新生儿及婴儿胆汁淤积症诊断方法及流程进展

<正>胆汁淤积症(cholestasis)是以高结合胆红素血症为主要临床表现的综合征~([1]),病因复杂;除胆道闭锁(biliary atresia,BA)、早产儿静脉营养相关、感染等病因外,多种导致胆汁淤积症的遗传学病因,逐渐被认识。尽早确定病因,是改善患儿预后的关键,但目前国内关于新生儿及婴儿胆汁淤积症的临床诊断流程尚未达成共识。本文就胆汁淤积症不同诊断方法进展及国内外诊断管理方案最新     

遗传代谢相关的婴儿胆汁淤积症

胆汁淤积症是婴儿期较常见的疾病,在引起婴儿胆汁淤积症的病因中,遗传代谢异常受到了越来越多的关注,如Citrin缺陷导致的新生儿胆汁淤积症、进行性家族性肝内胆汁淤积症等。在临床上,遇到婴儿胆汁淤积症的患儿除考虑感染因素外,应注意遗传代谢因素。     

APRI评价胆道闭锁和胆汁淤积综合征肝脏纤维化程度的临床意义

目的 探讨肝功能检查和门冬氨酸氨基转移酶/血小板指数(aspartate aminotransferase-to-platelet ratio index,APRI)与肝脏纤维化程度的关系,阐述其在BA肝纤维化评估中的临床价值.方法 收集2006年2月至2011年8月间在我院治疗的胆道闭锁患儿38例和胆汁淤积综合征患儿25例为研究对象.临床观察指标包括肝功能检查,肝脏活检切片,血小板指数;肝硬化程度采用Metavir分类,APRI的诊断性评估采用ROC曲线,应用SPSS 16.0统计学软件进行统计分析.并对本组患儿进行随访,随访时间是3～69个月(平均随访时间:20.7个月).结果 胆道闭锁组患儿ALP、γ-GT、DBIL(564.14±257.75、153.36±97.47、7.55±2.57)较胆汁淤积综合征组患儿存在明显升高(P＜0.05);胆道闭锁肝硬化组患儿Age、ALT、AST、γ-GT(84.50±24.72、225.07±109.68、331.64±130.93、951.07±667.24)较非肝硬化组明显升高,两组差异具有统计学意义(P＜0.05);胆汁淤积综合征肝纤维化组患儿Age、ALT、AST(84.76±14.28、159.92±61.76、238.15±62.60)较非肝纤维化组(54.17±11.17、98.92±58.08、151.17±41.44)明显升高,两组差异具有统计学意义(P＜0.05).患儿绘制APRI的ROC曲线,用于判定肝硬化程度,胆道闭锁组敏感性为79％,特异性为88％;胆汁淤积综合征组敏感性为91％,特异性为79％.胆道闭锁中肝硬化组病死率显著高于非肝硬化组,且自体肝生存情况低于非肝硬化组.结论 肝功能检查可以作为胆道闭锁的初步判断指标,绘制APRI的ROC曲线对于评价胆道闭锁及胆汁淤积综合征患儿的肝脏纤维化情况均有较高准确性和可靠性,可用于预测预后和提早做好肝移植准备,因其简单、无创性可以在临床上广泛应用.     

婴儿胆汁淤积性肝病的诊断及鉴别诊断北大核心CSCD

婴儿胆汁淤积性肝病是婴儿期（包括新生儿期）常见的肝脏疾病,涉及肝内和肝外多种病因,首先应鉴别胆道闭锁和非胆道闭锁,依据临床、实验室、影像学和肝脏病理进行综合评估诊断。肝内胆汁淤积性肝病病因甚多,遗传因素已成为研究热点,病因及适当治疗可显著改善预后。     

2017年北美及欧洲儿科胃肠肝脏病和营养学会婴儿胆汁淤积性黄疸评估指南的胆道闭锁评估解读

胆汁淤积(cholestasis)按病因可分为胆管性(梗阻、肝外胆管扩张或肝内胆管过小)和肝细胞性(膜转运体缺陷,遗传或代谢性障碍)[1].胆汁淤积性黄疸在足月产婴儿发病率约为1/2 500,临床上常与新生儿内科性黄疸相混淆[2].婴儿胆汁淤积性黄疸常见的病因包括胆道闭锁(25％～40％)、遗传性疾病(25％)、胆总管结石或胆总管囊肿导致的肝外梗阻、代谢障碍(酪氨酸血症Ⅰ型、半乳糖血症、先天性胆汁酸代谢障碍)、全垂体功能减退、Alagille综合征、感染及肠外营养相关的肝脏疾病[3].     

胆道闭锁疑似病例的临床特征和诊断依据分析

目的 回顾手术确诊非胆道闭锁和胆道闭锁两组病例的临床资料,分析胆道闭锁疑似病例的临床特征和术前疑诊为胆道闭锁的原因.方法 收集2004年至2010年本院术前拟诊为胆道闭锁而行腹腔镜或开腹胆道造影的602例患儿的临床资料,依据术中胆道造影的诊断结果分为非胆道闭锁组和胆道闭锁组.分析近年非胆道闭锁病例所占比例,对照两组患儿黄疸发生日龄、肝功能及B型超声结果.计算同位素肝胆排泄性造影诊断胆道闭锁的阳性预测值及假阳性率,以及非胆道闭锁病例的疾病构成.结果 非胆道闭锁组83例,胆道闭锁组519例.近年行手术探查的所有患儿中非胆道闭锁比例无明显下降.两组出现黄疸的日龄、入院TBIL(169.9 mmol/L比172.3 mmol/L,P＞0.05)、DBIL(128.7 mmol/L比132.5 mmol/L,P＞0.05)、DBIL/TBIL(0.76比0.77,P＞0.05)、ALT(141.3 mmol/L比114.9 mmol/L,P＞0.05)比较均无统计学差异.γ-GT非胆道闭锁组显著低于胆道闭锁组(263.2 mmol/L比902.7 mmol/L,P＜0.01),B型超声检查肝脏肋下大小,非胆道闭锁组小于胆道闭锁组(2.99比3.61,P＜0.01).同位素肝胆排泄性造影阳性患儿共498例,其中术后诊断为非胆道闭锁患儿66例,假阳性率为13.3％.83例非胆道闭锁组包括:婴儿肝炎综合征58例,胆道发育不良16例,TPN相关性胆汁淤积症5例,胆道穿孔和浓缩胆栓综合征各2例.结论 肝功能检查的相似性及过度依赖同位素肝胆排泄性造影可能是非胆道闭锁患儿疑诊为胆道闭锁的主要原因,术前仔细分析黄疸出现的日龄、γ-GT、B型超声检查肝脏大小有利于非胆道闭锁病例术前的鉴别诊断.     

α1-抗胰蛋白酶缺乏症合并胆道闭锁1例报告及文献复习

目的探讨α1-抗胰蛋白酶缺乏症合并胆道闭锁的临床特点及早期诊断。方法回顾性分析1例α1-抗胰蛋白酶缺乏症合并胆道闭锁患儿的临床资料,并复习国内外相关文献。结果患儿,男,新生儿期即出现黄疸、肝脏肿大,血清谷丙转氨酶及谷草转氨酶升高、总胆红素和直接胆红素升高、γ-谷氨酰转肽酶增高,行十二指肠引流未引流出胆汁,手术探查、术中胆道造影及术后病理证实为胆道闭锁。基因检测发现SERPINA1突变,明确诊断为α1-抗胰蛋白酶缺乏症合并胆道闭锁。复习国内外文献,α1-抗胰蛋白酶缺乏性肝病患儿主要表现为胆汁淤积性黄疸、肝脾肿大、低白蛋白血症、血清谷丙转氨酶及谷草转氨酶升高、维生素K缺乏或肝脏合成功能障碍导致的凝血异常疾病;若早期不能及时诊断及进行干预治疗可引起进行性肝病或肝硬化。结论对不明原因胆汁淤积性肝病的患儿应积极寻找病因,必要时行基因检测,及早诊断、治疗,改善预后。     

Alagille综合征五例临床和病理特点

Alagiue综合征是一种可累及肝脏、心脏、骨骼、眼睛和颜面等多系统或器官的显性遗传性疾病,常以婴儿期胆汁淤积为突出表现,临床上和胆道闭锁鉴别困难。国内以往未见该病报道。我院自2004年开始在婴儿期胆汁淤积患儿中明确诊断Alagille综合征5例,并进行了较系统的临床随访和肝脏病理研究,报告如下。     

北京市应用大便比色卡进行胆道闭锁症筛查的临床研究

目的探索建立胆道闭锁症的筛查流程及大便比色卡用于胆道闭锁症筛查的方法学评价。方法对2013年12月4日至2014年4月30日在北京市朝阳区所属的25家助产机构分娩的新生儿发放大便比色卡,家长根据该卡片比对婴儿大便颜色至生后4个月,通过短信、电话和42天门诊进行结果追访,总结大便比色卡筛查胆道闭锁症的结果。结果共有19 252名新生儿参加了大便比色卡筛查胆道闭锁症,根据2014年1~3月的筛查数与活产数,应用大便比色卡筛查胆道闭锁症的筛查率91.3%;增加短信提醒追访方式后,门诊可疑患儿就诊率由0.65‰增加到1.89‰。大便比色卡阳性结果 12例,1例在生后55天确诊胆道闭锁症(Ⅲ型),3例分别于生后75天、47天、55天诊断为巨细胞病毒感染性肝炎、乳儿肝炎、肠道外营养相关性胆汁淤积症。其他8例为一过性大便比色卡阳性便。1例于生后24 h因黄疸住院,7天诊断为胆道闭锁症(Ⅲ型),未发现大便比色卡阳性便。胆道闭锁症的发病率为1∶9626。结论大便比色卡是简便有效的筛查胆道闭锁症的方法,可早期发现黄疸不明显的患儿,同时还可筛查出其他引起胆汁淤积症的疾病。     

婴幼儿胆汁淤积性黄疸的外科诊疗决策

正婴幼儿在生后1周内约60%~80%出现黄疸,多数情况下如不伴有肝胆系统疾病,黄疸很快消退。如果黄疸延迟消退一定要尽快明确病因,及时给予合理诊疗,避免延误外科疾病导致黄疸的治疗。婴幼儿胆汁淤积症病因复杂,包括肝外胆道梗阻、感染、内分泌异常、代谢和基因紊乱以及药物性肝损伤,胆道闭锁是引起     

Hepatobiliary scintigraphy in arteriohepatic dysplasia (Alagille's syndrome)

Hepatobiliary scintigraphy has proven to be of great utility in distinguishing biliary atresia from other causes of neonatal cholestasis. Arteriohepatic dysplasia (Alagille's syndrome) is an uncommon entity characterized by typical facial features, pulmonary artery stenosis, and a liver disorder which presents during the neonatal period as progressive jaundice. Two neonates, who were later shown to have Alagille's syndrome, underwent hepatobiliary scintigraphy to rule out biliary atresia. Findings on the hepatobiliary scans from the two patients were similar to those usually associated with biliary atresia and both finally required surgical exploration to rule out biliary atresia. The findings on hepatobiliary scans in these patients with Alagille's syndrome are discussed and compared with those associated with other forms of neonatal cholestasis.     

Phenobarbital-enhanced hepatobiliary scintigraphy in the diagnosis of biliary atresia: two decades of experience at a tertiary center

Background

Hepatobiliary scintigraphy is highly sensitive for diagnosing biliary atresia; however, its specificity has varied in the literature from 35% to 97%.

Objective

The purpose of this study was to re-evaluate the accuracy of phenobarbital-enhanced hepatobiliary scintigraphy in differentiating biliary atresia from other causes of neonatal cholestasis.

Materials and methods

We retrospectively reviewed all hepatobiliary scans of infants with cholestasis at our institution from December 1990 to May 2011. Per our routine protocol the scans were obtained after pretreatment with phenobarbital (5 mg/kg/day for 5 days) to achieve a serum level of ≥15 mcg/ml. Normal hepatic uptake with no biliary excretion by 24 h was considered consistent with biliary atresia.

Results

One hundred eighty-six infants with 210 hepatobiliary scans composed the study group. Forty-three (23%) infants had the final diagnosis of biliary atresia. Hepatobiliary scintigraphy was 100% sensitive, 93% specific and 94.6% accurate in diagnosing biliary atresia. Of the 186, 39/111 (35.1%) term and 2/68 (2.9%) preterm infants had biliary atresia; two of seven children with unknown gestational age also had biliary atresia. Other diagnoses included neonatal hepatitis, total parenteral nutrition cholestasis, Alagille syndrome, cystic fibrosis, choledochal cyst, hypothyroidism, alpha-1 antitrypsin deficiency and persistent cholestasis of unknown etiology.

Conclusion

Phenobarbital-enhanced hepatobiliary scintigraphy is highly accurate in differentiating biliary atresia from other causes of neonatal cholestasis. Biliary atresia is rare in premature infants.     

Neonatal cholestasis

OBJECTIVE: To warn pediatricians about the early recognition of cholestasis in newborns and infants. METHODS: A bibliographic research about cholestasis was performed using Medline, and emphasizing the most relevant publications of the last 30 years. RESULTS: The concept of cholestasis and the causes of cholestatic tendency in newborns and infants are described. Several causes of intra and extrahepatic cholestasis are reported as well. In this review, only the diseases with diagnostic, therapeutic or prognostic peculiarities are commented, including extrahepatic biliary atresia, idiopathic neonatal hepatitis, galactosemia, and Alagille s syndrome. Furthermore, several resources are discussed for the diagnosis of cholestasis. CONCLUSIONS: The establishment of the diagnosis of cholestasis through the detection of hyperbilirubinemia in newborns who present jaundice after 14 days of life is a goal that could change the prognosis of several diseases responsible for neonatal cholestasis.     

The infant with prolonged jaundice: investigation and management

Jaundice for more than 14 days in the newborn is pathological and requires investigation. Minimum investigations include serum total and conjugated bilirubin. Conjugated hyperbilirubinaemia, dark urine and pale stools are pathognomic of the neonatal hepatitis syndrome which should be investigated urgently. The neonatal hepatitis syndrome has many causes and should be investigated by a structured protocol. The most important differential diagnosis is biliary atresia and affected infants should have a Kasai portoenterostomy carried out by an experienced surgeon, ideally before 60 days of age.Genetic causes of the neonatal hepatitis syndrome are increasingly recognized and early diagnosis facilitates genetic advice and, in some situations, specific treatment.The management of cholestasis is largely supportive, consisting of aggressive nutritional support with particular attention to fat-soluble vitamin status. The use of ursodeoxycholic acid is associated with improvement in biochemical measures of cholestasis and may improve the natural history of cholestasis in some circumstances.Outcome is dependent on aetiology. In idiopatic neonatal hepatitis, more than 90 make a complete biochemical and clinical recovery.     

Analysis of delay in diagnosis of extrahepatic biliary atresia]

Prognosis of extrahepatic biliary atresia depends on an early surgical treatment. This survey studied the delay to surgery of infants treated for biliary atresia and analysed the causes of late diagnosis and referral. MATERIAL AND METHODS: Medical files of 21 infants treated for biliary atresia between 1988 and 1998 were retrospectively analysed. RESULTS: Median age at biliary operation was 57 days and did not change during time. In only 3/21 cases, surgery was performed before 45 days of age. The first clinical or biological sign of cholestasis was noted at a median age of 12 days. In eight cases, the first medical visit for cholestasis (median age of 21 days) was not followed by a blood test. In 11 cases, infants presenting with biological cholestasis were referred to hospital more than seven days later. False diagnosis was noted in seven cases and delayed significantly the operation. CONCLUSION: The delay to surgical treatment is too long and does not decrease whereas a majority of infants visit their physician early. Medical information is mandatory for all physicians taking care of infants.     

Diagnostic utility of hepatobiliary scintigraphy with 99mTc-DISIDA in neonatal cholestasis

We retrospectively evaluated the utility of hepatobiliary scintigraphy and various clinical factors in differentiating intrahepatic cholestasis from biliary atresia in 28 consecutive infants with neonatal cholestasis. One millicurie of technetium-labeled diisopropyliminodiacetic acid (DISIDA) was administered intravenously, and images were obtained for up to 24 hours or until gastrointestinal excretion was noted. Nine separate studies in seven infants with biliary atresia were correctly interpreted as showing no gastrointestinal excretion of radionuclide. Of the 21 patients with intrahepatic cholestasis, only nine had gastrointestinal excretion on the first study; in eight without excretion, a second study was done, and five of these showed gut excretion. All infants with either neonatal hepatitis (six) or inspissated bile syndrome (three) had demonstrable gastrointestinal excretion either on the first or second DISIDA study. However, five of six infants with paucity of intrahepatic bile ducts, two of six infants with cholestasis secondary to total parenteral nutrition, and one infant with cholangiolitis did not show evidence of gastrointestinal excretion. The mean birth weight, mean gestational age, and mean weight at study were significantly greater (P less than 0.005) for infants with biliary atresia without excretion than for infants with intrahepatic cholestasis without excretion. The mean direct bilirubin concentration was 6.0 mg/dL for both infants with biliary atresia and infants with intrahepatic cholestasis without excretion; however, infants with excretion had a significantly lower (P less than 0.02) mean direct bilirubin value of 3.4 mg/dL. Excretion was noted in four infants with total bilirubin values greater than 10.0 mg/dL. The absence of gut excretion on the first DISIDA study was 100% sensitive but only 43% specific for biliary atresia. In infants without gut excretion of DISIDA, birth weight greater than 2200 g was 100% sensitive and 92% specific for biliary atresia. We conclude that DISIDA scanning, together with clinical data, is useful in differentiating extrahepatic from intrahepatic cholestasis. The absence of gut excretion on the first DISIDA study does not necessarily indicate extrahepatic obstruction; the study should be repeated if the diagnosis is not clear.     

血清γ-谷氨酰转肽酶联合直接胆红素诊断婴儿胆道闭锁的价值

目的 探讨血清γ-谷氨酰转肽酶（GGT）联合直接胆红素（DB）对胆道闭锁的诊断价值。方法 选取2010年7月至2018年12月住院治疗的胆汁淤积症患儿667例为研究对象,根据术中胆管造影结果和随访情况,将患儿分为胆道闭锁组（n=234）和胆汁淤积组（n=433）。比较两组的发病年龄、性别,以及血清总胆红素（TB）、DB、丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、总胆汁酸（TBA）、GGT水平。将有统计学意义的指标纳入受试者工作特征曲线（ROC）分析,计算ROC曲线下面积（AUC）和最佳诊断界值。结果 胆道闭锁组患儿发病年龄早于胆汁淤积组（P < 0.001）。两组患儿性别、ALT及AST水平比较差异无统计学意义（P > 0.05）。胆道闭锁组TB、DB、TBA、GGT水平显著高于胆汁淤积组（P < 0.05）。GGT联合DB诊断胆道闭锁的AUC最大,为0.892（95% CI：0.868~0.916）。当GGT取值为324.0 U/L,DB取值为115.1 μmol/L时,GGT与DB联合诊断胆道闭锁的敏感度和特异度分别为79.8%、83.2%。结论 GGT联合DB诊断胆道闭锁的敏感度和特异度较高,可作为诊断胆道闭锁的有效指标之一。     

胆道闭锁围生期危险因素的病例对照研究

摘要 目的：探讨胆道闭锁的危险因素,为早期鉴别诊断及其病因和发病机制的研究提供可能的线索。方法：自行设计胆道闭锁危险因素调查问卷,包括患儿自身、母亲、父亲和环境共22项因素,对2016年7月21日至2017年6月21日在重庆医科大学附属儿童医院肝胆外科因不明原因黄疸住院的＜7月龄患儿在入院时行问卷调查。在每个病例随访至少3个月后并从病志中截取所有调查对象的临床资料,确定胆道闭锁组和对照组,并按性别、年龄±10 d行两两匹配。先行单因素分析后,以结果中P<0.2的指标为自变量行多因素Logistic回归分析,考察问卷中的各项因素与胆道闭锁的相关性。结果：发放调查问卷146份,均回收,满足胆道闭锁组、对照组的纳入和排除标准者分别为96和42例,胆道闭锁组与对照组两两匹配后各42例进入本文分析。单因素分析显示,孕期四维彩超胆道异常、低出生体重、出生时不良事件、生后大便颜色变浅、母亲孕期补充微量元素、孕期补充叶酸、孕期存在并发症在两组间差异有统计学意义。多因素Logistic回归分析显示,母亲存在孕期并发症（OR=21.27,95%CI：3.50~129.21）、患儿生后大便颜色变浅（OR=6.70,95%CI：1.73~26.02）是胆道闭锁的独立危险因素;低出生体重是胆道闭锁发病的独立保护因素（OR=0.05,95%CI：0.00~0.67）。结论：母亲存在孕期并发症（妊娠期糖尿病、高血压、肝内胆汁淤积症）、生后大便颜色变浅可能是胆道闭锁的独立危险因素,对于胆道闭锁与其他黄疸性疾病的早期鉴别诊断有一定意义。     

Recent developments in diagnostics and treatment of neonatal cholestasis

Neonatal cholestasis is characterized by conjugated hyperbilirubinemia in the newborn and young infant and is a sign common to over 100 hepatobiliary and/or metabolic disorders. A timely evaluation for its etiology is critical in order to quickly identify treatable causes such as biliary atresia, many of which benefit from early therapy. An expanding group of molecularly defined disorders involving bile formation, canalicular transporters, tight junction proteins and inborn errors of metabolism are being continuously discovered because of advances in genetic testing and bioinformatics. The advent of next generation sequencing has transformed our ability to test for multiple genes and whole exome or whole genome sequencing within days to weeks, enabling rapid and affordable molecular diagnosis for disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Thus, our diagnostic algorithms for neonatal cholestasis are undergoing transformation, moving genetic sequencing to earlier in the evaluation pathway once biliary atresia, “red flag” disorders and treatable disorders are excluded. Current therapies focus on promoting bile flow, reducing pruritus, ensuring optimal nutrition, and monitoring for complications, without addressing the underlying cause of cholestasis in most instances. Our improved understanding of bile formation and the enterohepatic circulation of bile acids has led to emerging therapies for cholestasis which require appropriate pediatric clinical trials. Despite these advances, the cause and optimal therapy for biliary atresia remain elusive. The goals of this review are to outline the etiologies, diagnostic pathways and current and emerging management strategies for neonatal cholestasis.     

The role of reovirus type 3 infection in an established murine model for biliary atresia.

AIM OF THE STUDY: Infection of newborn Balb/c-mice with Rhesus rotavirus (RRV) leads to cholestasis and biliary atresia. In this current model, Reovirus Type 3 was investigated to ascertain whether Reovirus Type 3 causes the same or similar hepatobiliary lesions as RRV. METHODS: Newborn Balb/c-mice were infected with Reovirus Type 3 Dearing and Reovirus Type 3 Abney on the first day of life. Clinical observation followed for a period of at least 10 days. Cholestatic and/or dystrophic mice were prepared and specimens were taken for histological examination. RESULTS: Infection with RRV showed a 85 % morbidity for biliary atresia as described before. Clinical disease, following an infection with Reovirus T3 Dearing, showed neurological symptoms such as ataxia, and all mice died within 3 weeks. No obstructive or atretic changes of the hepatobiliary ducts could be seen either macroscopically or histomorphologically. 60 % of the mice having been infected with Reovirus T3 Abney showed signs of cholestasis and oily fur syndrome, but almost 15 % recovered from the disease. Although the histological findings did not reveal biliary atresia, inflammation and destruction of bile ducts could be observed. CONCLUSION: In comparison to the RRV infection in a Balb/c-mice model, where biliary atresia could be induced, infection with Reovirus T3 in this model did not lead to biliary atresia. But Reovirus T3 Abney infection revealed inflammatory signs as described in the literature before. The question as to why different hepatotrophic viruses lead to different changes in the murine hepatobiliary tract has to be investigated in further studies.