Surgical treatment for intractable cholangitis with left-sided biliary cysts followed by Kasai operation in biliary atresia

doi:10.21203/rs.3.rs-2311277/v1

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Surgical treatment for intractable cholangitis with left-sided biliary cysts followed by Kasai operation in biliary atresia

https://doi.org/10.21203/rs.3.rs-2311277/v1

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Background: Intrahepatic biliary cysts (IBCs) after Kasai portoenterostomy (KPE) are associated with intractable recurrent cholangitis. This study aimed to investigate the feasibility of its use as well as indication for surgical management of IBCs in pediatric patients.

Methods: We retrospectively reviewed the medical records and imaging studies of patients who underwent KPE for biliary atresia from 2010 to 2020.

Results: In 28 of 129 patients, IBCs were identified by an imaging study (21.7%). Among them, five patients were subjected to surgical treatment for intractable cholangitis. The median time from KPE to the development of IBCs was 1.7 years. Four out of five patients had IBCs confined to the left lateral lobe, and in one patient, the IBCs were in the hepatic hilum. All five patients experienced more than one cholangitis. Although they received intravenous antibiotic treatment and percutaneous transhepatic cholangiodrainage (PTCD) as treatment, they were intractable. Three patients underwent hepatectomy, and two underwent cystojejunostomy. There was no recurrence of cholangitis during the median follow-up period of 2.9 years.

Conclusions: Surgical treatment for IBCs after KPE could be considered a safe and effective surgical procedure for children if appropriate indications are applied.

Health sciences/Medical research/Study design

Health sciences/Diseases

Health sciences/Gastroenterology

Intrahepatic biliary cyst

Kasai portoenterostomy

Cholangitis

Pediatrics

The development of intrahepatic biliary cysts (IBCs) or bile lakes (BLs) following Kasai portoenterostomy (KPE), has an estimated incidence of 6–25% [1–4]. Several mechanisms have been hypothesized with regard to the formation of IBCs after KPE for the management of biliary atresia (BA), but bile stasis commonly occurs in the damaged bile duct, causing repeated cholangitis [3, 5–7]. This condition has a poor prognosis and is associated with an increased risk of liver transplantation [3–5]. However, its optimal treatment remains under debate. Percutaneous transhepatic cholangiodrainage (PTCD) and continuous use of antibiotics as a treatment strategy for intractable recurrent cholangitis caused by IBCs has limited efficacy due to repeated hospitalization and poor quality of life. In this study, we aimed to verify the effectiveness of surgical management in patients with intractable cholangitis caused by IBCs in whom the liver function was maintained. In addition, we established criteria for implementing surgical treatment for the management of IBCs.

We performed KPE on 129 patients with BA from 2010 to 2020 and routinely followed them up at 3-month intervals for 1 year at the outpatient clinic; the interval was adjusted according to individual patient condition. Patients with IBC underwent magnetic resonance imaging (MRI) or computed tomography (CT) to confirm liver stiffness. The indications for surgical treatment were as follows: 1. The focus of fever was cholangitis. 2. Patients with recurrent cholangitis caused by IBCs who did not respond to conventional treatment. 3. Patients with Pediatric End-stage Liver Disease (PELD) or Model for End-stage Liver Disease (MELD) scores of < 10 and without ascites or portal hypertension who were not eligible for liver transplantation (LT). Based on clinical records, we conducted a retrospective review of the treatment courses, complications, and outcomes of patients who underwent KPE before and after surgical treatment for intractable cholangitis. The value of total serum bilirubin was periodically checked after surgery, and persistent jaundice was defined as a value observed higher than 2.0 mg/dL. Postoperative complications were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All the procedures performed in this study involving human participants were in accordance with the ethical standards of the ethics committee of Asan Medical Center Children’s Hospital of Ulsan University (IRB No. 2020 − 1409) and the study approved by the ethics committee of Asan Medical Center Children’s Hospital of Ulsan University (IRB No. 2020 − 1409).

In our study, among patients who underwent KPE, IBCs occurred in 28 of 129 (21.7%), of which five patients were surgically treated for intractable cholangitis. The characteristics of the IBCs and patients are shown in Table 1. The median time to the onset of IBCs after KPE was 1.7 years (range, 0.2–12.3 years). Of the five patients, three had multiple cystic lesions, one had beaded cystic lesions, and one had solitary cystic lesions. All 5 patients had at least one cholangitis, and percutaneous transhepatic cholangiodrainage (PTCD) was administered to four patients who were refractory to intravenous antibiotic treatment. The other patient who did not undergo PTCD underwent surgical treatment. The degree of hepatic fibrosis in patients varied from mild to early liver cirrhosis on liver elastography and MRI. In Case 4, collateral vessels and narrowing of the portal vein caused by liver fibrosis were confirmed. No patients with ascites were observed due to portal hypertension. Surgical drainage was performed according to each patient’s condition, and the results are shown in Table 2. We performed lobectomy in Cases 1–3 and bile drainage through cystojejunostomy in Cases 4 and 5. Cases 1–2 received left lobectomy, and Case 3 underwent left lateral segmentectomy considering remnant liver function. The median follow-up period was 2.9 years (range, 0.8–5.4 years), and neither persistent jaundice nor hospitalization for recurrent cholangitis was noted. Case 5 developed an ileus with CTCAE v5 grade 3, 6 months after cystojejunostomy, and adhesiolysis was performed. The remaining patients had no serious complications. To date, all patients have maintained survival with the native liver.

Table 1

Characteristics of IBCs in patients after Kasai operation
Case number	Sex	Age at Kasai	Period taken for manifestation of IBCs after Kasai	Location of IBCs	Number of IBCs	Size of IBCs (max)		PTCD	Hepatic fibrosis	Ascites/ Varices	PELD or MELD score
1	M	70 d	7.0 y	LLS, S4, S8	beaded	1.2 cm	> 10	Failed	moderate	- / -	8
2	F	60 d	1.7 y	LLS	multiple	2 cm	5	Failed	mild	- / -	6.2
3	F	20 d	2.1 m	LLS	multiple	4.2 cm	8	Failed	severe	- / +	2.8
4	F	81 d	10.1 m	Hepatic hilum	multiple	1.8 cm	1	Failed	early LC	- /-	1
5	F	60 d	12.3 y	LLS	single	2.0 cm	> 10	NA	mild	- /-	9
NA, not applicable

Table 2

Surgical drainage and outcomes
Case number	Surgical drainage methods	Bilirubin at surgical drainage, µmol/L	Bilirubin at 3 months, µmol/L	Follow-up period	Outcomes
1	LL	1.2	0.5	5.4 y	SNL
2	LLS	3.9	0.4	6.5 y	SNL
3	LL	0.5	0.4	2.9 y	SNL
4	S3 PH, cystojejunostomy	0.7	0.5	2.2 y	SNL
5	S4 PH, cystojejunostomy	1.6	0.7	0.2 y	SNL
SNL, survival of the native liver

IBCs worsen the function of native liver and are a significant complication affecting the survival of patients undergoing KPE for BA [8, 9]. Although these lesions indicate poor prognosis, the exact incidence of this association is not well known. The incidence of IBC is approximately 6–25% [1–4]. We investigated the IBC of postoperative BA patients using periodic MRI. In this study, the incidence of IBC was 28 in 129 patients (21.7%), which is also comparable to the results of previous studies.

There are several hypotheses regarding the development of IBCs in patients who undergo KPE for BA as follows: 1) The fibro-obliterative process of BA in the intrahepatic lobular spaces results in a damage to the biliary epithelium [3]; 2) progressive inflammation leads to intrahepatic biliary obstruction [6]; and 3) ductal plate malformation is considered a factor in the development of IBCs [7]. These pathologic changes cause insufficient bile drainage that results in biliary stasis and cholangitis, which gradually progress to hepatic fibrosis and cirrhosis. Tainaka et al. histologically demonstrated that bile stasis in the intrahepatic bile ducts forms calculi within the bile ducts. Calculi then repeatedly cause cholangitis and form IBCs by fusing with the damaged bile ducts [10].

Some studies have reported a close relationship between IBCs and cholangitis [3, 5–7]. Cholangitis, often accompanied by fever without other infectious causes, is a frequent complication with various symptoms after KPE for BA. Its incidence during the first postoperative year ranges from 40–93%, and gradually decreases as the bile flow and stasis of bile improve after a successful surgery [11–13]. In addition, cholangitis caused by IBCs is intractable even with PTCD and prolonged antibiotics, and the rate of recurrent cholangitis in patients with multiple intrahepatic cysts is as high as 93.8% [4, 14, 15]. Ginstrom et al. reported that the annual frequency of cholangitis episodes in patients with IBCs was more than five times higher than that in patients without IBCs. In addition, an increase in the occurrence of cholangitis had a detrimental effect on native liver survivors. Intractable cholangitis associated with IBC results in the obstruction of bile flow and subsequent deterioration of hepatic function and cirrhosis [13, 16]. Persistent hepatic dysfunction is related to various physiological problems, such as decreased synthetic function and malabsorption of nutrients, further leading to growth retardation.

IBCs have been managed by conservative treatments such as PTCD and prolonged intravenous antibiotics. PTCD is effective in treating single cysts, but not in the management of multiple cysts [14, 17]. We inserted PTCD in four patients with multiple IBCs, and very small amount of bile was drained in each patient, and cholangitis was not controlled by the procedure. Previous studies have also reported that patients with multiple IBCs are do not respond to conventional treatment and show a poor prognosis [1, 4]. Bu et al. reported that the mean interval between cyst detection and death was 3.75 months in patients with multiple IBCs. In Case 5 with a single IBC, surgical treatment for IBC was planned immediately without PTCD. Magnetic resonance cholangiography revealed the corresponding biliary dilatation and IBC was not associated with portojejunostomy. We suggest that the cyst was noncommunicating, and the IBC would not disappear or regress after a recommunication extending from the cyst to the intestine following PTCD. Moreover, older children with IBCs with late onset of symptoms tend to resist these conventional treatment modalities [18]. Unless IBC is managed effectively, LT will inevitably be considered due to permanent liver injury in the long term [19]. If cystic dilatation was confined to the LLS or the remnant liver function of the dominant lobe was maintained, transplantation was not considered.

LT may be considered in patients with multiple IBCs because the therapeutic effect of PTCD is insufficient. However, if the liver function is still well maintained, that is, if the PELD or MELD score is not high enough to receive LT, it is better to avoid excessive surgery. Two cases of lobectomy or cystojejunostomy as surgical treatments for intractable IBCs have been reported [20–22]. Despite the several studies on the process and effect of IBCs in BA, the effectiveness of surgical treatment remains to be elucidated. Therefore, in this study, we carefully selected patients and surgical methods by considering various factors to determine the patients indicated for surgical treatment. We first selected patients with low PELD/MELD score (PELD/MELD score < 10) as subjects for surgery and in whom we could expect survival of the native liver (SNL) if only cholangitis was resolved [23–26]. The method of surgical treatment for IBCs was determined according to the dominant lobe for liver function and the location of the IBCs. When the left lobe was a non-dominant lobe and the main IBCs were located, we performed left lobectomy or left lateral segmentectomy according to the remnant liver function of patients (Cases 1–3) [Fig. 1]. When IBCs were in the dominant lobe or hilum, a cystojejunostomy was performed (Cases 4 and 5) [Fig. 2]. Further, IBCs in the right lobe, are considered more complicated. Cystenterostomy is difficult to perform when the lesion is on the right lobe, compared to when it is on the left lobe due to portojejunostomy, and liver resection may affect remnant liver function. Thus, further studies are warranted in future considering the factors associated with successful surgical outcomes in the management of IBCs.

Considering the MELD/PELD score and the location of IBCs, patients who underwent surgical treatment did not develop persistent jaundice during the follow-up period and maintained the SNL well, which is satisfactory in terms of quality of life.

The generalizability of the efficacy of surgical treatment was limited due to the small number of patients in our study. Further research is needed to identify the long-term outcomes in more cases.

IBCs are a common complication in patients with postoperative BA. Recurrent cholangitis, poor biliary drainage, and pathological changes in the intrahepatic biliary structure contribute to the development of multiple IBCs. Intractable cholangitis caused by multiple IBCs or poor biliary drainage persistently worsens liver function that may require LT. Surgical management of IBCs could be useful as a safe and effective procedure for IBCs of BA treatment in children if the surgery is selectively applied considering MELD/PELD scores and the location of lesions. Furthermore, it could be expected to improve the patients' quality of life by establishing a strategy to extend SNL.

Funding: Not applicable

Conflicts of Interest: The authors declare no conflicts of interest.

Statement of Informed consent: Informed consent was obtained from the parents of the patients.

Data availability: All data generated or analyzed during this study are included in this published article and its supplementary information files.

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No competing interests reported.

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Surgical treatment for intractable cholangitis with left-sided biliary cysts followed by Kasai operation in biliary atresia

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