The association between hypoalbuminemia and risk of death due to cancer and vascular disease in individuals aged 65 years and older: findings from the prospective Moli-sani cohort study

Abstract

Background: Serum albumin is inversely associated with overall mortality, but its association with specific causes of death remains uncertain. This study aims to investigate whether hypoalbuminemia, defined as serum albumin levels ≤35 g/L, is associated with mortality specifically attributed to cancer and/or vascular diseases.

Methods: Serum albumin levels were measured in the population-based, prospective cohort of the Moli-sani study, established between 2005 and 2010. Hypoalbuminemia was defined as serum albumin levels ≤35 g/L. Cause-specific mortality was assessed using the validated Italian mortality registry and coded according to the International Classification of Diseases, Revision 9. Over a median follow-up period of 13.1 years, the relationship between serum albumin and mortality, adjusted for covariates, was investigated using competing-risk survival analysis.

Findings: The analysed cohort comprised 17,930 individuals aged ≥35 years, of whom 8445 were men (47.1%). The mean age was 54 years (standard deviation (SD) = 11 years), with 3299 individuals (18.4%) aged older than 65 years. All participants had C-reactive protein levels <10 mg/L and no history of liver, renal, cardiovascular, or cancer disease. Hypoalbuminemia was found in 406 individuals (2.3%). The study documented a total of 1428 deaths, with 574 attributed to cancer and 464 to vascular causes. Hypoalbuminemia was independently associated with mortality when compared to serum albumin >40 g/L (Hazard Ratio (HR) = 1.61, 95% Confidence Interval: 1.21-2.13). A decrease of 1-SD in serum albumin levels corresponded to HR of 1.16 (1.09-1.22), 1.16 (1.05-1.28), and 1.13 (1.03-1.23) for total, vascular and cancer mortality, respectively. Upon stratifying by age, hypoalbuminemia was associated with total mortality solely in those aged ≥65 years (HR = 1.83; 1.33-2.50) but not in the <65 years group (HR = 1.03; 0.53-2.00; P < 0.0001 for difference). Similar age-related patterns emerged for vascular death (per 1-SD decrease HR = 1.19; 1.07-1.33 in individuals ≥65 years and HR = 1.05; 0.86-1.29 in individuals <65 years) and cancer mortality (HR = 1.15; 1.02-1.30; ≥65 years and HR = 1.08; 0.96-1.23; <65 years).

Interpretation: Individuals ≥65 years old with serum albumin levels ≤35 g/L are at higher risk of total, cancer, and vascular mortality.

Funding: This paper was developed within the project funded by Next Generation EU-"Age-It - Ageing well in an ageing society" project (PE0000015), National Recovery and Resilience Plan (NRRP)-PE8-Mission 4, C2, Intervention 1.3.

Keywords: Albumin; Cancer; Mortality; Vascular disease.

Fig. 1

Spline curves for the association of serum albumin levels with all-cause mortality. Panel A) whole cohort; panel B) individuals aged 35–65 years; panel C) individuals aged ≥65 years. Multivariable dose–response association of all-cause mortality with serum albumin levels (g/L) amongst participants from the Moli-sani Study cohort in Italy (2005–2010), in the whole cohort and according to age. Hazard ratios with 95% confidence interval were obtained from a multivariable model adjusted for age (when not stratified for), sex, educational level, housing, smoking status, BMI, adherence to Mediterranean diet, total calories intake, percentage of calories from vegetable proteins, percentage of calories from animal proteins, leisure time physical activity, history of diabetes, hypertension, hyperlipidaemia, log (hs-CRP), FIB-4 score and eGFR. The dashed lines indicate 95% confidence bands. 3 knots were used, located at the 5th, 50th, and 95th percentiles of the serum albumin distribution. Reference value was fixed at 41 g/L (median value of the serum albumin distribution). Analyses were generated using the first imputed dataset. The other imputed datasets were similar and thus omitted.