Using NHANES-III data we could replicate the results of the Swedish AMORIS study
. The combination of serum levels of CRP, albumin, GGT, and HDL was positively associated with mortality and was even predictive in patients with low comorbidity based on CCI. Furthermore, the association between the score and mortality was found to be similar among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans.
The three suggested mechanisms, inflammation, liver dysfunction, and lipid metabolism, have been associated with early death and comorbidities in several different research settings. The inflammation-based Glasgow Prognostic Score (GPS), based on serum levels of CRP and albumin, has repeatedly been shown to be a predictor of survival, independent of tumor stage, performance status and treatment
[3, 18–20]. In a study of 540 cancer patients, increasing GPS correlated with more aggressive tumor biology in terms of tumor size, presence of lymph node metastasis, and higher tumor recurrence rate
. In addition to being a marker of liver dysfunction, high levels of GGT (>28 U/L) have been found to be positively associated with risk of all cause mortality and risk of developing cancer
[21, 22]. It is also thought that persistent production of reactive oxygen stress following increased GGT expression in tumor cells contributes to genetic instability and tumor progression
. Finally, HDL cholesterol, as a component of the metabolic syndrome, has been extensively studied in relation to early death and comorbidities
[12, 23]. Apart from its link with the lipid metabolism, HDL is also associated with inflammation
[6, 23, 24]. More specifically, HDL has been linked with pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α)
. It has been shown that HDL reduces free TNF-α resulting in reduced tissue damage, reduced infiltration of macrophages and neutrophils, and potential attenuated tumor formation
. A prospective study of 989 persons aged 65 and over, showed that high levels of HDL were significantly associated with low total risk of death in men
As in the Swedish AMORIS study, the HRs found using data from NHANES III were also of a magnitude that may be of clinical relevance. Even though Figure
1 did not show a clear pattern by specific markers of the mortality score, albumin and GGT seemed to contribute slightly more to the prediction of death than the other markers. It is important to note that these results are slightly different from our analysis based on continuous levels of the four studied biomarkers, which is likely explained by the more medically relevant cut-offs used in our mortality score. The findings in Figure
1 suggest that markers of inflammation and reactive oxygen species are more strongly associated with risk of death. Because of limited sample size, it was not possible to perform identical age-stratified analysis so that we could not identify the predictive strength of the score in those aged 50–65. In our analysis, the score was found to be equally predictive of death among those younger and older than 65. Interestingly, we also replicated the findings stratified by categories of the CCI. Among those with CCI<3, there was a positive trend between the mortality score and all-cause mortality as well as circulatory disease-specific death. The association was not statistically significant with cancer-specific death; this may be due to the comparably small number of cancer deaths (24 versus 42%). Nevertheless, the results by categories of CCI indicate that the mortality score is predictive for mortality over and above the prediction by CCI.
In our study we could also evaluate the mortality score in different ethnic groups. A study evaluating the clinical utility of the triglycerides-to-HDL ratio showed that this ratio may identify insulin-resistance in Aboriginals, Chinese, and Europeans, but not South Asians, thus reflecting possible ethnic differences in normal lipid levels
. Also, levels of albumin also differed by ethnicity. Among UK resident patients of white European or south Asian ethnicity with type 2 diabetes mellitus there were significant differences in microalbuminuria
. In addition, the association between CRP and disease outcome appeared to be influenced by ethnicity. In a multi-ethnic cohort including 2362 Caucasians, 1601 African Americans, 1353 Hispanics, and 751 Chinese, CRP was only associated with the risk of circulatory disease in Caucasians
. This variation by ethnicity was smaller for GGT. In another study based on NHANES III, the correlation between GGT and risk of hypertension was consistent by race-ethnicity
. In our study there was also no effect-modification by race-ethnicity; the mortality score seemed to predict all cause, cancer-specific and circulatory death in a consistent way across ethnic groups. This may suggest that a combination of these four biomarkers is more general and less susceptible to subgroup differences.
This study has several strengths including its generalizibility following the use of nationally representative data. Therefore it was also possible in our analysis to perform a stratified analysis by race/ethnicity. We were able to adjust for many potential confounding factors and examine interactions by age and the CCI. In a sensitivity analysis, we used different medical cut-offs by sex for HDL and GGT, but this did not materially alter our findings (results not shown). Another limitation of this study and the mortality score is that it relies on one single measurement so that it may be prone to measurement error and within-person variation. Repeated measurements may strengthen the accuracy of the score. In addition, it is important to note that the current mortality score only represents a selection of mechanisms and markers associated with early death. It is possible that other markers such as hypertension or the ratio of total to HDL cholesterol may also be good components of a mortality score, however we believe that the current mortality score already represents three important mechanisms associated with early death. A next step in the process of potentially taking this score in clinic is the performance of sensitivity and specific tests in order to determine the most predictive cut-offs for the different biomarkers used.