URIC ACID Variability at Midlife: Independent Harbinger of CHD and All-cause Long term Mortality

Variability of serum uric acid (SUA) has been seldom examined in connection with long-term morbidity and mortality. To the best of our knowledge such variability has only been shown to precede chronic kidney disease. We present results from the Israeli IHD study (IIHD). estimating associations of higher variability of SUA with long-term all-cause and cause-specific mortality.

Patients and Methods: Of 10,059 men, aged 40-65, tenured civil servants and municipal employees in the areas of Tel Aviv, Haifa and Jerusalem, 8822 participants in three extensive examinations in 1963, 1965 and 1968 also had assessment of diabetic and coronary morbidity status. We conducted analysis examining whether the standard deviations of Z-scores of SUA (SUA-Z) across study visits predicted fatal outcomes. SUA-Z was defined as the difference between the individual SUA and the mean of SUA, divided by the standard deviation (SD) for the pertinent examination, namely separately for the 1963, 1965 and 1968 means and SD. Hazard ratios (HR) associated with the SD of SUA-Z were calculated for 18-yr stroke and CHD mortality (1968 to 1986) and the 18-yr all-cause mortality associated with quartiles of the above variability. The lowest quartile served as the referent, adjusting for age. A subsequent model adjusted additionally for the baseline value of SUA as well as for baseline frequency of diabetes mellitus and coronary heart disease (CHD)

Results: Multivariate analysis of 18-yr CHD mortality (1968-1986, 906 deaths among 8822 men) yielded a significant association with the 1963-1968 SD of SUA-Z with age adjusted HR of CD mortality of 0.99, 1.12 and 1.43 for quartiles 2 to 4 respectively (P using Mantel trend test=0.0002). Further adjustment for baseline prevalence of diabetes and CHD somewhat decreased the above HR estimates (table).

Table: Hazard ratios for CHD mortality by quartile of SD of SUA-Z

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Variable| HR P [95% CI]

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Age (5yrs) | 1.54 0.00 1.47 1.61

Quartile 2 | 0.98 0.81 0.80 1.19

Quartile 3 | 1.04 0.70 0.86 1.26

Quartile 4 | 1.29 0.00 1.07 1.45

Diabetes | 2.99 0.00 2.42 3.70

CHD in 1963 2.29 0.00 1.93 2.71

Baseline uric acid (1963) per 1 mg/Dl

1.15 0.00 1.07 1.23

The results for all-cause mortality (2836 deaths through 1986) similarly and strongly indicated increasing age-adjusted mortality risk with increasing SD of SUA-Z: HRs= 1.08 (95% CI,0.97-1.21) ,1.15 (1.03-1.28) , and 1.37 (1.23-1.51). No association was observed between the SD of SUA-Z and 18 years stroke mortality was observed. Sensitivity analysis, incorporating the last (1968) SUA levels assessed, rather than the 1963 ones, yielded virtually identical HRs.

Conclusion: In this cohort of tenured male workers, with diverse occupation, higher variability of SUA measurement taken in1963-5-8 were clearly predictive of 18-year CHD and all-cause mortality, above and beyond the SUA levels proper.