,同时合并肝功能异常、肾功能不全、凝血功能障碍,排除其他原因引起的上述临床表现)和Swansea标准进行诊断试验与统计学分析。基因检测:9个患AFLP的患者以家庭为单位,共采集27个样本进行基因检测。采用芯片捕获高通量测序(即二代基因测序)方法,和一代基因测序验证来共同完成。采集患者及配偶的静脉血5ml、患者配偶父母静脉血5ml、新生儿脐带血或静脉血2ml进行目标基因编码区及临近剪切区的DNA检测,再进行分析。【结果】1、在73例患者中,有5例由于资料无法获得未纳入病例组,即n=68。发病平均孕周35.6±2.81周。存在上消化道症状的有89.71%(n=61),其中恶心呕吐占67.65%,乏力纳差占66.18%。肝功能异常为100%(n=68),肾功能不全为86.76%(n=59),凝血功能障碍为91.18%(n=62)。2、新诊断策略诊断AFLP的灵敏度Se=92.65%,特异度Sp=95.24%,阳性预测值PV+=96.92%,误诊率α=4.76%,漏诊率β=7.35%,阴性预测值PV-=88.89%,阳性似然比LR+=19.46,阴性似然比0.08。进行Kappa值效度评价,Kappa值为0.88,经一致性检验有统计学意义(P=0.000),认为诊断AFLP的两种方法具有一致性。3、对9个AFLP的患者进行基因检测,发现异常的2例,占22.22%。4、患者A的CPT2基因上存在c.365CT的杂合性突变,为临床意义未明突变。患者的丈夫无基因突变,患者在患AFLP时的男胎死亡未获得基因检测。后再次妊娠2次,未发病分娩的女新生儿,无基因异常;未发病分娩的男新生儿同样存在c.365CT杂合突变。患者B无基因突变,患者的再婚丈夫在ACADVL基因上存在c.439GA的杂合性突变,发病期间分娩的男新生儿无基因异常。5、患者C在HADHA基因上有两个杂合性突变(c.2228_2229 ins AACA和c.652GC)。患者配偶的HADHA基因上,存在杂合性突变(c.1720_1721 del CT和c.415AG)。患者配偶父亲在HADHA基因上存在杂合突变(c.415AG),患者配偶母亲在HADHA基因上存在杂合性突变(c.1720_1721 del CT)。患者前次妊娠患AFLP期间的男胎死亡,无法获取基因,后再次妊娠未发病分娩的女新生儿在HADHA基因上存在杂合突变(c.415AG)。【结论】1、AFLP的发病平均孕周接近36周。上消化道症状以恶心呕吐、乏力纳差居多。AFLP是多器官同时受累疾病,同时存在肝功能异常、肾功能不全和不同程度的凝血功能障碍。2、本研究提出的新诊断策略(妊娠晚期发病,有上消化道症状,同时合并肝功能异常、肾功能不全、凝血功能障碍,排除其他原因引起的上述临床表现)和Swansea诊断标准在诊断AFLP这一疾病上存在一致性。即新诊断策略诊断AFLP是有效、可靠、可行,且新诊断策略简明、易于掌握、便于早期诊断。3、AFLP的发病是多因素共同导致的,相关基因的缺陷只是其中一个因素。4、CPT2、ACADVL、HADHA基因缺陷可能与AFLP发病相关。
[Abstract]:[Objective] 1, in order to diagnose the Swansea standard of acute fatty liver (AFLP) in pregnancy, a retrospective analysis was carried out, a new diagnostic strategy was proposed, the diagnostic value of the new diagnostic strategy was.2, and 27 patients with AFLP were detected by gene, spouses, spouses, newborns at the onset of the disease, and the new birth of the second pregnancy. The 9 genes of the child were used to explore the diagnostic significance of related gene detection to AFLP. [Methods] a new diagnostic strategy: 73 AFLP cases were collected from our hospital and third people's Hospital of Shenzhen from 2003 to January 2017. The diagnostic criteria were based on the liver biopsy, or the diagnostic criteria established by the British Swansea University, and included in the case group. Patients with the same age, similar to upper gastrointestinal symptoms and abnormal liver function were selected as the control group. The new diagnosis strategy (late pregnancy, upper gastrointestinal symptoms, combined liver dysfunction, renal insufficiency, coagulation dysfunction, excluding the above clinical manifestations of his causes) and the Swansea standard were diagnosed. Test and statistical analysis. Gene detection: 9 patients with AFLP were used in the family as a unit, 27 samples were collected for gene detection. A chip capture high throughput sequencing (two generation gene sequencing) method and a generation of gene sequencing validation were used together to collect the patient and matching vein blood 5ml, the patient's spouse parents' venous blood 5ml, newborn DNA detection in the target gene coding region and adjacent shear zone of the umbilical cord blood or venous blood 2ml was analyzed. [results] 1, among the 73 patients, 5 cases were unable to obtain the unincluded case group, that is, the average gestational age of n=68. was 35.6 + 2.81 weeks. There were 89.71% (n=61) of the upper gastrointestinal symptoms, including nausea and vomiting, 67.65%, and hypoemesis. The abnormal liver function of 66.18%. was 100% (n=68), renal insufficiency was 86.76% (n=59), coagulation dysfunction was 91.18% (n=62).2, the new diagnostic strategy diagnosed AFLP sensitivity Se=92.65%, specificity Sp=95.24%, positive predictive value PV+=96.92%, misdiagnosis rate alpha =4.76%, missed diagnosis rate beta =7.35%, negative predictive value PV-=88.89%, positive likelihood ratio, negative ratio, Yin, Yin The Kappa value validity was evaluated by sexual likelihood ratio (0.08.), Kappa value was 0.88, and the consistency test was statistically significant (P=0.000). It was found that the two methods for diagnosis of AFLP were consistent.3, gene detection for 9 AFLP patients, found 2 cases of abnormal 22.22%.4, and there were c.365CT heterozygosity mutations in the A CPT2 gene of the patient, which was not of clinical significance. The patient's husband had no genetic mutation, and the patient had no gene detection at the time of AFLP. 2 times of pregnancy again, the female newborns who had not been given birth, had no genetic abnormalities; the unborn male newborn also had the c.365CT heterozygous mutation. The patient had no genetic mutations in B, and the remarried husband of the patient had c.439 on the ACADVL gene. The heterozygosity mutation of GA, the male neonates childbirth during the onset of the disease had no genetic abnormalities.5, and the patient C had two heterozygous mutations (c.2228_2229 ins AACA and c.652GC) on the HADHA gene. There is a heterozygosity mutation (c.1720_1721 del CT) in the HADHA gene of the patient's spouse. The male fetal death during the first pregnancy with AFLP cannot obtain the gene, and the female newborns who have not been given birth after the second pregnancy have the heterozygous mutation (c.415AG) in the HADHA gene. [Conclusion] 1, the average gestational age of AFLP is close to 36 weeks. .AFLP, with nausea and vomiting, and asthenia, is a multi organ concomitant disease, with abnormal liver function, renal insufficiency and different degree of coagulation dysfunction.2. The new diagnosis strategy (late pregnancy, upper gastrointestinal symptoms, simultaneous liver dysfunction, renal dysfunction, coagulation dysfunction, exclusion, exclusion) The clinical manifestations of other causes are consistent with the Swansea diagnostic criteria in the diagnosis of AFLP. That is, the new diagnostic strategy is effective, reliable and feasible, and the new diagnostic strategy is simple, easy to master, easy to master, and facilitate the early diagnosis of.3. The pathogenesis of AFLP is caused by the common cause of polyin, and the defect of the related genes is only one of them. Factors.4, CPT2, ACADVL and HADHA gene defects may be related to the pathogenesis of AFLP.
【学位授予单位】：暨南大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R714.255
本文编号：2168056
[Abstract]:[Objective] 1, in order to diagnose the Swansea standard of acute fatty liver (AFLP) in pregnancy, a retrospective analysis was carried out, a new diagnostic strategy was proposed, the diagnostic value of the new diagnostic strategy was.2, and 27 patients with AFLP were detected by gene, spouses, spouses, newborns at the onset of the disease, and the new birth of the second pregnancy. The 9 genes of the child were used to explore the diagnostic significance of related gene detection to AFLP. [Methods] a new diagnostic strategy: 73 AFLP cases were collected from our hospital and third people's Hospital of Shenzhen from 2003 to January 2017. The diagnostic criteria were based on the liver biopsy, or the diagnostic criteria established by the British Swansea University, and included in the case group. Patients with the same age, similar to upper gastrointestinal symptoms and abnormal liver function were selected as the control group. The new diagnosis strategy (late pregnancy, upper gastrointestinal symptoms, combined liver dysfunction, renal insufficiency, coagulation dysfunction, excluding the above clinical manifestations of his causes) and the Swansea standard were diagnosed. Test and statistical analysis. Gene detection: 9 patients with AFLP were used in the family as a unit, 27 samples were collected for gene detection. A chip capture high throughput sequencing (two generation gene sequencing) method and a generation of gene sequencing validation were used together to collect the patient and matching vein blood 5ml, the patient's spouse parents' venous blood 5ml, newborn DNA detection in the target gene coding region and adjacent shear zone of the umbilical cord blood or venous blood 2ml was analyzed. [results] 1, among the 73 patients, 5 cases were unable to obtain the unincluded case group, that is, the average gestational age of n=68. was 35.6 + 2.81 weeks. There were 89.71% (n=61) of the upper gastrointestinal symptoms, including nausea and vomiting, 67.65%, and hypoemesis. The abnormal liver function of 66.18%. was 100% (n=68), renal insufficiency was 86.76% (n=59), coagulation dysfunction was 91.18% (n=62).2, the new diagnostic strategy diagnosed AFLP sensitivity Se=92.65%, specificity Sp=95.24%, positive predictive value PV+=96.92%, misdiagnosis rate alpha =4.76%, missed diagnosis rate beta =7.35%, negative predictive value PV-=88.89%, positive likelihood ratio, negative ratio, Yin, Yin The Kappa value validity was evaluated by sexual likelihood ratio (0.08.), Kappa value was 0.88, and the consistency test was statistically significant (P=0.000). It was found that the two methods for diagnosis of AFLP were consistent.3, gene detection for 9 AFLP patients, found 2 cases of abnormal 22.22%.4, and there were c.365CT heterozygosity mutations in the A CPT2 gene of the patient, which was not of clinical significance. The patient's husband had no genetic mutation, and the patient had no gene detection at the time of AFLP. 2 times of pregnancy again, the female newborns who had not been given birth, had no genetic abnormalities; the unborn male newborn also had the c.365CT heterozygous mutation. The patient had no genetic mutations in B, and the remarried husband of the patient had c.439 on the ACADVL gene. The heterozygosity mutation of GA, the male neonates childbirth during the onset of the disease had no genetic abnormalities.5, and the patient C had two heterozygous mutations (c.2228_2229 ins AACA and c.652GC) on the HADHA gene. There is a heterozygosity mutation (c.1720_1721 del CT) in the HADHA gene of the patient's spouse. The male fetal death during the first pregnancy with AFLP cannot obtain the gene, and the female newborns who have not been given birth after the second pregnancy have the heterozygous mutation (c.415AG) in the HADHA gene. [Conclusion] 1, the average gestational age of AFLP is close to 36 weeks. .AFLP, with nausea and vomiting, and asthenia, is a multi organ concomitant disease, with abnormal liver function, renal insufficiency and different degree of coagulation dysfunction.2. The new diagnosis strategy (late pregnancy, upper gastrointestinal symptoms, simultaneous liver dysfunction, renal dysfunction, coagulation dysfunction, exclusion, exclusion) The clinical manifestations of other causes are consistent with the Swansea diagnostic criteria in the diagnosis of AFLP. That is, the new diagnostic strategy is effective, reliable and feasible, and the new diagnostic strategy is simple, easy to master, easy to master, and facilitate the early diagnosis of.3. The pathogenesis of AFLP is caused by the common cause of polyin, and the defect of the related genes is only one of them. Factors.4, CPT2, ACADVL and HADHA gene defects may be related to the pathogenesis of AFLP.
【学位授予单位】：暨南大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R714.255
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