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Recent surgical and clinical developments in the field of pediatric hepato-biliary-pancreatic disease

Welfare Center for Persons with Developmental Disabilities—Aichi Prefectural Colony Hisami Ando, MD

Although pediatric hepato-biliary-pancreatic diseases are benign, in most cases long-term medical treatment is needed and the results of this treatment have a large influence on patients’ lives. However, the evidence-based article about pediatric hepato-biliary-pancreatic diseases is very limited because the diseases are rare. Here, I introduce the results of several recent studies on congenital biliary dilatation, pancreaticobiliary maljunction, and biliary atresia published by the Journal of Hepato-Biliary-Pancreatic Sciences that may inform future clinical treatment.

I. Congenital biliary dilatation and pancreaticobiliary maljunction

Congenital biliary dilatation (CBD; a.k.a. choledochal cyst) was first described by Vater A. in 1723 (Qua Scirris viscerum dissert, c.s. ezlerus, vol. 70, University Library, Edinburgh 19: 1723), and pancreaticobiliary maljunction (PBM) was first described by Arnolds H. in 1906 (Dtsch Med Wochenschr 1906;32:1804). Therefore, CBD and PBM have a long history in the literature. CBD is more common in Asian countries than in the West. For example, in Japan, the incidence of CBD is 1 in 1,000 individuals, whereas in Western countries it is 1 in 50,000–150,000 individuals, although it remains unclear whether the frequency is low there or whether CBD is just not well known by Western doctors. Despite CBD being more common in Japan, CBD did not attract much attention until Komi N. introduced an article described by Babbitt DP. (Ann Radiol 1969;12:231–40) that demonstrated the cholangiography of PBM.

Until recently, there was no consensus on the definition of, or diagnostic criteria for, CBD and /or PBM. To address this issue, Hamada et al. and the Japanese Study Group on Pancreaticobiliary Maljunction[1] published a paper in which they defined CBD as a congenital malformation involving both local dilatation of the extrahepatic bile duct, including the common bile duct, and PBM. In their diagnostic criteria for CBD, according to Todani’s classification (J Hepatobiliary Pancreat Surg 1997;4:276–82) type Ia, Ic, and IV-A are diagnosed as CBD, but type Ib, type II (diverticulum of the bile duct), type III (choledochocele), IV-B, and type V (Caroli disease) are excluded from CBD. They also reported that a decision about whether there is dilatation of the bile duct or not should be done carefully and the standard diameter of the bile duct as measured by ultrasound, was significantly correlated with age, and therefore that diagnoses of dilatation should be based on the upper limit of bile duct diameter in the individual patient. These definitions helped to clarify the diagnosis of CBD.

In children with CBD, the major clinical symptoms are recurrent abdominal pain (82%), nausea and vomiting (66%), and mild jaundice (44%). On the basis of the protein plug theory, in which the increasing intraductal pressure in the pancreatobiliary tract is the result of the development of protein plugs, Tsuchiya et al. [2] used endoscopic short-tube stenting for biliary drainage in patients with persistent or exacerbated symptoms and found that symptoms were relieved soon after biliary drainage. At an operation, it was revealed that the obstructing materials were indeed protein plugs. Tsuchiya et al. concluded that endoscopic short-tube stenting is effective for preoperative management of symptoms and that protein plugs are the underlying cause of clinical symptoms. Conventionally, the onset of symptoms had been assumed to be due to biliary stenosis; therefore, the findings of Tsuchiya et al. are an interesting suggestion in the field.

For PBM, although various classifications have been reported, none has been widely adopted. Urushihara et al.[3] proposed classifying PBM into four types: (A) stenotic, (B) non-stenotic, (C) dilated channel, and (D) complex (Fig. 1); they then conducted a retrospective multicenter study in 317 children to clarify the clinical features and postoperative pancreatic complications associated with these four types. Patients with stenotic type were younger and more likely to have cystic dilatation (88.5%). Patients with non-stenotic type were less likely to have biliary dilatation (22.4%). Abdominal pain with hyperamylasemia was frequently seen in patients with non-stenotic or dilated-channel type. In particular, the incidences of protein plugs (56.1%) and biliary perforation (14.3%) were higher in dilated-channel type than in the other types. In children with complex type, recurrent pancreatitis was found, even after excisional surgery, because of associated pancreatic anomalies. As a guide for treatment, this proposed classification is simple to use and correlated with clinical features than previous classification.

II. Biliary atresia

Biliary atresia (BA) is sclerosing inflammation of unknown etiology that occurs in the neonatal or early infant stage. This sclerosing inflammation obstructs flow through the extrahepatic bile ducts, interrupting biliary excretion from the liver to the duodenum, leading to fibrotic changes or scar formation that obstructs the hepatic portal region, the extrahepatic bile ducts, and the intrahepatic bile ducts. As a result, a serious bile excretion disorder develops. Irrespective of whether a timely portoenterostomy is conducted, BA results in cirrhosis, which is the leading cause of pediatric liver transplantation. The incidence of BA is 1 in 10,000 births. Many theories about the cause of BA have been reported, including ductal plate malformation, viral infection, immune abnormality and others; however, there is currently no consensus on the pathogenesis of BA.

To evaluate the role of arteriopathy as an etiologic factor in BA, Fratta et al.[4] investigated hypoxia and the angiogenic response in liver biopsy specimens collected at exploratory laparotomy. They observed higher hypoxia-inducible factor expression and decreased vascular endothelial growth factor A expression in most BA patients than in patients of intrahepatic cholestasis. These results suggest that hypoxia-ischemia is present in the livers of patients with BA, and that it progresses over time, leading to decreased cholangiocyte mass. In other words, medial thickening of the hepatic artery induces ischemic cholangiopathy because the bile ducts are then only nourished by arterioles of the peribiliary vascular plexus. There were speculated theories previously that impaired oxygen supply to the bile duct in the fetus leads to obstruction of the bile duct. However, there was no article using the concrete index that elucidating the changes in the intrahepatic bile ducts of BA patients. Therefore, this article will provide the useful information for future research of the etiology of BA.

Kasai M. et al. (Shujyutu 1959;13:733–9) reported the first successful surgery for noncorrectable type in 1959. Since then, hepatoportoenterostomy (the Kasai procedure) by open surgery has become a common procedure for the treatment of BA and has enabled the long-term survival of many patients. Laparoscopic hepatoportoenterostomy is generally not used for the treatment of BA because of its poorer outcome compared with that of open surgery. However, Yamataka [5] reported the use of laparoscopic hepatoportoenterostomy in which the level of transection of the hepatic porta was more akin to that in Kasai’s original description—that is, dissection of the hepatic porta was confined to a shallow area around the base of the fibrous remnant; all of 8 patients who underwent this laparoscopic procedure were reported to be jaundice-free postoperatively. Many pediatric surgical procedures may be replaced laparoscopically because of excellent intraoperative visualization, reduced early postoperative pain, prevention of adhesions, excellent aesthetics, and quick resumption of activities. Therefore, this report by Yamataka provides encouraging results for using laparoscopic hepatoportoenterostomy to treat pediatric BA.

III. Clinical practice guidelines for CBD and BA, and future prospects

There are many issues that remain to be addressed in CBD and/or BA. Clinical practice guidelines for CBD have already been published[6], and those for BA will be published in Journal of Hepato-Biliary-Pancreatic Sciences. These clinical practice guidelines are scientifically based and are being published with the goal of improving the treatment of intractable pediatric hepato-biliary-pancreatic diseases. It is hoped that these guidelines will further medical experts’ understanding of CBD and BA, which will in turn benefit the patients and their families by improving the provision of treatments and care.

There are many interesting articles in Journal of Hepato-Biliary-Pancreatic Sciences about pediatric hepato-biliary-pancreatic diseases; these articles provide avenues for research to solve the current issues regarding these diseases. I am sure that medical experts who are engaged in the treatment of pediatric hepato-biliary-pancreatic disease are hoping for more evidence-based medicine. Therefore, we hope that many more articles concerning pediatric hepato-biliary-pancreatic disease will be submitted to Journal of Hepato-Biliary-Pancreatic Sciences in the near future.

References

1) Y. Hamada, H. Ando, T. Kamisawa, T. Itoi, N. Urushihara, T. Koshinaga, et al. Diagnostic criteria for congenital biliary dilatation 2015. J Hepatobiliary Pancreat Sci 2016;23:342–6.
http://onlinelibrary.wiley.com/doi/10.1002/jhbp.346/full

2) H. Tsuchiya, K. Kaneko, A. Itoh, H. Kawashima, Y. Ono, T. Tainaka, et al. Endoscopic biliary drainage for children with persistent or exacerbated symptoms of choledochal cysts. J Hepatobiliary Pancreat Sci 2013;20:303-6.
http://onlinelibrary.wiley.com/doi/10.1007/s00534-012-0519-5/full

3) N. Urushihara, Y. Hamada, T. Kamisawa, H. Fujii, T. Koshinaga, Y. Morotomi, et al. Classification of pancreaticobiliary maljunction and clinical features in children. J Hepatobiliary Pancreat Sci 2017;24:449-55.
http://onlinelibrary.wiley.com/doi/10.1002/jhbp.485/full

4) L.X.S. Fratta, G.R.W. Hoss, L. Longo, C. Uribe-Cruz, T.R. da Silveira, S.M.G. Vieira, et al. Hypoxic-ischemic gene expression profile in the isolated variant of biliary atresia. J Hepatobiliary Pancreat Sci 2015;22:846-54.
http://onlinelibrary.wiley.com/doi/10.1002/jhbp.297/full

5) A. Yamataka. Laparoscopic Kasai portoenterostomy for biliary atresia. J Hepatobiliary Pancreat Sci 2013;20:481-6.
http://onlinelibrary.wiley.com/doi/10.1007/s00534-013-0607-1/full

6) H. Ishibashi, M. Shimada, T. Kamisawa, H. Fujii, Y. Hamada, M. Kubota, et al. Japanese clinical practice guidelines for congenital biliary dilatation. J Hepatobiliary Pancreat Sci 2017;24:1-16.
http://onlinelibrary.wiley.com/doi/10.1002/jhbp.415/full

Figure 1: Classification of pancreaticobiliary maljunction (J Hepato-Biliary-Pancreat Sci. 2017;24:449–55)