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Prenatal Diagnosis of Familial Type I Choledochal Cyst


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Prenatal Diagnosis of Familial Type I Choledochal


Matthew S. Clifton, MDa, Ruth B. Goldstein, MDb, Anne Slavotinek, PhDd, Mary E. Norton, MDc, Hanmin Lee, MDa, Jody Farrell, RN, MSNa,

Kerilyn K. Nobuhara, MDa

Departments ofaSurgery,bRadiology,cObstetrics/Gynecology, anddPediatrics, University of California, San Francisco, California

The authors have indicated they have no financial relationships relevant to this article to disclose.


Familial choledochal cysts are extremely rare. High-resolution ultrasound now allows for the antenatal diagnosis of these anomalies. After delivery, elective surgical resection should be planned; however, increases in size, deterio-ration of liver function, and ascending cholangitis frequently force early intervention. We report an unusual occurrence of siblings with type I choledochal cysts and review the existing literature on cause, genetics, classifica-tion, diagnosis, and management of this disease.


AMILIAL CHOLEDOCHAL CYSTS are extremely rare. High-resolution ultrasound now allows for the an-tenatal diagnosis of these anomalies. After delivery, elec-tive surgical resection should be planned; however, in-creases in size, deterioration of liver function, and ascending cholangitis frequently force early interven-tion. We report an unusual occurrence of siblings with type I choledochal cysts and review the existing litera-ture on cause, genetics, classification, diagnosis, and management of this disease.


A 28-year-old gravida 5 para 3– 4 aborta 1 woman was referred to our institution for prenatal evaluation of a fetal abdominal mass that initially was detected on a 24-week sonogram at another hospital. On our detailed obstetric 31-week sonogram, the mass measured 2.6⫻ 2.1 cm on an axial image of the abdomen and was located to the right of midline (Fig 1A). A small gallblad-der with irregular margins was also identified (Fig 1B), and the stomach and the duodenum seemed normal. Of note, the mother had 1 previous child who received a diagnosis at 8 years of age of a choledochal cyst, raising the clinical suspicion of a similar entity in this fetus (see “Family History”). The case was discussed at length with the Fetal Treatment Center team; given the size of the cyst and family history, the decision was made for monthly sonographic surveillance and postnatal inter-vention as appropriate. Follow-up sonogram at 36 weeks demonstrated a slight increase in size at 3.2⫻1.9 cm but no overall change in appearance of the cystic mass. The

female infant was born at 38 weeks’ gestation, weighing 4125 g, via spontaneous vaginal delivery. The infant tolerated ad libitum feedings and passed normal stools. A postnatal abdominal sonogram revealed a normal liver and contracted gallbladder (Fig 2A) with an enlarged, bilobed structure in the position of the common bile duct (Fig 2B), which communicated with the gallbladder via the cystic duct (Fig 2C). The intrahepatic ducts were normal. These findings were consistent with the diagno-sis of choledochal cyst, and the absence of intrahepatic ductal dilation excluded Caroli’s disease. Serial evalua-tion revealed initial total and direct bilirubin levels of 7.7 and 2.2 mg/dL on day-of-life 1 and increased steadily to 11.8 and 4.3 mg/dL, respectively, by the third day of life (reference range: 0.3–1.3 and 0.1– 0.3 mg/dL, respec-tively). Aspartate aminotransferase was slightly elevated on the third day of life at 57 U/L (reference range: 16 – 41 U/L), whereas alanine aminotransferase was normal at 24 U/L (reference range: 11–59 U/L).␥-Glutamyl trans-ferase was elevated at 173 U/L (reference range: 5–39 U/L). Of note, the family history is significant for a 10-year-old sibling who underwent resection of a type I

Key Words:congenital abnormalities, liver disease, prenatal diagnosis

Abbreviations:PBM, pancreaticobiliary maljunction; PKD, polycystic kidney disease www.pediatrics.org/cgi/doi/10.1542/peds.2005-1411


Accepted for publication Aug 19, 2005


choledochal cyst at 8 years of age (case report 2). On physical examination, the right upper quadrant was firm but nontender and was otherwise unremarkable.

The infant was taken to the operating room on the sixth day of life because of worsening liver function tests. At laparotomy, an intraoperative cholangiogram was performed revealing a Todani type I choledochal cyst (Fig 3). Resection of the choledochal cyst and cholecys-tectomy were performed, followed by roux-en-Y hepati-cojejunostomy. Postoperatively, the serum direct biliru-bin continued a steady decline to 2.7 mg/dL on the day of discharge (postoperative day 8). Pathology was con-sistent with choledochal cyst. At the 6-month follow-up, the infant is healthy with normal expected growth and complete resolution of the hyperbilirubinemia.


Two years before the presentation of our patient, her 8-year-old brother presented to a community hospital

with a 1-day history of epigastric abdominal pain, nau-sea, and vomiting. He experienced 1 similar episode 2 weeks earlier, which was self-limited. Evaluation re-vealed an elevated serum amylase and lipase. Work-up included an abdominal sonogram, which revealed a cyst extending from the common bile duct to the common hepatic duct and a normal-appearing gallbladder. Com-puted tomography scan of the abdomen revealed a 4.5-⫻ 6.5-cm cyst extending from the porta hepatis to the FIGURE 1

A, Level II antenatal ultrasound of case report 1. Transverse image demonstrating cystic structure (*) located posteriorly in subhepatic space, adjacent to inferior vena cava (arrow). B, Transverse image showing small gallbladder with irregular wall thickening (arrow).



head of the pancreas, in communication with the com-mon hepatic duct. He was treated with bowel rest for 24 hours, with resolution of the abdominal pain, and sub-sequently was transferred to our institution. On exami-nation, there was no evidence of scleral icterus or jaun-dice and no palpable abdominal mass. Laboratory values revealed a bilirubin of 0.9 mg/dL, alkaline phosphatase of 272 U/L (reference range: 60 –321 U/L), and amylase of 74 U/L (decreased from 237 U/L at the time of initial presentation; reference range: 23–134 U/L).

The patient was taken to the operating room for a laparoscopic excision of a Todani type I choledochal cyst with roux-en-Y hepaticojejunostomy reconstruction. His postoperative recovery was uneventful, and he was dis-charged from the hospital on postoperative day 8, toler-ating a regular diet with minimal incisional pain. Pathol-ogy was consistent with a choledochal cyst and normal gallbladder without evidence of lithiasis.

Our case report patient had 2 unaffected siblings in addition to the brother with a choledochal cyst. Mater-nal and paterMater-nal ethnicity was Mexican, and consan-guinity was denied.


Choledochal cysts are exceedingly rare in the general population, and reports of familial occurrence are scarce. Choledochal cysts occur more commonly in female than male individuals (with a ratio of 3– 4:1), and the inci-dence in Western nations (Europe and North and South America) is 1 in 100 000 to 150 000 live births.1 Al-though classically considered a disease of infancy, an increased number of patients are now being discovered in adulthood.2Familial case reports of congenital chole-dochal cysts are extremely rare, with only 6 such reports in the literature.3 Choledochal cysts occur most com-monly in patients of Asian descent, with more than two thirds of the reported cases occurring in Japanese pa-tients.3There is no evidence of increased incidence in the Hispanic population.


The cause of choledochal cysts remains uncertain, al-though several theories exist. Pancreaticobiliary mal-junction (PBM), a condition whereby the pancreatic duct joins the common bile duct 1 to 2 cm proximal to the sphincter of Oddi,4creates an anomalously long common channel (⬎15 mm in length). This anatomic variation allows pancreatic secretions to reflux into the biliary ductal system and may lead to increased ductal pressure and subsequent dilation.5Evidence in favor of this theory points to the high rate of PBM in Japanese patients with choledochal cyst disease. However, PBM alone cannot explain the predominance in female indi-viduals or those of Asian ancestry,1and the presence of a long common channel does not guarantee develop-ment of a choledochal cyst. In addition, choledochal cysts occur in the absence of PBM. Other theories sug-gest an acquired ductal cause, such as a web, stricture, or dysfunction at the sphincter of Oddi as a source of dis-ease.6Familial cases point to a possible inherited/genetic component predisposing to formation of choledochal cysts.


The initial attempt at classification of congenital chole-dochal cysts, wherein 3 distinct types were described, was undertaken by Alonso-Lej et al7in 1959. Although the use of the word “cyst” is a misnomer, it has contin-ued to be used to this day. Later, in 1977, Todani et al8 further subdivided the classification while also adding types IV and V. Most recently, Visser et al6 proposed abandoning the numbering system in favor of a simpli-fied nomenclature. The Todani classification system is based solely on morphologic/gross appearance. In real-ity, types I and IV represent a continuum of disease and possess similar risk profiles for malignant degeneration. Choledochal cyst is a term reserved for previously de-scribed types I and IV cysts, because the intrahepatic ducts are never entirely normal in this setting. Chole-dochal diverticulum describes the previous Todani type II: a diverticulum of the common bile duct, sometimes resembling a duplicated gall bladder. Choledochocele is considered a variant of duodenal duplication, manifested by dilation of the intraduodenal common bile duct, and is a distinct entity.

Caroli’s disease, previously type V choledochal cyst, is an autosomal recessive inherited condition characterized by cystic dilation of intrahepatic bile ducts. It has been linked to various chromosomal abnormalities, including an unbalanced translocation between chromosomes 3 and 8.9Although possessing some radiologic similarities to choledochal cyst, it is also a distinct entity.6The indi-vidual classification schemes are detailed in Table 1. FIGURE 3



It remains unclear as to whether a genetic predisposition to choledochal cysts and Caroli’s disease exists. Familial case reports of congenital choledochal cysts have been described but are limited to 4 cases of mother-daughter transmission, 1 case of father-daughter transmission, 2 affected sisters, and 2 affected pairs of brother and sis-ter.10In twin studies, a high incidence of concordance for a phenotypic feature between monozygous twins can be indicative of a significant genetic contribution to the cause. Only 1 of 8 pairs of reported monozygous twins has been concordant for a choledochal cyst,3,7and there is 1 report of a twin pair with Caroli’s disease.11 The evidence for a genetic contribution to the cause of cho-ledochal cysts therefore is tempered by a lack of concor-dance in twin pairs and few Mendelian pedigrees, mak-ing a complex pattern of inheritance or a multifactorial cause most likely for the majority of families. No loci have been mapped for choledochal cysts, and there are no known biochemical or chromosome markers for this anomaly.

Caroli’s disease can occur with both autosomal reces-sive and autosomal dominant polycystic kidney disease (PKD). A mutation in thePKD1gene has been identified in a family with Caroli’s disease and dominant PKD,12 and 2 mutations were reported in the PKHD1 gene in Caroli’s disease with recessive PKD.13 Caroli’s disease was present in 1 patient who had familial adenomatous polyposis and a deletion of chromosome 5q.14 Finally, clonal chromosomal aberrations of uncertain signifi-cance have also been described in a liver biopsy speci-men from a patient with Caroli’s disease without PKD.9


The classic triad of jaundice, right upper quadrant pain, and a palpable abdominal mass is present in ⬍20% of cases. Most patients present with abdominal pain, fever, and/or nausea and vomiting. Laboratory values will reflect a picture that is consistent with mechanical ob-struction of the pancreaticobiliary ductal system, with ele-vated bilirubin, alkaline phosphatase, ␥-glutamyl trans-ferase, and potential elevation of transaminases (aspartate aminotransferase and alanine aminotransferase) and se-rum amylase.1Within the past 10 years, routine use of high-resolution prenatal ultrasound has allowed the

ante-natal diagnosis of subhepatic cysts, later confirmed to be choledochal cysts.15Fewer than 10 familial cases have been described in the literature,3and this represents only the third report of siblings with choledochal cyst disease.

The optimal timing of intervention for neonates has not yet been established.10 Although it is universally accepted that complete extrahepatic biliary excision in-cluding the gallbladder is the treatment of choice, the timing in the neonate is unclear. It has been suggested that progressive intrahepatic ductal dilation, cyst en-largement, and deterioration of liver function are har-bingers of obstruction and/or cholangitis, prompting early surgical intervention.15,16 As a temporizing mea-sure, in the setting of nutritional compromise or acute infection, external drainage procedures can be under-taken as a bridge to definitive excision. The best long-term therapy is resection of the cyst with biliary-enteric reconstruction, most commonly a roux-en-Y hepaticoje-junostomy.6,16New developments in minimally invasive surgery have made these lesions amenable to laparo-scopic resection and reconstruction.17

Internal drainage procedures without cyst excision, although commonplace in the past, have shown a pre-dilection for malignancy. The reasons for this are not yet entirely clear, but proposed mechanisms include biliary stasis, biliary lithiasis, superinfection, recurrent cholan-gitis, pancreatitis, and conversion of bile salts to carcino-genic substances by chronic infections.1,15Types I and IV cysts carry the highest risk of cancer.18The majority of cancers that are associated with choledochal cysts are cholangiocarcinoma arising within the cyst; however, there are reports of malignant conversion throughout the biliary tree.19,20Approximately 10% of choledochal cyst malignancies are gallbladder cancers.21The high rate of malignant conversion has led to the current recom-mendation of cyst excision before age 30 in any patient who has previously undergone a drainage procedure.6 Development of cancer after excision occurs in⬍1% of patients, with most of these cases occurring in the setting of incomplete resection.19


We acknowledge the help of Drs. Keith Meredith and Michael Foley in the clinical follow-up of these patients.

TABLE 1 Classification Schemes for Choledochal Cysts6 – 8

Type I Type II Type III Type IV Type V

Alonso-Lej Congenital cystic dilation of common bile duct

Congenital diverticulum of common bile duct

Congenital choledochocele Todani (a) Common type, (b) segmental

dilation, (c) diffuse/cylindrical dilation

Diverticulum type in any part of extrahepatic duct

Choledochocele (a) Multiple cysts in intra-and extrahepatic ducts, (b) multiple cysts in extrahepatic ducts only

Intrahepatic bile duct cyst (single or multiple)



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3. Iwata F, Uchida A, Miyaki T, et al. Familial occurrence of congenital bile duct cysts. J Gastroenterol Hepatol. 1998;13: 316 –319

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5. Iwai N, Yanagihara J, Tokiwa K, Shimotake T, Nakamura K. Congenital choledochal dilatation with emphasis on patho-physiology of the biliary tract.Ann Surg.1992;215:27–30 6. Visser BC, Suh I, Way LW, Kang SM. Congenital choledochal

cysts in adults.Arch Surg.2004;139:855– 862

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9. Parada LA, Hallen M, Hagerstrand I, Tranberg K-G, Johansson B. Clonal chromosomal abnormalities in congenital bile duct dilatation (Caroli’s disease).Gut.1999;45:780 –782

10. Hamada Y, Tanano A, Sato M, Kato Y, Hioki K. Rapid enlarge-ment of a choledochal cyst: antenatal diagnosis and delayed primary excision.Pediatr Surg Int.1998;13:419 – 421

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syndrome in twin sisters. Am J Gastroenterol.1996;91:1024 – 1026

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13. Sgro M, Rossetti S, Barozzino T, et al. Caroli’s disease: prenatal diagnosis, postnatal outcome and genetic analysis.Ultrasound Obstet Gynecol.2004;23:73–76

14. Hodgson SV, Coonar AS, Hanson PJ, et al. Two cases of 5q deletions in patients with familial adenomatous polyposis: pos-sible link with Caroli’s disease.J Med Genet.1993;30:369 –375 15. Lugo-Vicente HL. Prenatally diagnosed choledochal cysts: ob-servation or early surgery?J Pediatr Surg.1995;30:1288 –1290 16. Marchildon MB. Antenatal diagnosis of choledochal cyst: the

first four cases.Pediatr Surg Int.1988;3:431– 436

17. Lee H, Hirose S, Bratton B, Farmer DL. Initial experience with complex laparoscopic biliary surgery in children: biliary atresia and choledochal cyst.J Pediatr Surg.2004;39:804 – 807 18. Todani T, Tabuchi K, Watanabe Y, Kobayashi T. Carcinoma

arising in the wall of congenital bile duct cysts.Cancer1979; 44:1134 –1141

19. Watanabe Y, Toki A, Todani T. Bile duct cancer developed after cyst excision for choledochal cyst.J Hepatobiliary Pancreat Surg. 1999;6:207–212

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DOI: 10.1542/peds.2005-1411 originally published online February 1, 2006;



Lee, Jody Farrell and Kerilyn K. Nobuhara

Matthew S. Clifton, Ruth B. Goldstein, Anne Slavotinek, Mary E. Norton, Hanmin

Prenatal Diagnosis of Familial Type I Choledochal Cyst


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DOI: 10.1542/peds.2005-1411 originally published online February 1, 2006;



Lee, Jody Farrell and Kerilyn K. Nobuhara

Matthew S. Clifton, Ruth B. Goldstein, Anne Slavotinek, Mary E. Norton, Hanmin

Prenatal Diagnosis of Familial Type I Choledochal Cyst


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by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.


FIGURE 1A, Level II antenatal ultrasound of case report 1. Transverse image demonstrating cysticstructure (*) located posteriorly in subhepatic space, adjacent to inferior vena cava(arrow)
FIGURE 3alone cannot explain the predominance in female indi-viduals or those of Asian ancestry,1 and the presence ofIntraoperative cholangiogram
TABLE 1Classification Schemes for Choledochal Cysts6–8


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