胆道闭锁的诊断及治疗新进展

胆道闭锁的诊断基于临床表现、筛查及相关化验检查。近年来血液标志物的研发和超声检查手段的提高使得胆道闭锁的就诊年龄普遍提前,其中最具代表性的突破为血清基质金属蛋白酶-7,以其高灵敏度和特异度超越了现有血生化指标的诊断效能,并正在向临床推广应用;肝弹性成像技术在诊断及预后判断方面也能在很大程度上提高诊断效能。手术仍是治疗胆道闭锁的唯一方法,当前序贯手术治疗方案首先是Kasai肝门空肠吻合术,加以抗感染、减轻炎症等药物治疗方案,而Kasai手术失败及肝功能丧失的患者,最终需要肝移植挽救生命。因此胆道闭锁目前的研究重点内容为早期诊断标志物,以及特异性靶向性、防止进行性肝纤维化药物的研发。该文将综述目前胆道闭锁的诊断方法和治疗措施,并探讨潜在的研究方向。 ［中国当代儿科杂志,2022,24（11）：1269-1274］     

影响胆道闭锁早期诊治的原因分析

目的：分析影响胆道闭锁早期诊断和治疗的因素并探讨解决对策。方法：回顾性总结与分析70例胆道闭锁患儿就诊年龄与临床表现、主诊医生和家长对本病的认识、影像学检查结果等方面对早期诊断的影响，探讨延误诊治的各种原因。结果：影像学检查中，肝胆核素检查27例，6例误诊。B超检查在未掌握观察肝门纤维块前，23例中仅有14例诊断正确，而在掌握该方法后，检查38例，35例诊断正确。结论：先天性胆道闭锁延误诊治的原因有：临床表现不典型、观察病情不细致、主诊医生对本病的认识不足、影像学检查的误诊等。因此建议：仔细体检,医生亲自观察大便颜色；B超检查内容包括观察肝门纤维块和胆囊进食前后的变化。肝胆核素检查， 应防止放射物污染，减少同位素在体内的分解水化。     

The prelaparotomy diagnosis of extrahepatic biliary atresia.

The diagnostic accuracy of laboratory investigations in the prelaparotomy differentiation between extrahepatic biliary atresia (EHBA) and intrahepatic disease (IHD) was assessed in 86 consecutive infants presenting with conjugated hyperbilirubinaemia. Forty five infants had EHBA and 41 IHD. The mean serum bilirubin concentration, gamma-glutamyltranspeptidase (GGT) activity, and the GGT/aspartate transaminase (AST) ratio were appreciably higher in infants with EHBA than in those with IHD. In infants with IHD, however, serum bilirubin concentrations were in the EHBA range in 19 (47%), as were GGT values in 29 (71%), and GGT/AST ratios in 33 (80%). In individual patients neither increasing nor decreasing GGT values were of diagnostic importance. Failure of biliary excretion of 99Tcm-p-Butyl-ida occurred in 29 of 30 (97%) patients with EHBA but also in 22 of 23 (67%) with IHD. In all 5 patients with IHD associated with alpha 1 antitrypsin deficiency these 4 investigations gave results in the EHBA range. Liver biopsy specimen interpretation, correct in 38 of 42 infants with EHBA, gave an overall accuracy of diagnosis of 86%: the results of 3 further biopsies were equivocal. In 33 of 40 infants with IHD bile duct obstruction was excluded; the remaining 7, including 4 with alpha 1 antitrypsin deficiency, showed equivocal changes. Faecal excretion of 131I rose bengal faecal excretion was less than 10% in 36 of 37 patients with EHBA and in 9 of 26 with IHD, giving an overall accuracy of diagnosis of 84%. In patients in whom genetic disorders, such as alpha 1 antitrypsin deficiency had been excluded, interpretation of liver biopsy specimens together with 131I rose bengal faecal excretion remain the most accurate means of identifying those who need surgery for EHBA and of avoiding unnecessary laparotomy in infants with IHD.     

Use of gamma-glutamyl transpeptidase in the diagnosis of biliary atresia

A simple, nonsurgical means of differentiating biliary atresia (BA) from neonatal hepatitis has remained elusive. To determine its diagnostic usefulness, serum gamma-glutamyl transpeptidase (GGTP) levels were measured prospectively in 17 infants (aged 5 to 16 weeks) admitted consecutively to rule out BA. Seven patients were found to have BA, seven had neonatal hepatitis (NH), and three had alpha 1-antitrypsin (A1A) deficiency. The mean maximal GGTP level in those patients with NH (183 +/- 54 IU/L) was significantly lower than that found in patients with BA (760 +/- 492 IU/L) or A1A deficiency (1,725 +/- 921 IU/L). In the 14 patients without A1A deficiency, a serum GGTP level greater than 300 IU/L correctly identified six of seven patients with BA, while a GGTP level less than 300 IU/L correctly identified seven of seven patients with NH, although including one false-negative finding, in a patient with choledochal cyst and BA.     

The use of ultrasonography in the diagnosis of biliary atresia

Preoperative upper abdominal ultrasonograms of babies with biliary atresia were reviewed in order to determine the efficacy of this technique in the differential diagnosis of biliary atresia and neonatal hepatitis. In 4 patients with neonatal hepatitis and 8 normal controls, ultrasonograms showed echoes of the gallbladder. In 14 patients with biliary atresia, echoes of the gallbladder were not apparent. It is concluded that preoperative ultrasonograms provide an efficient diagnostic method for differentiating biliary atresia from neonatal hepatitis.Offprint requests to: T. Okasora     

Laparoscopic cholangiogram in biliary atresia: a refinement in the gallbladder hitch technique

Introduction

The study describes a refinement in the gallbladder hitch stitch and assesses the value of the laparoscopic cholangiogram in children with suspected biliary atresia.

Methods

Twenty children with neonatal jaundice and no drainage as shown on the HIDA scan underwent a diagnostic laparoscopy through an umbilical 5 mm port. A 3 mm laparoscopic needle holder inserted through a 3.5 mm port to the left of the umbilicus was used to hitch the gallbladder to the abdominal wall. The stylet of a large bore 16F IV cannula then was used to penetrate the gallbladder to perform the laparoscopic cholangiogram.

Results

There was no need for conversion in all 20 children by this technique. Patent biliary anatomy was demonstrated in 11 children (11/20). These children had no further procedures. In 3 (3/20) children, the common bile duct was demonstrated, while the hepatic ducts were not. These children had a laparotomy for Kasai procedure after an open cholangiogram with a vascular bulldog clamp on the CBD confirmed the finding. Six (6/20) had no demonstrable patency; 3 had it confirmed when the abdomen was opened for the Kasai procedure; only those proceeding to Kasai portoenterostomy (3 hepatic duct atresia, 3 complete biliary atresias) had an epidural catheter placed by the anesthetist. The remaining 3 had no further procedure performed due to the advanced nodular liver with ascites and evidence of portal hypertension.

Conclusion

The findings of laparoscopic cholangiogram were confirmed in all six children who underwent laparotomy for Kasai procedure. The laparoscopic cholangiogram using gallbladder hitch reliably demonstrates a patent biliary system (11/11) and was valuable in avoiding further invasive procedures in 70% (14/20) of babies.

     

Biliary atresia: making the diagnosis by the gallbladder ghost triad

OBJECTIVE: To describe the gallbladder ghost triad and evaluate its usefulness in the sonographic diagnosis of extrahepatic biliary atresia (BA). METHODS: From October 1997 to February 2002, 217 fasted infants with cholestatic jaundice aged 2-12 weeks were examined sonographically. We defined the gallbladder ghost triad as gallbladder length <1.9 cm, lack of smooth/complete echogenic mucosal lining with an indistinct wall and irregular/lobular contour, and used it as a criteria for BA. Gallbladder wall thickness, triangular cord, diffuse periportal echogenicity and hepatic artery calibre were also recorded. Diagnosis of BA was confirmed surgically and histologically. RESULTS: Thirty of 31 babies with BA demonstrated the gallbladder ghost triad. No false-positives were recorded. The 31st BA baby showed a normal gallbladder at 6 weeks, but developed the ghost triad at 8 weeks. Gallbladder wall thickening was seen in 46/186 non-BA babies, but not in BA. Triangular cord was observed in 24/31 babies. Twenty-two of 186 non-BA babies and 5/31 BA babies showed diffuse periportal echogenicity. The hepatic artery appeared more prominent in BA. All 31 babies diagnosed sonographically as BA had surgery. Three non-BA babies had "negative" laparotomies showing hypoplastic bile ducts. CONCLUSIONS: The gallbladder ghost triad is a very accurate sign of BA. Indeterminate cases require close follow-up.     

十二指肠内胆红素光吸收值监测在胆道闭锁诊断中的应用研究

目的本研究对〈4个月阻塞性黄疸婴儿十二指肠内的胆红素进行光吸收值动态监测，评价光吸收值在胆道闭锁诊断中的意义。方法研究对象分为胆道闭锁患儿（biliary atresia，BA）17例（男11例，女6例；年龄2～16周，平均5．7周）及婴儿肝炎综合征患儿（infantile hepatitis syndrome，IHS）20例（男14例，女6例；年龄3～7周，平均5周）。37例患儿接受了Bilitec十二指肠内胆红素光吸收值的监测，观察原始光吸收值曲线图，分析、比较最高光吸收值、光吸收值≥0．14U及≥0．25U的时间百分比。结果胆道闭锁组的光吸收值明显低于婴儿肝炎综合征组。结论十二指肠内胆红素光吸收值监测可为鉴别BA与IHS提供客观依据。     

Extrahepatic biliary atresia: from diagnosis to liver transplantation

Thirty infants were diagnosed with extrahepatic biliary atresia (EBA) from July 1978 to July 1989; 28 have undergone a Kasai or Lilly-Altman modification of the Kasai portoenterostomy; 2 were excluded from surgery because they presented after 3 months of age and had advanced biliary cirrhosis. Immediate postoperative drainage (>30 ml/day was achieved in 24 patients (86%), with 14 (50%) surviving free of jaundice. The average follow-up was 2.25 years (range 3 months to 10 years); the longest survivor is 10.3 years old. The overall survival was 64%, and 5-year survival 50%. Of 24 infants operated on at <12 weeks of age, 14 are free of jaundice (58%), 4 are alive with jaundice (17%), and 6 have died (25%). No correlation existed between subsequent bile drainage and duct size at the porta hepatis, presence or absence of hepatic fibrosis, giant-cell transformation, or hepatic inflammation. Complications included cholangitis (57%), progressive hepatic failure (39%), portal hypertension (21%), gastrointestinal bleeding (21%), esophageal varices (18%), stomal hemorrhage (11%), seizures (7%), rickets (3.5%), biliary calculus in the Roux-en-Y (3.5%), and hepatic abscess (3.5%). Five infants required revision, with 1 patient undergoing six reoperations, each followed by successful re-establishment of bile drainage. One infant had a successful liver transplant, and 2 are currently candidates for transplantation. Based on this analysis, an algorithm has been formulated for the diagnostic evaluation and subsequent surgical management from initial portoenterostomy to orthotopic liver transplantation for infants diagnosed with EBA. From our review of this experience and the literature on EBA and orthotopic liver transplantation, we have concluded that portoenterostomy has a substanial chance (P <0.05) of providing bile drainage and survival is comparable to that after liver transplantation. Although ultimate failures occur at a steadily increasing rate, portoenterostomy delays transplantation until children are older and can more easily undergo transplantation with its attendant risks of immunosuppression and complications.     

不同诊断入径对胆道闭锁诊治影响的探讨

目的总结分析内科和外科不同诊断入径对胆道闭锁手术年龄和诊断准确率的影响,探讨统一胆道闭锁诊断流程的必要性。方法收集2015年3月至2016年3月本院收治的因梗阻性黄疸拟诊为胆道闭锁,经腹腔镜探查、胆道造影的患儿临床资料。将首诊于外科并收治在外科病房的病例定为外科组;首诊于内科并收治在内科病房最后转入外科治疗的病例定为内科组。回顾性分析两组资料:①手术年龄(包括小于60 d手术患儿比例和大于90 d手术患儿比例),术前住院时间;②胆道闭锁诊断准确率;③Kasai术后3个月黄疸清除率;④总住院时间和住院费用。结果共收集患儿273例,根据首诊入径分为外科组237例和内科组36例,其中术中确诊为胆道闭锁者分别为202例和26例。对两组资料进行统计学分析,结果表明,外科组根治手术年龄较内科组低(66.50±20.52)d vs(72.58±27.01)d,差异不具有统计学意义(z=0.995,P=0.319 6);而术前住院时间,外科组(2.21±1.12)d,明显短于内科组(6.85±3.52)d(r=7.561,P0.001);确诊率外科组(85.23%)高于内科组(72.22%),χ~2=3.842 5,P=0.05;Kasai术后3个月黄疸清除率两组差异不明显(P0.05);胆道闭锁Kasai根治手术患儿外科组总住院时间明显短于内科组,(18.07±5.62)d vs(21.63±3.92)d,P0.000 1,总住院费用明显低于内科组,(34 154.66±7 457.43)元vs(39 657.52±6 163.36)元,P0.000 1)。结论内外科不同诊断入径虽然不明显影响胆道闭锁患儿的手术年龄,但外科入径对缩短住院时间和减少治疗费用均有积极作用,且诊断准确率并不低于内科入径,提示内外科统一诊断流程的必要性。     

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.