Biomarkers of Liver and Gallbladder Function: Indirect Bilirubin

Optimal Takeaways

Indirect unconjugated bilirubin is the most abundant form of bilirubin in circulation. It is a potent antioxidant that can help inhibit LDL-C oxidation and reduce atherosclerosis and CVD risk. Lower levels of indirect bilirubin are associated with more severe carotid stenosis, coronary heart disease, liver fibrosis, and inflammation.

Standard Range: 0.20 - 1.20 mg/dL (3.42 - 20.52 umol/L)

The ODX Range: 0.40 - 0.75 mg/dL (6.84 – 12.83 umol/L

Low indirect bilirubin levels may be associated with more severe atherosclerotic plaque, carotid stenosis, and cardiovascular risk (Lapenna 2018). Lower levels of IBIL may be associated with moderate to severe inflammation and moderate to severe liver fibrosis (Salomone 2013). Decreasing levels of IBIL are also associated with an increased risk for metabolic syndrome (Hao 2020).

High indirect bilirubin levels can be associated with hepatitis, cirrhosis, hemolytic jaundice, hemolytic anemia, pernicious anemia, sickle cell anemia, blood transfusions, resorption of hematoma, sepsis, Crigler– Najjar syndrome, and Gilbert syndrome (Pagana 2021). Levels may also be elevated with megaloblastic and sideroblastic anemia if liver conjugation is compromised, heart failure due to decreased blood flow to the liver, Lucy-Driscoll syndrome, and medication use, including cholecystographic contrast, rifampin, gentamycin, novobiocin, pregnanediol, flavaspidic acid, and protease inhibitors (Singh 2021).

Overview

Indirect unconjugated bilirubin (IBIL) represents 70-85% of circulating bilirubin under normal circumstances. Accelerated hemolysis of RBCs or hepatitis can increase this percentage and cause unconjugated hyperbilirubinemia and related jaundice (Pagana 202). Dysregulation of bilirubin metabolism can lead to elevated IBIL in the event of increased production, decreased conjugation in the liver, or impaired hepatic uptake (Singh 2021).

Decreases in IBIL and TBIL may reflect the severity of atherosclerosis and CVD risk. A study of 32 endarterectomy patients found that a lower IBIL and TBIL were significantly correlated with increased lipid peroxidation and severity of atherosclerotic plaque. Those with the most severe atherosclerotic carotid stenosis (90% or more) had a mean IBiL of 0.56 mg/dL (9.65 umol/L) versus 0.71 mg/dL (12.1 umol/L) in those below 90%. Total bilirubin in the most severe atherosclerosis was 0.67 mg/dL (11.4 umol/L) versus 0.85 mg/dL (14.5 umol/L) in the below 90% stenosis group. Researchers note that IBIL can effectively inhibit lipid peroxidation, especially as it is carried by albumin into atherosclerotic lesions, where it can be released by the acidic environment there. Indirect bilirubin can also be produced in the vascular wall, amplifying its anti-atherosclerotic effects (Lapenna 2018).

One prospective study of 12,097 healthy subjects found a U-shaped association between incident coronary heart disease and IBIL, as well as TBIL The lowest CAD risk occurred in the third quintile of IBIL within a range of 0.50-0.61 mg/dL (8.5–10.5 umol/L). Researchers attribute the cardioprotective effect of higher TBIL to a relative increase in IBIL, whereas a relative rise in DBIL was associated with increased CAD risk (Lai 2018).

Bilirubin may also be protective in steatohepatitis, and lower levels may increase pathogenesis. In patients with non-alcoholic steatohepatitis and fibrosis, mean IBIL was significantly lower with moderate to severe inflammation versus absent or mild inflammation at 0.52 mg/dL (8.89 umol/L) versus 0.69 mg/dL (11.8 umol/L) respectively. Researchers note that oxidative stress can facilitate progression from the fatty liver stage to steatohepatitis, and bilirubin’s antioxidant actions may help mitigate that progression (Salomone 2013).

References

Hao, Hao et al. “Association of total bilirubin and indirect bilirubin content with metabolic syndrome among Kazakhs in Xinjiang.” BMC endocrine disorders vol. 20,1 110. 22 Jul. 2020, doi:10.1186/s12902-020-00563-y

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

Lapenna, Domenico et al. “Association of serum bilirubin with oxidant damage of human atherosclerotic plaques and the severity of atherosclerosis.” Clinical and experimental medicine vol. 18,1 (2018): 119-124. doi:10.1007/s10238-017-0470-5

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

Singh, Anand, et al. “Unconjugated Hyperbilirubinemia.” StatPearls, StatPearls Publishing, 6 December 2021.

Salomone, Federico et al. “Unconjugated bilirubin, a potent endogenous antioxidant, is decreased in patients with non-alcoholic steatohepatitis and advanced fibrosis.” Journal of gastroenterology and hepatology vol. 28,7 (2013): 1202-8. doi:10.1111/jgh.12155