Published online February 1, 2006
PEDIATRICS
Vol. 117
No. 3
March 2006, pp.
e596-e600
(doi:10.1542/peds.2005-1411)
Prenatal Diagnosis of Familial Type I Choledochal Cyst
Matthew S. Clifton, MDa,
Ruth B. Goldstein, MDb,
Anne Slavotinek, PhDd,
Mary E. Norton, MDc,
Hanmin Lee, MDa,
Jody Farrell, RN, MSNa and
Kerilyn K. Nobuhara, MDa
a Surgery
b Radiology
c Obstetrics/Gynecology
d Pediatrics, University of California, San Francisco, California
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ABSTRACT
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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, deterioration 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, classification, diagnosis, and management of this disease.
Key Words: congenital abnormalities • liver disease • prenatal diagnosis
Abbreviations: PBM, pancreaticobiliary maljunction • PKD, polycystic kidney disease
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, deterioration 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, classification, diagnosis, and management of this disease.
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CASE REPORTS
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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 x 2.1 cm on an axial image of the abdomen and was located to the right of midline (Fig 1A). A small gallbladder 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 intervention as appropriate. Follow-up sonogram at 36 weeks demonstrated a slight increase in size at 3.2 x 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 diagnosis of choledochal cyst, and the absence of intrahepatic ductal dilation excluded Caroli's disease. Serial evaluation 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, respectively). 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 transferase 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 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.
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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).
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FIGURE 2 A, Abdominal ultrasound of case report 1. Transverse cross-sectional view demonstrating decompressed gallbladder (GB) with irregular wall thickening and no intrahepatic biliary ductal dilation. CC, choledochal cyst. B, Transverse cross-sectional view caudal to A demonstrating CC. C, Transverse cross-sectional view demonstrating junction of cystic duct (CD) with choledochal cyst (CC).
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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 cholecystectomy were performed, followed by roux-en-Y hepaticojejunostomy. Postoperatively, the serum direct bilirubin continued a steady decline to 2.7 mg/dL on the day of discharge (postoperative day 8). Pathology was consistent with choledochal cyst. At the 6-month follow-up, the infant is healthy with normal expected growth and complete resolution of the hyperbilirubinemia.
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FIGURE 3 Intraoperative cholangiogram. Contrast fills the fusiform, bilobed CC and refluxes up into the common hepatic duct (CHD). The CD is also visible (arrow).
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FAMILY HISTORY
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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, nausea, and vomiting. He experienced 1 similar episode 2 weeks earlier, which was self-limited. Evaluation revealed 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. Computed tomography scan of the abdomen revealed a 4.5- x 6.5-cm cyst extending from the porta hepatis to the head of the pancreas, in communication with the common hepatic duct. He was treated with bowel rest for 24 hours, with resolution of the abdominal pain, and subsequently was transferred to our institution. On examination, there was no evidence of scleral icterus or jaundice 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 discharged from the hospital on postoperative day 8, tolerating a regular diet with minimal incisional pain. Pathology 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. Maternal and paternal ethnicity was Mexican, and consanguinity was denied.
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INCIDENCE
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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 incidence in Western nations (Europe and North and South America) is 1 in 100000 to 150000 live births.1 Although classically considered a disease of infancy, an increased number of patients are now being discovered in adulthood.2 Familial case reports of congenital choledochal cysts are extremely rare, with only 6 such reports in the literature.3 Choledochal cysts occur most commonly in patients of Asian descent, with more than two thirds of the reported cases occurring in Japanese patients.3 There is no evidence of increased incidence in the Hispanic population.
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CAUSE
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The cause of choledochal cysts remains uncertain, although several theories exist. Pancreaticobiliary maljunction (PBM), a condition whereby the pancreatic duct joins the common bile duct 1 to 2 cm proximal to the sphincter of Oddi,4 creates 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.5 Evidence 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 individuals or those of Asian ancestry,1 and the presence of a long common channel does not guarantee development of a choledochal cyst. In addition, choledochal cysts occur in the absence of PBM. Other theories suggest an acquired ductal cause, such as a web, stricture, or dysfunction at the sphincter of Oddi as a source of disease.6 Familial cases point to a possible inherited/genetic component predisposing to formation of choledochal cysts.
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CLASSIFICATION
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The initial attempt at classification of congenital choledochal cysts, wherein 3 distinct types were described, was undertaken by Alonso-Lej et al7 in 1959. Although the use of the word "cyst" is a misnomer, it has continued 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 simplified nomenclature. The Todani classification system is based solely on morphologic/gross appearance. In reality, 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 described types I and IV cysts, because the intrahepatic ducts are never entirely normal in this setting. Choledochal 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 8.9 Although possessing some radiologic similarities to choledochal cyst, it is also a distinct entity.6 The individual classification schemes are detailed in Table 1.
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GENETICS
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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 sister.10 In 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,3,7 and there is 1 report of a twin pair with Caroli's disease.11 The evidence for a genetic contribution to the cause of choledochal cysts therefore is tempered by a lack of concordance in twin pairs and few Mendelian pedigrees, making 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 recessive and autosomal dominant polycystic kidney disease (PKD). A mutation in the PKD1 gene 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 significance have also been described in a liver biopsy specimen from a patient with Caroli's disease without PKD.9
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DIAGNOSIS AND MANAGEMENT
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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 obstruction of the pancreaticobiliary ductal system, with elevated bilirubin, alkaline phosphatase, -glutamyl transferase, and potential elevation of transaminases (aspartate aminotransferase and alanine aminotransferase) and serum amylase.1 Within the past 10 years, routine use of high-resolution prenatal ultrasound has allowed the antenatal diagnosis of subhepatic cysts, later confirmed to be choledochal cysts.15 Fewer than 10 familial cases have been described in the literature,3 and 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 including the gallbladder is the treatment of choice, the timing in the neonate is unclear. It has been suggested that progressive intrahepatic ductal dilation, cyst enlargement, and deterioration of liver function are harbingers of obstruction and/or cholangitis, prompting early surgical intervention.15,16 As a temporizing measure, in the setting of nutritional compromise or acute infection, external drainage procedures can be undertaken 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 hepaticojejunostomy.6,16 New developments in minimally invasive surgery have made these lesions amenable to laparoscopic resection and reconstruction.17
Internal drainage procedures without cyst excision, although commonplace in the past, have shown a predilection for malignancy. The reasons for this are not yet entirely clear, but proposed mechanisms include biliary stasis, biliary lithiasis, superinfection, recurrent cholangitis, pancreatitis, and conversion of bile salts to carcinogenic substances by chronic infections.1,15 Types I and IV cysts carry the highest risk of cancer.18 The 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.19,20 Approximately 10% of choledochal cyst malignancies are gallbladder cancers.21 The high rate of malignant conversion has led to the current recommendation 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
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ACKNOWLEDGMENTS
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We acknowledge the help of Drs. Keith Meredith and Michael Foley in the clinical follow-up of these patients.
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FOOTNOTES
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Accepted Aug 19, 2005.
Address correspondence to Kerilyn Nobuhara, MD, Department of Surgery, University of California, Box 0570, 513 Parnassus Ave, San Francisco, CA 94143-0570. E-mail: nobuharak{at}surgery.ucsf.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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ABSTRACT
CASE REPORTS
