The peptide procalcitonin – a precursor to the calcium-regulating hormone calcitonin – is present at very low levels in healthy individuals, but when inflammation takes hold its levels rise. It is therefore used as an indicator of severe bacterial infections and sepsis, and has also been associated with prognosis in other conditions where inflammation plays a role, such as cancer and myocardial infarction. However until now the link between procalcitonin levels in healthy individuals and subsequent cardiovascular or cancer mortality had not been closely examined. Alexandru Schiopu from Lund University, Sweden and colleagues investigated this relationship in over 3000 middle-aged adults, as published in a recent study in BMC Medicine, revealing a strong association between procalcitonin levels and cancer mortality in men, but not women. Schiopu explains more about these surprising findings.
How did this research come about and what was the main goal?
The incidence of cardiovascular disease and cancer, the two most frequent causes of death worldwide among non-communicable diseases, is constantly increasing. New biomarkers are needed for improved risk prediction in the general population, in order to identify the individuals who would benefit the most from clinical screening and risk factor control. Inflammation plays a central role in both cardiovascular disease and cancer and inflammatory biomarkers, in particular high sensitivity C-reactive protein (hsCRP), have been correlated with disease incidence and mortality. However, measurement of hsCRP only adds a mild improvement to the already established risk scores based on traditional risk factors such as smoking, diabetes, blood pressure and plasma lipids.
Procalcitonin is a pro-inflammatory and immunosuppressive mediator that is involved in the pathogenesis of bacterial infections and sepsis. Elevated procalcitonin levels in patients already diagnosed with acute coronary syndrome and cancer were shown to be correlated with increased mortality. The aim of our study was to elucidate whether procalcitonin may be used as a biomarker to predict total and cause-specific mortality in apparently healthy individuals. Additionally, we performed a comparative analysis in order to assess whether measurement of procalcitonin offers additional prognostic information compared to hsCRP, as an already established inflammatory biomarker.
What is already know about procalcitonin?
Procalcitonin is the pro-hormone of calcitonin, which is involved in calcium metabolism. Procalcitonin is mainly produced in the neuroendocrine C cells of the thyroid gland and in the K cells of the lung, but human adipose tissue is also able to secrete procalcitonin under the influence of certain stimuli. Procalcitonin concentrations are low in healthy individuals but increase dramatically in systemic inflammatory response syndrome (SIRS) associated with sepsis, trauma, surgery, burns and pancreatitis. In healthy individuals procalcitonin is associated with the components of metabolic syndrome, such as obesity and insulin resistance. We have recently shown that several of the traditional cardiovascular risk factors are correlated with plasma procalcitonin levels and that procalcitonin is associated with the incidence of coronary events in apparently healthy individuals (J Intern Med. 2012, 272(5):484-91).
What are the main findings of your study?
We studied the relationship between procalcitonin, hsCRP and the incidence of all-cause, cardiovascular and cancer mortality in 3322 middle-aged individuals with no previous history of cardiovascular disease or cancer, recruited from the general population. We demonstrate that procalcitonin is strongly associated with the risk of all-cause and cancer mortality and with the incidence of colon cancer in men, independently of smoking, diabetes, hypertension, Body Mass Index, plasma lipids, renal function and hsCRP. In contrast, hsCRP was independently associated with cardiovascular mortality, but not with cancer mortality in men. After adjustment for potential confounding risk factors and each other, neither biomarker was independently correlated with incident mortality in women.
How does this research add to our knowledge about procalcitonin?
We demonstrate for the first time an independent relationship between procalcitonin and mortality risk in healthy individuals, in line with previous findings in cardiovascular disease, cancer and sepsis patients. Importantly, this relationship was independent of hsCRP, suggesting that the two biomarkers might be involved in different pathogenic inflammatory pathways and provide complementary prognostic information. Although significant, the relationship between procalcitonin and the incidence of colon cancer should be interpreted with caution and needs to be confirmed in larger cohorts, due to the low number of incident colon cancer cases within our population.
What do you think could be the underlying mechanisms to explain the association of procalcitonin with all-cause and cancer mortality?
As opposed to CRP, procalcitonin has inherent inflammatory and immunosuppressive properties and might directly participate in the pathogenesis of cardiovascular disease and cancer. Procalcitonin stimulates the secretion of the pro-inflammatory cytokines TNFα and IL-6, which have been shown to play important roles in atherosclerosis and to link chronic inflammation and tumor development. In turn, TNFα is a strong stimulator of procalcitonin production, creating potential pro-inflammatory positive feedback loops. Procalcitonin has also been shown to be able to inhibit human monocyte and neutrophil mobility and might thus impair beneficial anti-tumor immune responses.
How do you think your findings could influence clinical practice in the future?
Our study reveals for the first time important independent correlations between the levels of the inflammatory mediator procalcitonin in middle-aged apparently healthy men and the future risk of cancer death. Unfortunately, we could not establish a clear cut-off value for procalcitonin as a cancer mortality predictor with an adequate sensitivity/specificity balance for direct use in clinical practice. However, the association between procalcitonin and the incidence of colon cancer in men might have important clinical implications for future cancer screening protocols, but needs to be further confirmed in studies adequately powered to answer this type of question.
Interestingly, we demonstrate clear differences between plasma levels of the inflammatory biomarkers procalcitonin and hsCRP with regard to the risk of death in healthy individuals. Procalcitonin was independently correlated with the incidence of cancer death and hsCRP with cardiovascular death in men, but neither biomarker was correlated with the risk of death in women. These important gender-specific and biomarker-specific differences should be taken into account in the design and interpretation of future clinical studies on cardiovascular disease and cancer.
What’s next for your research?
We will continue to focus our attention on the involvement of immune and inflammatory mechanisms and mediators in human disease, in particular cardiovascular disease and cancer. Although several inflammatory biomarkers have been proposed to correlate with morbidity and mortality in healthy individuals, none so far have shown sufficient specificity and sensitivity to enter clinical practice. A more individually-tailored approach is required in order to accurately predict incident disease in healthy individuals, combining genetic analysis, traditional risk factors and new biomarkers. The relationship between procalcitonin and the incidence of colon cancer in men is intriguing and needs to be confirmed in prospective case-control studies that particularly target this diagnosis. Additionally, it will be interesting to determine whether procalcitonin is linked to death due to a particular type of cancer or whether it reflects unspecific susceptibility to cancer mortality.
Questions from Stephanie Harriman, Deputy Medical Editor for BioMed Central.
Plasma procalcitonin is associated with all-cause and cancer mortality in apparently healthy men: a prospective population-based study
BMC Medicine 2013, 11:180
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