Clinical Characteristics of Choledochal Cysts With Intrahepatic Bile Duct Dilatations

Shuhao Zhang The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health Duote Cai The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health Yuebin Zhang The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health Ken Chen The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health Yi Jin The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health Wenjuan Luo The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health Zongwei Huang The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health Di Hu The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health Zhigang Gao (  6519040@zju.edu.cn ) The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health

(p=0.01 and 0.033, respectively). Preoperative total bilirubin (TB), direct bilirubin (DB), and indirect bilirubin (IDB) were also higher in group B than in group A (p=0.0052, 0.0005, and 0.0136, respectively), as were preoperative levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total bile acid (TBA) (p=0.0057, 0.0250, 0.0002, and 0.0242, respectively). Early postoperative GGT levels in group B remained abnormal and were signi cantly higher than in group A (p=0.0003). The risk of liver brosis or cirrhosis was signi cantly increased for group B compared with group A (p=0.012) and also occurred earlier in group B (p<0.001), among them, dilated IHBDs recovered to normal in 89.23% (7/65) of patients. Meanwhile, the incidence of postoperative pancreatitis increased signi cantly in group B as well (p=0.003).
Conclusion: CC with IHBD dilatation was associated with signi cantly increased preoperative bilirubin levels, abnormal liver function, and higher incidence of liver brosis or cirrhosis early in the disease course. Timely radical surgery is recommended for such patients and postoperative extinction of the IHBD dilatation occurs early in most of those patients.

Background
Choledochal cysts (CCs) are cystic or fusiform dilations of the common bile duct. As advanced imaging techniques facilitate improved CC diagnostics, its incidence has increased, particularly in neonates due to a distinct increase in prenatally diagnosed CC [1]. The clinical features of CC differ according to age.
Neonates and young infants usually present with an abdominal mass, jaundice, or acholic stools, depending on the degree of obstruction. To date, CC is primarily grouped according to the Todani classi cation that was proposed in 1977, in which Todani type IV-a cysts are accompanied by IHBD dilation. The incidence of IHBD dilatation accounts for 30-40% of all CC cases [2]. After properly dealing with the EHBDs, spontaneous extinction of the IHBD dilatation occurs early in some cases; however, some IHBD dilatation is persistent, and whether this residual dilatation has any effect on the long-term prognosis of children with CC is unclear.
In this study, we reviewed our institution's records from October 2016 to December 2019 for cases of CCs, which revealed that CC with IHBD dilatation had conspicuous pre-and postoperative clinical characteristics compared with CC cases without IHBD dilatation. Thus, we summarized the clinical characteristics and outcomes of CC with IHBD dilatation based on the clinical symptoms, laboratory indices, and liver biopsies to establish guidelines for the future clinical management of this disease.

Inclusion criteria
The inclusion criteria for group B included: 1) a preoperative abdominal scan [B ultrasound, computed tomography (CT), or magnetic resonance cholangiopancreatography (MRCP)] showed moderately-toseverely dilatated IHBD [3]; 2) dilatated EHBDs were identi ed during surgery; 3) postoperative pathological con rmation of CC; and 4) well-documented clinical data were available. The remaining CC patients were included in group A.  Table 1.   Table 1). Further analysis of liver biopsies from the two groups showed that the proportion of liver brosis and cirrhosis was signi cantly increased in group B compared with group A (p=0.012; Table 3); furthermore, there was also an increased incidence of postoperative pancreatitis in group B (p=0.003; Table 3). Finally, Kaplan-Meier analysis indicated that liver brosis and cirrhosis occurred earlier in group B than in group A (p<0.001; Figure 1).

Discussion
Type IV-a CC has been reported more and more in recent years, and accounts for up to 29% of some series [4]. In our series, Type IV-a CC accounts for 33.85% of all the patients. Most of the dilated IHBDs could recover to normal after removing the obstruction by excision of dilated EHBDs and hepaticojejunostomy; while for some type IV-a CC cases, IHBD dilatation will persist postoperatively [5].
Here, we have shown that CC patients with IHBD dilatation had conspicuous clinical symptoms and needed aggressive intervention.
Patients with initial manifestation of CC usually have nonspeci c symptoms, and the classic triad (abdominal pain, jaundice, and abdominal mass) has proven to be rare [2]. In this study, the predominant symptoms were abdominal pain and vomiting, followed by jaundice and fever. And the incidence of the latter two symptoms was much higher in patients with IHBDs dilatation. It is probable that the increased pressure in the biliary tract results from biliary obstruction and poor bile drainage were more prone to cause recurrent fever and jaundice [6,7]. The signi cantly elevated pre-and postoperative GGT levels in group B which was related to the biliary obstruction [8,9] further veri ed the increased biliary pressure.
Notably, previous studies also had con rmed a signi cant stepwise increased pressure between two common types (type 1<type 4) [5,10].
Actually, it has been shown that early excision of the extrahepatic portion of the cyst for type IV-a CC without removing the cystic dilation of IHBD provides satis ed prognosis [11,12]. And previous studies had reported that the intrahepatic portion of the cyst diminished or disappeared after surgery, and that preoperative IHBD dilatation was not signi cantly associated with prognosis [12,13]. In our study, type IVa CC patients with early surgery also experienced satis ed outcome and normal liver function even IHBDs dilatation persisted (Figure 2 and Table 4). However, some studies reported that the incidence of malignancy was higher in patients who underwent Roux-en-Y hepaticojejunostomy without radical resection of cysts compared with patients who did not undergo any surgery [14], and the dilated bile ducts might be vulnerable to bile infection, resulting stone formation [15]. And such case that intrahepatic cholangiocarcinoma (IHCC) arising many years after excision of a type IV-a congenital choledochal cyst also have occasionally been reported [16,17]. According to previous research, the incidence of malignancy before the age of 18 was 0.42 versus 11.4% in adults [18]. The average follow-up time of our cohort already exceed one year and almost all patients in our study (190/192) except two patients with liver cirrhosis experienced early satisfactory outcomes after complete resection of dilated EHBDs without removing dilated IHBDs. However, those patients with persistent IHBDs dilatation needs longer-term follow-up to con rm whether the remained intrahepatic cysts will in uence their symptom-free survival. Although postoperative hepatic biochemical indices restored to normal early in our cohort, the incidences of liver brosis and cirrhosis were signi cantly increased in group B as well as the incidence of postoperative pancreatitis. Two patients with IHBD dilatation even developed postoperative liver cirrhosis at 8.2 and 9.8 months, respectively. Our Kaplan-Meier analysis used liver brosis as a preliminary biomarker for patient assessments [19] and indicated that liver brosis or cirrhosis appeared also signi cantly earlier in type IV-a CC. In a word, CC patients with IHBD dilatation should receive timely surgery as more recent studies have supported the idea that liver brosis is a reversible process if the injury-causing stimulus is withdrawn, while liver cirrhosis is not [20,21].

Conclusions
In conclusion, CC patients with IHBD dilatation had relatively conspicuous preoperative symptoms, highly elevated bilirubin, and abnormal liver function, and they were more prone to develop liver brosis or cirrhosis in early stages. Therefore, timely radical surgery is recommended once surgical contraindications are excluded and meticulous follow-up is needed for CC patients with IHBD dilatation.
Mostly, patients with IHBDs dilatation experiences satisfactory outcomes and IHBDs dilatation diminish spontaneously in most cases.  Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
All authors have no con icts of interest to disclose regarding this study.

Figure 1
Prognostic analyses of CC patients with or without IHBD dilatation Kaplan-Meier analysis of liver brosis or cirrhosis free survival for group A (high) and group B (low) was analyzed. Log-rank test was used.