Clinical Characteristics of Choledochal Cysts With Intrahepatic Bile Duct Dilatation

Shuhao Zhang Zhejiang University School of Medicine Duote Cai Zhejiang University School of Medicine Yuebin Zhang Zhejiang University School of Medicine Ken Chen Zhejiang University School of Medicine Yi Jin Zhejiang University School of Medicine Wenjuan Luo Zhejiang University School of Medicine Zongwei Huang Zhejiang University School of Medicine Di Hu Zhejiang University School of Medicine Zhigang Gao (  6519040@zju.edu.cn ) Zhejiang University School of Medicine


Introduction
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. All patients received excision of dilated EHBDs and hepaticojejunostomy, which were performed by three experienced surgeons. Patients received postoperative imipenem-cilastatin sodium as an antimicrobial treatment for 3-to-5 d, then the antibiotic was changed to cephalosporin if white blood count (WBC) and C-reactive protein (CRP) levels decreased and the patient had recovered well. The gastrointestinal decompression tube could be removed 5 d postoperatively if the patients felt well (without nausea, vomiting, or abdominal distension), then liquid and semi-liquid diets could be gradually introduced. The abdominal drainage tube could be removed when the postoperative daily drainage volume less than 15-20 mL and the seroperitoneum less than 2 cm.

Statistical analysis
Data are presented as the median ± IQR. All statistical analyses were performed with SPSS18.0 (SPSS Inc., Chicago, IL, USA) and GraphPad Prism 6 (GraphPad Software, Inc., San Diego, CA, USA) software packages. The independent samples t-test was used to compare samples. Comparisons of liver brosis and cirrhosis were conducted by the chi-square test. Survival curves were drawn using Kaplan-Meier univariate estimates. P-values <0.05 were considered statistically signi cant.

Preoperative clinical data
In total, 192 CC patients (47 males and 145 females) were included in this study, among whom 127 (31 males and 96 females) were without IHBD dilatation (group A), and 65 (16 males and 49 females) had IHBD dilatation (group B). The proportions of symptomatic patients were 62.99% in group A and 75.38% in group B. In both groups, abdominal pain was the most common symptom (47.24% in group A and 49.23% in group B), followed by vomiting, jaundice, and fever. The incidence of jaundice and fever in group B were signi cantly higher than in group A (p=0.01 and p=0.033, respectively). ( . The incidence of jaundice in group B was signi cantly higher than in group A (p=0.01), and preoperative total bilirubin, direct bilirubin, and indirect bilirubin levels were also higher in group B (p=0.0052, p=0.0005, and p=0.0136, respectively). Compared with group A, preoperative liver function (ALT and AST) was signi cantly increased in group B (p=0.025 and p=0.0057, respectively). Finally, preoperative GGT levels were also signi cantly higher in group B compared with group A [363.00 (IQR: 53.00-614.00) vs. 79.00 (IQR: 15.00-270.00), p=0.0242]. (Table 1) Postoperative clinical data Following surgery, the average levels of total bilirubin, direct bilirubin, indirect bilirubin, ALT, AST, and GGT recovered to normal at fth day in group A; these same indices also recovered to normal at fth day in group B, except GGT, which remained signi cantly increased  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).

Follow-up data
The average follow-up time were 13.24 (2.45-32.30) and 12.35 (1.63-29.00) months in group A and group B, respectively. Dilated IHBDs recovered to normal after surgery in 89.23% (58/65) of patients in group B.
The average follow-up time of these 7 patients with remained IHBDs dilatation was 6.70 (2.70-17.00) months.

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 proactive 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].
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.

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. Although, patients with IHBDs dilatation experiences satisfactory outcomes and IHBDs dilatation diminish spontaneously in most cases, proactive treatment is recommended once surgical contraindications are excluded for CC patients with IHBD dilatation and meticulous follow-up is needed.   Figure 1 Prognostic analyses of CC patients with or without IHBD dilatation

List Of Abbreviations
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.