Letter to the Editor: Bilirubin normalization: A crucial outcome to assess in biliary drainage

Abstract

A recent study by Naidu et al published in the World Journal of Gastrointestinal Endoscopy prospectively evaluated the bilirubin normalization rate and its kinetics following endoscopic retrograde pancreatic cholangiography in both benign and malignant extrahepatic biliary obstructions. This letter highlighted the crucial role of the bilirubin normalization in evaluating the efficacy of any biliary drainage technique, especially in the malignant setting. However, despite its significant impact on clinical and oncological outcomes, the bilirubin normalization rate is often underreported in favor of the clinical success defined by a reduction of total bilirubin of 50%-75% within 2-4 weeks. Nevertheless, this clinical success is not synonymous with bilirubin normalization. The systematic evaluation of this key outcome in a standardized fashion should be strongly encouraged in future trials, especially in those comparing standard-of-care techniques with emerging ones.

Key Words: Endoscopic retrograde cholangiopancreatography; Endoscopic ultrasound-guided biliary drainage; Biliary obstruction; Distal biliary obstruction; Distal malignant biliary obstruction; Bilirubin normalization

Core Tip: The bilirubin normalization is a key outcome in biliary drainage, especially in the malignant setting. However, despite its profound effect on clinical and oncological outcomes, the bilirubin normalization rate is generally underreported. Its systematic and standardized assessment should be strongly encouraged in future trials.

TO THE EDITOR

We read with great interest the article by Naidu et al[1] published in the World Journal of Gastrointestinal Endoscopy, which prospectively evaluated the kinetics of the bilirubin normalization following endoscopic retrograde cholangiopancreatography (ERCP) for both benign and malignant extrahepatic biliary obstruction (EHBO). In this article, we would like to highlight the pivotal role of the bilirubin normalization as a key outcome of ERCP and any other biliary drainage modalities for EHBO, especially in the malignant setting.

Notably, the authors reported an overall bilirubin normalization (total bilirubin < 3 mg/dL) rate at 15 days and 30 days of 69.3% and 85.1%, respectively. In the malignant EHBO subset, despite the prevalent placement of biliary plastic stents compared to self-expandable metal stents (88.5% vs 11.5%), the authors reported a bilirubin normalization rate at 15 days and 30 days of 60.6% and 78.7%, respectively. Worth mentioning, the failure to achieve bilirubin < 3 mg/dL by day 15 was shown to be an independent predictor of mortality[1].

ERCP is currently regarded as the modality of choice for the treatment of both benign and malignant EHBO[2-4]. In the malignant scenario, percutaneous transhepatic biliary drainage or endoscopic ultrasound (EUS)-guided choledochoduodenostomy are recommended as second-line techniques[3-6]. In recent years, novel EUS-guided biliary drainage techniques have been proposed as potential first- and/or second-line alternatives[7-10]. In this regard, we would like to underline the critical importance of the bilirubin normalization as a main outcome to be systematically addressed, especially when comparing standard of care techniques to potential alternatives. Worth mentioning, a standardized definition of the bilirubin normalization is currently lacking. While a fully normalization of the total bilirubin seems appropriate in the benign scenario, the bilirubin normalization defined by the achievement of a total bilirubin < 3 mg/dL at day 15 and day 30, as in the study by Naidu et al[1], appears to be clinically suitable for malignant EHBO. Indeed, a total bilirubin level < 1.5 times the upper normal level is generally considered mandatory before commencing standard neoadjuvant or palliative chemotherapy and for its continuation[11-13]. Although underreported, the bilirubin normalization is a crucial outcome for any biliary drainage modalities, having reported to be associated with an improved quality of life, a lower mortality, and a more favorable oncological outcomes[14-16]. Moreover, the bilirubin normalization at 14 days has been recently incorporated into the definition of clinical success by the latest Tokyo criteria[17]. However, this key outcome is often overlooked or not specifically addressed in favor of clinical success defined by a reduction in total bilirubin of 50%-75% within 2-4 weeks[6]. Nevertheless, this clinical success is not synonymous with bilirubin normalization. Indeed, it may not be a “true” success in a non-negligible proportion of malignant EHBO patients, typically showing severe hyperbilirubinemia (total bilirubin > 10-15 mg/dL).

EUS-guided gallbladder drainage has been recently proposed as a promising first- and second-line modality in patients with malignant EHBO and a patent cystic duct[10-19]. Indeed, EUS-guided gallbladder drainage has been shown to be associated with excellent technical success, high clinical efficacy and good safety profile[10,18]. However, a recent review from our group found that only two of the currently existing trials specifically addressed the bilirubin normalization rate[20], highlighting current inconsistent reporting of this key outcome and the need for further evidence. In fact, bilirubin normalization was broadly defined as total bilirubin < 3 mg/dL or full bilirubin normalization over the follow-up period, and widely ranged from 19.2% to 65.6%[20].

CONCLUSION

In conclusion, due to its significant impact on clinical and oncological outcomes, the bilirubin normalization has a crucial role in evaluating the effectiveness of any biliary drainage modality. Its evaluation in a standardized fashion should be strongly encouraged and carefully addressed in future trials, especially in those comparing standard-of-care techniques to potential alternatives.