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Hyponatremia, all-cause mortality, and risk of cancer diagnoses in the primary care setting: A large population study

Published:August 13, 2016DOI:https://doi.org/10.1016/j.ejim.2016.07.028

      Highlights

      • Hyponatremia in primary care is associated with increased mortality.
      • Both mild, moderate and severe hyponatremia is associated with increased mortality.
      • Sodium is a predictor of later diagnosis of head and neck and pulmonary cancer.

      Abstract

      Background

      Hyponatremia has been associated with increased all-cause mortality in hospitalized individuals. In this study we examine the risk of all-cause mortality in primary care subjects with hyponatremia, while also exploring the association with subsequent diagnosis of cancer.

      Methods

      Retrospective cohort study on subjects who underwent blood tests, consulting their general practitioner 2000–2012 in Copenhagen, Denmark. Reference range for sodium was 135–145 mmol/L, and mild, moderate, and severe hyponatremia were defined as 130–135, 125–129, and <125 mmol/L, respectively. Primary outcome was all-cause mortality, and secondary outcomes overall and specific types of cancer diagnoses.

      Results

      Among 625,114 included subjects (mean age 49.9 [SD ± 18.4] years; 43.5% males), 90,926 (14.5%) deaths occurred. All-cause mortality was increased in mild, moderate, and severe hyponatremia (age-adjusted mortality rates [IRs, incidence rates] 26, 30, and 36 per 1000 person-years (py), respectively and incidence rate ratios [IRRs] 1.81 [95% CI: 1.76–1.85], 2.11 [2.00–2.21], and 2.52 [2.26–2.82], respectively) compared with individuals with normonatremia (IR 14 per 1000 py). For the secondary endpoint an increased level-dependent risk was found with lower sodium levels in relation to cancer overall, head and neck cancers, and pulmonary cancer, with severe hyponatremia associated with the highest IRRs (1.77 [1.39–2.24], 5.24 [2.17–12.63]), and 4.99 [3.49–7.15], respectively).

      Conclusions

      All levels of hyponatremia are associated with all-cause mortality in primary care patients and hyponatremia is linked to an increased risk of being diagnosed with any cancer, particularly pulmonary and head and neck cancers.

      Keywords

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      References

        • Schrier R.W.
        • Verbalis J.G.
        The syndrome of inappropriate antidiuretic hormone secretion and other hypoosmolar disorders.
        in: Diseases of the kidney and urinary tract. Lippincott Williams & Wilkins, 2007
        • Corona G.
        • Giuliani C.
        • Parenti G.
        • et al.
        Moderate hyponatremia is associated with increased risk of mortality: Evidence from a meta-analysis.
        PLoS One. 2013; 8: e80451
        • Holland-Bill L.
        • Christiansen C.F.
        • Heide-Jørgensen U.
        • et al.
        Hyponatremia and mortality risk: A Danish cohort study of 279508 acutely hospitalized patients.
        Eur J Endocrinol. 2015; 173: 71-81
        • Hawkins R.C.
        Age and gender as risk factors for hyponatremia and hypernatremia.
        Clin Chim Acta. 2003; 337: 169-172
        • Zilberberg M.D.
        • Exuzides A.
        • Spalding J.
        • et al.
        Epidemiology, clinical and economic outcomes of admission hyponatremia among hospitalized patients.
        Curr Med Res Opin. 2008;
        • Waikar S.S.
        • Mount D.B.
        • Curhan G.C.
        Mortality after hospitalization with mild, moderate, and severe hyponatremia.
        Am J Med. 2009; 122: 857-865
        • Doshi S.M.
        • Shah P.
        • Lei X.
        • Lahoti A.
        • Salahudeen A.K.
        Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes.
        Am J Kidney Dis. 2012; 59: 222-228
        • Berghmans T.
        Hyponatremia related to medical anticancer treatment.
        Support Care Cancer. 1996; 4: 341-350
        • Schrier R.W.
        • Gross P.
        • Gheorghiade M.
        • et al.
        Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.
        N Engl J Med. 2006; 355: 2099-2112
        • Corona G.
        • Giuliani C.
        • Verbalis J.G.
        • Forti G.
        • Maggi M.
        • Peri A.
        Hyponatremia improvement is associated with a reduced risk of mortality: Evidence from a meta-analysis.
        PLoS One. 2015; 10: e0124105
        • Hoorn E.J.
        • Rivadeneira F.
        • van Meurs J.B.J.
        • et al.
        Mild hyponatremia as a risk factor for fractures: The Rotterdam study.
        . 2011; 26: 1822-1828
        • Olesen J.B.
        • Gislason G.H.
        • Charlot M.G.
        • et al.
        Calcium-channel blockers do not alter the clinical efficacy of clopidogrel after myocardial infarction: A nationwide cohort study.
        J Am Coll Cardiol. 2011; 57: 409-417
        • Lynge E.
        • Sandegaard J.L.
        • Rebolj M.
        The Danish National Patient Register.
        Scand J Public Health. 2011; 39: 30-33
        • WHO Collaborating Centre for Drug Statistics Methodology
        Guidelines for ATC classification and DDD assignment.
        • Kildemoes H.W.
        • Sorensen H.T.
        • Hallas J.
        The Danish National Prescription Registry.
        Scand J Public Health. 2011; 39: 38-41
        • Helweg-Larsen K.
        The Danish register of causes of death.
        Scand J Public Health. 2011; 39: 26-29
        • Baadsgaard M.
        • Quitzau J.
        Danish registers on personal income and transfer payments.
        Scand J Public Health. 2011; 39: 103-105
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • et al.
        The strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies.
        Lancet. 2007; 370: 1453-1457
        • Madsen M.
        • Davidsen M.
        • Rasmussen S.
        • Abildstrom S.Z.
        • Osler M.
        The validity of the diagnosis of acute myocardial infarction in routine statistics: A comparison of mortality and hospital discharge data with the Danish MONICA registry.
        J Clin Epidemiol. 2003; 56: 124-130
        • Krarup L.H.
        • Boysen G.
        • Janjua H.
        • Prescott E.
        • Truelsen T.
        Validity of stroke diagnoses in a national register of patients.
        Neuroepidemiology. 2007; 28: 150-154
        • Nuttall M.
        • van der Meulen J.
        • Emberton M.
        Charlson scores based on ICD-10 administrative data were valid in assessing comorbidity in patients undergoing urological cancer surgery.
        J Clin Epidemiol. 2006; 59: 265-273
        • Thygesen S.K.
        • Christiansen C.F.
        • Christensen S.
        • Lash T.L.
        • Sorensen H.T.
        The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of patients.
        BMC Med Res Methodol. 2011; 11: 83
        • Liamis G.
        • Milionis H.
        • Elisaf M.
        A review of drug-induced hyponatremia.
        Am J Kidney Dis. 2008; 52: 144-153
        • Fine J.P.
        • Gray R.J.
        A proportional hazards model for the subdistribution of a competing risk.
        J Am Stat Assoc. 1999;
        • Sajadieh A.
        • Binici Z.
        • Mouridsen M.R.
        • Nielsen O.W.
        • Hansen J.F.
        • Haugaard S.B.
        Mild hyponatremia carries a poor prognosis in community subjects.
        . 2009; 122: 679-686
        • Renneboog B.
        • Musch W.
        • Vandemergel X.
        • Manto M.U.
        • Decaux G.
        Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.
        . 2006; 119: 71.e71-71.e78
        • Verbalis J.G.
        • Barsony J.
        • Sugimura Y.
        • et al.
        Hyponatremia-induced osteoporosis.
        . 2010; 25: 554-563
        • Miriam Rachel Usala G.
        • Fernandez S.J.
        • Mete M.
        • et al.
        Hyponatremia is associated with increased osteoporosis and bone fractures in a large U. S. health system population.
        J Clin Endocrinol Metab. 2015; : jc20151261
        • Friedman E.
        • Shadel M.
        • Halkin H.
        • Farfel Z.
        Thiazide-induced hyponatremia. Reproducibility by single dose rechallenge and an analysis of pathogenesis.
        Ann Intern Med. 1989; 110: 24-30
        • Hillier T.A.
        • Abbott R.D.
        • Barrett E.J.
        Hyponatremia: Evaluating the correction factor for hyperglycemia.
        Am J Med. 1999; 106: 399-403
        • Bankir L.
        • Bardoux P.
        • Ahloulay M.
        Vasopressin and diabetes mellitus.
        Nephron. 2001; 87: 8-18
        • Schou M.
        • Valeur N.
        • Torp-Pedersen C.
        • Gustafsson F.
        • Køber L.
        Plasma sodium and mortality risk in patients with myocardial infarction and a low LVEF.
        Eur J Clin Investig. 2011; 41: 1237-1244
        • Peterson J.C.
        • Paget S.A.
        • Lachs M.S.
        • Reid M.C.
        • Charlson M.E.
        The risk of comorbidity.
        . 2012; 71: 635-637
        • Holm J.P.
        • Amar A.O.S.
        • Hyldstrup L.
        • Jensen J.E.B.
        Hyponatremia, a risk factor for osteoporosis and fractures in women.
        Osteoporos Int. 2015; 1-13
        • Mouallem M.
        • Friedman E.
        • Shemesh Y.
        • Mayan H.
        • Pauzner R.
        • Farfel Z.
        Cardiac conduction defects associated with hyponatremia.
        Clin Cardiol. 1991; 14: 165-168
        • Robertson G.L.
        Vaptans for the treatment of hyponatremia.
        Nat Rev Endocrinol. 2011; 7: 151-161
        • Kamoi K.
        • Kurokawa I.
        • Kasai H.
        • Mizusawa A.
        • Ebe T.
        Asymptomatic hyponatremia due to inappropriate secretion of antidiuretic hormone as the first sign of a small cell lung cancer in an elderly man.
        Intern Med. 1998;
        • Gschwantler M.
        • Weiss W.
        Hyponatremic coma as the first symptom of a small cell bronchial carcinoma.
        Dtsch Med Wochenschr. 1994; 119: 261-264
        • Kasi P.M.
        Proposing the use of hyponatremia as a marker to help identify high risk individuals for lung cancer.
        Med Hypotheses. 2012; 79: 327-328
        • Sejling A.-S.
        • Thorsteinsson A.-L.
        • Pedersen-Bjergaard U.
        • Eiken P.
        Recovery from SIADH-associated osteoporosis: A case report.
        J Clin Endocrinol Metab. 2014; 99: 3527-3530
        • Verbalis J.G.
        • Goldsmith S.R.
        • Greenberg A.
        • et al.
        Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations.
        Am J Med. 2013; : S1-42