Introduction
Benign recurrent intrahepatic cholestasis, first described by Summerskill and Walshe in 1956 [1], is a rare autosomal recessive condition from a group of familial cholestatic diseases, presenting as recurrent bouts of cholestasis, which may start at any age (usually before the second decade of life) [2]. There are two genetically characterized forms of benign recurrent intrahepatic cholestasis (BRIC): BRIC1, which is caused by a partial deficiency in ATP8B1 [3], and BRIC2, which is caused by a partial deficiency in ABCB11 [4].
The disease is characterized by jaundice, pruritus, and fatigue [5].
An attack of the disease is usually heralded by malaise and fatigue, and occasionally diarrhea or vomiting is present. In the majority of cases, there is no progression to end stage liver disease, although patients with BRIC have multiple attacks of disease [6]. The episodes of jaundice may last from weeks to months, usually accompanied by severe pruritus.
Currently, there is no definitive treatment for BRIC, and management focuses on symptomatic relief. Conservative medication in BRIC is directed toward improving cholestasis (e.g. ursodeoxycholic acid) and elimination of pruritogens from the enterohepatic circulation (e.g. anion exchange resins) [7, 8] but generally is not effective.
In severe cases, intermittent endoscopic nasobiliary drainage (NBD), partial external biliary diversion (PEBD), and even liver transplantation have been reported [9–11].
Symptomatic improvements after extracorporeal removal of pruritogens have been demonstrated using charcoal hemoperfusion, plasmapheresis or liver dialysis – single pass albumin dialysis (SPAD), molecular adsorbent recirculating system (MARS) and the Prometheus system [12–14].
Nasobiliary drainage has emerged as a potential treatment option for inducing remission in BRIC patients. This article aims to provide a case history of our patient and an overview of the existing literature on the efficacy and safety of NBD in BRIC management, focusing on studies and case reports published in high-impact medical journals. The search for “benign recurrent intrahepatic cholestasis and nasobiliary drainage – including related terms” was made on the Ovid database, which is the world’s most trusted medical research platform. This paper is a review of a rarely (especially in children) used technique in therapy of acute episodes of BRIC with a short presentation of a small series of patients in whom such a technique was applied in a single center.
Own experience
Table 1 below presents a summary of three pediatric patients who underwent therapy with NBD.
Table 1
Summary of three pediatric patients who underwent therapy with nasobiliary drainage (NBD)
[i] HAV – hepatitis A virus, HBV – hepatitis B virus, HCV – hepatitis C virus, CMV – cytomegalovirus, EBV – Epstein-Barr virus, HIV – human immunodeficiency virus, AIH – autoimmune hepatitis, WD – Wilson disease, MRCP – magnetic resonance cholangio-pancreatography, UDCA – ursodeoxycholic acid, BRIC – benign recurrent intrahepatic cholestasis, FUP – follow-up, CAP – controlled attenuation parameter, E – elastography
Literature review
Benign recurrent intrahepatic cholestasis is a very rare disease that is clinically diagnosed by five criteria: multiple (minimum two) episodes of cholestasis with severe pruritus; absence of factors known to be associated with cholestasis; normal intrahepatic and extrahepatic bile ducts; liver biopsy demonstrating bile thrombus formation; and symptom-free interval lasting several months to years.
In contrast to progressive familial intrahepatic cholestasis (PFIC), which progresses to liver failure with jaundice, BRIC has a fair prognosis without progression to cirrhosis. However, severe cholestasis, intractable itching, and failure to thrive disrupt patient’s activities of daily living. The inability to sleep markedly impairs patients’ quality of life.
Generally, conservative medical therapy is not effective in BRIC.
In PFIC patients, surgical treatment such as partial external biliary diversion (PEBD) or ileal exclusion has been employed successfully [15]. Although PEBD may also be effective in BRIC patients, its permanent character makes it controversial for application in a disorder that is only episodic.
Endoscopic NBD is a type of transpapillary external drainage wherein the distal end of the tube is left in the bile duct and the proximal end emerges out through the nose. The effectiveness of NBD may be explained by evidence showing that forced bile drainage blocks the enterohepatic circulation. NBD eliminates bile constituents including bilirubin, bile salts, and pruritogens, causing a subsequent reduction in the bile acid pool, and results in restored function of bile excretion transporters [16–18].
Ovid database contains over 100 full text articles regarding BRIC patients. Eleven of them are studies on BRIC patients who underwent NBD. Although the available literature is limited, the studies and case reports identified in the review suggest that generally NBD could be an effective treatment option for inducing remission in BRIC patients [19–23].
The largest retrospective multicenter analysis exploring the effects of NBD on BRIC was published in 2016 by Yakar et al. [21]. All 16 patients who underwent a total of 25 procedures in their study benefitted from NBD, showing significant improvements in pruritus and cholestasis parameters within 3 days after NBD placement. The median days of drainage was 17, and during regular follow-up for three years, none of the patients suffered from another attack.
Stapelbroek et al. reported complete and long-lasting disappearance of pruritus in three cholestatic BRIC patients within 24 hours of endoscopic NBD [11]. The time of normalization of serum total bilirubin levels was longer, and after the removal of NBD a transient elevation of bilirubin was observed. In two of three cases, the subsequent attack of cholestasis (after eight months in one and one year in the second case) was observed. One patient was successfully treated with another NBD procedure. In the second one, despite another NBD placement, no adequate bile flow was obtained and the cholestasis persisted.
Only two pediatric patients with biliary drainage have been reported in the literature [19, 23].
Zellos and coauthors presented a case of a 5-year-old boy with BRIC 2 [19]. The first drain placement was unsuccessful and complicated with pancreatitis. The second attempt led to fixation of a nasobiliary drain in the common bile duct and relief of itching and cholestasis. At biopsy, however, slight portal-tract fibrosis and deposits of metallothioneins indicating chronic cholestasis were found, which may suggest an intergrade between classic BRIC and classic PFIC.
The next pediatric case is also a genetically proven BRIC type 2 [23]. He had a first episode of cholestasis at the age of 9 months, which lasted for 8 months, with normalization of liver function after that. The second episode of cholestasis was at the age of 16 years, with no apparent therapeutic effect of 1 week of NBD. The authors believed that patients with BRIC type 2, because of lessened expression of BSEP (bile salt export pump) at the canalicular membrane of hepatocytes, may have a worse response to such treatment. Previously, some authors reported that in PFIC 2 patients (ABCB11 mutations) PEBD was less effective [18]. Also, it should be noted that all cases in the literature which did not respond to NBD were BRIC 2 [18, 23].
Although a liver biopsy is not mandatory for diagnosis, sometimes it is performed in patients, especially in the course of the first attack or when the molecular diagnosis is delayed or not available. Yakar and coauthors presented the biggest, retrospective, multicenter study consisting of 33 patients (mean age 23.42 ±6.23 years) with clinically diagnosed BRIC [21]. Twenty-two of them had liver biopsy. Six patients had canalicular cholestasis without fibrosis, nine canalicular cholestasis with severe cholestasis and six intra-acinar cholestasis with porto-portal fibrosis.
In our patient 1, we performed biliary drainage after obtaining liver biopsy. The treatment was successful, although initially not as spectacular as in some patients in the literature, when relief of itching is immediate and resolution of cholestasis occurs after a few days.
It is worth noting that some of the patients with BRIC syndrome were selected for liver transplantation due to nutritional failure and intractable pruritus. Appleby et al. [22] describe a female patient with reduction of quality of life secondary to pruritus and poor nutritional status who avoided the need for liver transplantation due to complete resolution of pruritus after a few weeks of NBD.
For patients with intolerance of nasobiliary drainage, a percutaneous endoscopic gastrostomy (PEG) may be implanted and two nasobiliary tubes placed through the PEG into the left and right hepatic ducts. Recent discoveries of ileal bile acid transport (IBAT) inhibitors, e.g. odevixibat and maralixibat, show additional possibilities for BRIC patients [24].
The rapid improvement in liver function tests and resolution of clinical symptoms reported in most studies support the potential benefits of NBD in the management of this rare genetic disorder. However, it is important to note that the available evidence is limited to a small number of studies and case reports, with varying methodologies and patient populations. Therefore, larger clinical trials and further research are needed to better understand the long-term impact of NBD on BRIC patients to establish its efficacy and safety in this patient population.
Conclusions
Nasobiliary drainage has shown promising results in the management of benign recurrent intrahepatic cholestasis, suggesting its potential efficacy in inducing remission. NBD as a treatment option for BRIC may improve the quality of life and in some severe cases allow liver transplantation to be avoided.
