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Low bilirubin levels increased lung cancer risk in male smokers
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Smokers who exhibited low bilirubin levels were at increased risk for lung cancer incidence and mortality compared with those who had the highest bilirubin levels, according to findings presented at the AACR Annual Meeting.
“Although it was expected that bilirubin may be protective against lung cancer incidence and mortality, we were somewhat surprised that the effect of bilirubin was only evident in smokers,” Xifeng Wu, MD, PhD, professor and chair of the department of epidemiology at The University of Texas MD Anderson Cancer Center, said in a press release. “[The findings] will have profound public health implications, given that 90% of lung cancers occur in smokers.”
Xifeng Wu
Using a novel multiphase study design, Wu and colleagues conducted global, unbiased metabolomic profiling in serum samples from 20 healthy controls, 20 patients in early-stage lung cancer and 20 patients in late-stage lung cancer.
Matching for age and gender, the researchers selected three differentially expressed metabolites for validation in two additional case-control populations, followed by final validation of one metabolite in a large Taiwanese prospective cohort of 435,985 participants.
Among the Taiwanese cohort, Wu and colleagues observed a 7.02 incidence rate of lung cancer per 10,000 person-years for men with bilirubin levels of 0.68 mg/dL or less (95% CI, 6.16-7.99) vs. an incidence rate of 3.73 (95% CI, 3.13-4.43) among men whose bilirubin levels were 1.12 mg/dL or more, translating into a 38% incidence increase for the low bilirubin group (P=.003).
The researchers also observed a lung cancer-specific mortality rate of 4.84 for men with the lowest levels of bilirubin compared with a mortality rate of 2.46 for men with the highest bilirubin levels, a 53% increase in lung cancer-specific mortality among those with the lowest bilirubin levels.
When Wu and colleagues examined smokers only in the cohort, they reported that those with the lowest levels of bilirubin exhibited a 69% increase in the risk for lung cancer development and a 76% increase in mortality compared with smokers with the highest levels of bilirubin.
An inverse relationship between serum bilirubin and lung cancer was significant in ever-smokers but not never-smokers. There was a significant shared effect between bilirubin level and smoking status on both lung cancer incidence and mortality, indicating the importance of bilirubin in ever-smokers independent of smoking.
“The ability to use low bilirubin to identify higher-risk smokers, over and above the number of ‘pack years’ smokers report having smoked, has significant public health impact in reducing lung cancer burden,” Wu said. “Low levels of bilirubin, established as an objective risk index for lung cancer incidence and mortality, may be viewed by smokers as an urgent health warning to drive them to quit.”
For more information:
Zhang F. Abstract #LB-27. Presented at: AACR Annual Meeting; April 6-10, 2013; Washington.
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Harry S. Jacob, MD, FRCPath(Hon)
These results beg for pathophysiologic hypotheses. Here’s one: Since bilirubin levels mainly result from breakdown of hemoglobin, the degree of hypoxia in smokers (with increased erythropoiesis) may be a critical clue. However, this can cut both ways, in that hypoxia-induced factors have been shown to be associated with increased gastric and ovarian cancer lethality and melanoma metastases, yet other products of heme oxygenase (producing bilirubin) — such as P53 and carbon monoxide — may be tumor suppressive.
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Gregory M. Vercellotti, MD
Bilirubin is an antioxidant and may quench radicals that might be derived from cigarette smoke that cause DNA damage. Patients with Gilbert’s syndrome with unconjugated bilirubin have less atherosclerotic events. The role of heme oxygenase-1 in carcinogensis should be explored further.
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