Elevated percent transferrin saturation (TS) has been shown to be associated with downstream morbidity and mortality (Mainous et al, 2004, Wells et al, 2004, Mainous et al, 2005A, Mainous et al, 2005B, Mainous et al, 2013). Elevated iron stores, as represented by percent transferrin saturation (TS), can damage cells and tissues through oxidative stress, thereby contributing to disease incidence and severity (McCord, 1998, Sullivan, 2005). Increased risk of heart disease, diabetes, dementia, cancer, and death has been found among individuals with elevated TS (Mainous et al, 2004, Wells et al, 2004, Mainous et al, 2005A, Mainous et al, 2005B, Ellervik et al, 2011A, Ellervik et al 2011B, Ellervik et al, 2012, Mainous et al, 2013A, Wlazlo et al, 2013).

General measures of current health status have significant value by being useful outcome measures across a broad range of disease entities (Rumsfeld et al, 1999, Curtis et al, 2002). Telomere length is a general measure of health status attributed to its representation of biological aging, disease risk, and cumulative oxidative stress damage (Von Zglinicki, 2000, Mainous et al, 2010, Shammas, 2011, Codd et al, 2013, Cohen et al, 2013, Mainous et al, 2013B). Similarly, general self-assessed health-related quality of life measures are important health status outcomes for patients across diseases (Ware Sherbourne, 1992). The purpose of this study was to examine the relationship between elevated transferrin saturation, telomere length, and patient-reported health-related quality of life.

We examined participants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study, a multicenter, multiracial-ethnic sample of 101,951 primary care adults 25 years of age or older in the United States and Canada (HEIRS Protocol, 2001, McLaren et al, 2003, Gordeuk et al, 2008). Details of study design and sampling methods have been published and can be found in the HEIRS Protocol (HEIRS Protocol, 2001, McLaren et al, 2003, Gordeuk et al, 2008). Interview data were obtained from initial screening of all participants (n=101,951) and blood specimen data from a subsequent Comprehensive Clinical Exam (CCE) (n=2746) for subjects from the initial screening identified as having the genotypic or phenotypic indication of hemochromatosis or iron overload. DNA specimens were collected from each participant during the CCE and stored at the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) at the National Heart Lung and Blood Institute. For the current study we requested 1,157 of these DNA specimens from CCE subjects for telomere length assays as part of a larger study assessing relationships between elevated iron phenotype, genotypic hemochromatosis, and outcomes (Mainous et al, 2013B). The telomere data (n=1,146) were then merged with variables from the CCE that were contained in the HEIRS data sets.

Demographic characteristics of the sample are featured in Table 1. Among all subjects in the sample (n=669), mean general health was 61.7 (range: 0–100, SD +/− 22.8), mean mental health was 79.1 (range: 8–100, SD +/− 18.0), and mean telomere length 250.8 (range: 58–967, SD: 97.1). Among individuals with elevated TS (≥45% for women and ≥50% for men), only 4.97% reported that they had “Too much iron in your body, iron overload, or hemochromatosis.” Even among individuals with elevated TS who have a usual source of care, only 5.23% had knowledge of having elevated iron suggesting that the vast majority of individuals with elevated TS are not being identified.

Table 2 shows that elevated TS is associated with worse general health status, mental health status and shorter telomere length in crude analyses, analyses adjusting for demographics and a full model adjusting for demographics and health conditions.

When TS is elevated ≥60% and is compared to individuals with non-elevated TS (<50% for men; <45% for women), in unadjusted analyses general health status is worse (55.1 vs 64.3, p<.001), mental health status is worse (75.3 vs 81.7, p<.01), and telomere length is shorter (238.1 vs 263.7, p<.01). In a fully adjusted model controlling for demographics, socio-economic, and disease covariates, individuals with TS elevated at ≥60% still had worse general health status (58.1 vs 63.8, p<.01) and worse mental health status (75.6 vs 82.2, p<.01), compared to individuals with non-elevated TS. The fully adjusted mean difference in GH between the ≥60% TS individuals and the non-elevated individuals was 5.7 while the mean difference between the ≥45/50% TS individuals and the non-elevated individuals was 3.4, indicating a greater impact of TS on GH with higher levels of TS. Similarly, the fully adjusted mean difference in MH between the ≥60% TS individuals and the non-elevated individuals was 6.6 while the mean difference between the ≥45/50% TS individuals and the non-elevated individuals was 5.7, indicating a greater impact of TS on MH with higher levels of TS. Telomere length was no longer statistically significantly different between the ≥60% TS group and the non-elevated group in the fully adjusted model (243.8 vs 261.3, p=.21).

The results of this study show that elevated TS levels are associated with a variety of current health status markers that are not limited to specific diseases. These associations exist even after controlling for demographic confounding variables like health insurance, age and race-ethnicity as well as common health conditions associated with hemochromatosis and iron overload. This study extends our knowledge of the associations between elevated TS and health status.

TS is an easily assessed, but not commonly ordered, biomarker for disease risk. Very few individuals (5%) of those in this sample who had elevated TS had any recognition that they had been told by a physician that they had elevated iron. Unfortunately, even among those with a usual source of care the proportion aware of their condition remained at 5%. The present results show that elevated TS is associated with a corresponding deficit in health-related quality of life in a general sense. Consequently, there may not be a specific sign or symptom (e.g., abdominal pain), related to elevated iron, that would make the physician suspect elevated iron as the potential cause for the patient’s decreased health status. When the results of this current study are interpreted in the context of recent evidence indicating that patients with elevated TS are likely to have longer lengths of stay in the hospital, they suggest that elevated TS may be an under-recognized predictor of a patient’s health status (Mainous et al, 2013A). Greater surveillance of the presence of elevated TS may be useful, especially among patients with low health-related quality of life, in notifying patients of their iron status and driving patient behavioral change to reduce iron load (Heath et al, 2008, Bao et al, 2012).

This study had several limitations that impact the generalizability of the results. First, this study was cross-sectional and thus allowed the researchers to evaluate associations only. Second, although a significant, independent association between elevated TS and worse health status was found even after controlling for demographics and a variety of health conditions associated with elevated iron, there may have been some residual confounding from unmeasured variables.

In conclusion, this study suggests that elevated TS is associated with worse patient-reported health-related quality of life with respect to both physical and mental indicators, as well as shorter telomere length. Recent data indicate that shorter telomere length has a causal role in development of diseases thus increasing the value of the finding that elevated TS was associated with shorter telomere length (Codd et al, 2013, Cohen et al, 2013). These findings add to the growing body of literature suggesting that increased attention to elevated TS in the health care environment in adults with nonspecific decreases in functional status may be in order.