Biomarkers of Liver and Gallbladder Function: Direct Bilirubin

Optimal Takeaways

Direct bilirubin is the conjugated fraction of bilirubin found in circulation. It is made water-soluble by conjugation in the liver so it can be easily excreted in the bile. Increasingly higher direct bilirubin can be associated with gallstones, extrahepatic duct obstruction, liver metastases, and CVD risk. Like total bilirubin, direct bilirubin is considered a potent antioxidant, and lower levels may contribute to metabolic syndrome and more atherogenic small dense LDL particles.

Standard Range: 0.00 - 0.20 mg/dL (0.00 - 3.42 umol/L)

The ODX Range: 0.1 - 0.15 mg/dL (1.71 – 2.57 umol/L)      

Low levels of direct bilirubin may be associated with metabolic syndrome (Li 2018), small dense, more atherogenic LDL particles (Kwon 2018), and an increased risk of NAFLD (Tian 2016).

High levels of direct bilirubin are associated with gallstones, extrahepatic duct obstruction, liver metastases, drug-induced cholestasis, Dubin-Johnson syndrome, and Rotor syndrome (Pagana 2021). Higher levels of DBIL are also associated with poor prognosis in critical illness (Nagae 2018), cirrhosis (Lee 2021), and CVD, especially in those who are male, smoke, drink, are sedentary, and have hypertension (Lai 2018).

Overview

Direct bilirubin (DBIL) represents the fraction of bilirubin circulating in the blood that is conjugated. Therefore, it has been processed by the liver and has become water-soluble, and it can then be excreted in the bile via the GI tract. Usually, only 15-30% of circulating bilirubin is in the conjugated form. An increase in DBIL suggests that the dysfunction or obstruction may be outside the liver though extensive liver metastases can contribute. Elevated levels may be caused by gallstones or extrahepatic duct obstruction due to surgery, scarring, inflammation, or tumor (Pagana 2021).

Although higher TBIL levels are associated with decreased CVD risk, a relative increase in DBIL may be associated with increased CVD risk. One prospective study of 12,097 healthy subjects study found that the risk of CHD began to increase with DBIL above a median of 0.12 mg/dL (2.1 umol/L) and was highest at a median DBIL of 0.35 mg/dL (6.0 umol/L). Those with higher DBIL were more likely to be male, smoke, drink alcohol, have hypertension, be less physically active, have less education, and have higher levels of ALT, AST, and ALP (Lai 2018).    

Researchers question whether the increase in DBIL may be a compensatory mechanism to fight oxidation and inflammation, as DBIL is an important chain-breaking antioxidant. In one study of 288 overweight and centrally obese women, researchers observed a significant and independent association between DBIL and LDL particle size. The study’s lowest DBIL of 0.10 mg/dL (1.71 umol/L) or below was associated with small dense, more atherogenic LDL particles. Metabolic stress, such as insulin resistance and its associated influx of fatty acids into the liver, inflammation, and pro-inflammatory cytokines, can increase sdLDL formation if left unchecked. Insufficiency of DBIL may allow for the production and oxidation of small dense atherogenic LDL particles, contributing to cardiometabolic disease (Kwon 2018).

A prospective study of 1,339 individuals free of metabolic syndrome observed a significant inverse association between DBIL and metabolic syndrome. The lowest baseline DBIL quartile value of 0.10 mg/dL (1.79 umol/L) was associated with the highest incidence of metabolic syndrome. The risk of metabolic syndrome decreased as DBIL increased to a more favorable range of 0.14-0.23 mg/dL (2.39-3.95 umol/L), representing the upper three quartiles (Li 2017).

References

Kwon, Y-J et al. “Direct bilirubin is associated with low-density lipoprotein subfractions and particle size in overweight and centrally obese women.” Nutrition, metabolism, and cardiovascular diseases: NMCD vol. 28,10 (2018): 1021-1028. doi:10.1016/j.numecd.2018.05.013

Lai, Xuefeng et al. “Direct, indirect and total bilirubin and risk of incident coronary heart disease in the Dongfeng-Tongji cohort.” Annals of medicine vol. 50,1 (2018): 16-25. doi:10.1080/07853890.2017.1377846

Lee, Han Ah et al. “Direct Bilirubin Is More Valuable than Total Bilirubin for Predicting Prognosis in Patients with Liver Cirrhosis.” Gut and liver vol. 15,4 (2021): 599-605. doi:10.5009/gnl20171

Li, Xiao-Hong et al. “Direct Bilirubin Levels and Risk of Metabolic Syndrome in Healthy Chinese Men.” BioMed research international vol. 2017 (2017): 9621615. doi:10.1155/2017/9621615

Nagae, Masaharu et al. “Association of direct bilirubin level with postoperative outcome in critically ill postoperative patients.” Korean journal of anesthesiology vol. 71,1 (2018): 30-36. doi:10.4097/kjae.2018.71.1.30

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Tian, Jianbo et al. “Association between bilirubin and risk of Non-Alcoholic Fatty Liver Disease based on a prospective cohort study.” Scientific reports vol. 6 31006. 3 Aug. 2016, doi:10.1038/srep31006