The Women's Health and Aging Study (WHAS) includes an ancillary study of selected biochemical, hematological, and hormonal markers that might be associated with higher levels of disability. This portion of the WHAS involved collection of blood samples from all participants who consented, after completion of their baseline evaluations. Approximately 75 percent of women enrolled in the study completed the phlebotomy at baseline. Venipuncture was performed in the home by a certified phlebotomist following a standardized protocol. Blood samples were obtained in a nonfasting state. Processing and aliquoting were carried out in the Core Genetics Laboratory of The Johns Hopkins University School of Medicine. Samples were shipped to the central laboratory of Corning Clinical Laboratories (formerly MetPath) in Teterboro, New Jersey, for analysis.
In this chapter, we describe selected baseline laboratory results focusing on commonly performed and basic biochemical and hematologic health status indices.
Serum albumin levels are, in general, a reliable indicator of visceral protein status in older persons (Mobarhan and Trumbore, 1991), and studies have shown that low levels of albumin are predictive of increased morbidity and mortality (Agarwal et al., 1988; Corti et al., 1994; Rudman et al., 1987). In the WHAS cohort, 4 percent of all participants had low levels of serum albumin (less than 3.5 gm/dL; Table 16.1). When evaluated by age group and level of disability, the proportion of women with low albumin was higher in the oldest age group and among women with the most severe disability. Specifically, the proportion of women with hypoalbuminemia was more than three times higher in women receiving help with activities of daily living (ADLs) compared with women classified as moderately disabled (7.2 versus 2.2 percent). Table 16.1 also shows that the proportion of women receiving help in ADLs who had low-normal serum albumin (3.5 to 3.8 gm/dL) was nearly twice that of the moderately disabled group (37 versus 17 percent).
Serum cholesterol in older adults is another measure of nutritional status and general health and may be a risk factor for cardiovascular disease among older adults. For many biologic measures, associations with adverse outcomes tend to be U-shaped, that is, with increased risk at the lower as well as the upper ranges. This appears to be the case with cholesterol: higher levels of morbidity and mortality are associated with levels below approximately 160 mg/dL and above approximately 240 mg/dL (Jacobs et al., 1992). Previous studies, particularly of individuals in acute and chronic care settings, have shown associations between low serum cholesterol and such adverse outcomes as mortality, iatrogenic complications, poor recovery from illness, and higher cost and duration of medical care (Jacobs et al., 1992; Noel et al., 1991; Rudman et al., 1988). Low serum cholesterol has also been identified as a marker for increased risk of cancer (Kritchevsky et al., 1991). On the other hand, elevated serum cholesterol has been widely associated with increased risk of cardiovascular disease in young and middle-aged adults (Stamler et al., 1986) and possibly in older adults (Corti et al., 1995; Harris et al., 1987).
Total cholesterol was measured by enzymatic methods. As with albumin, the proportion of women in the WHAS with lower levels of cholesterol was greatest in the oldest age group and in those with the most severe disability. Overall, 4 percent of these disabled women had serum cholesterol levels below 160 mg/dL. Stratified by age, 8 percent of women over age 85 had serum cholesterol levels below 160 mg/dL compared with 3 percent of women age 65 to 74 years. Thirty-nine percent of women age 85 years and older had cholesterol levels less than 200 mg/dL, compared with 22 percent of women age 65 to 74 years. The association between low cholesterol and disability level was less clear in this cohort of moderately to severely disabled women. Approximately one-third of women in every age and disability category had cholesterol levels over 239 mg/dL.
High-density lipoprotein cholesterol (HDL-C) level, like total cholesterol, is associated with morbidity and mortality. Epidemiologic evidence has shown that within a population group, HDL-C level is strongly and inversely correlated with the risk of cardiovascular disease (Corti et al., 1995; Kannel, 1987; Stampfer et al., 1991). Levels of HDL-C in older persons have recently been associated with such modifiable risk factors as obesity, use of certain medications, and glucose tolerance (Ettinger et al., 1992).
Table 16.1 displays the HDL-C levels, determined using phosphotungstic precipitation and enzymatic cholesterol, for the WHAS population. The cut-points for total and HDL cholesterol levels were selected according to the guidelines of the National Cholesterol Education Program (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 1994). HDL-C levels below 35 mg/dL are considered abnormal; levels above 60 are most clearly associated with reduced incidence of cardiovascular disease. Unlike total cholesterol, mean HDL-C level did not differ among the age groups. However, as with total cholesterol, the mean HDL-C level was noticeably lower in the most disabled group. A higher proportion of those receiving help with ADLs had low HDL-C compared with those with moderate disability (14 percent versus 5 percent). Additionally, in comparison with those with moderate disability, a much lower proportion of women in the highest disability group were found to have high levels of HDL-C (20 percent versus 36 percent).
Hematopoiesis, the process of producing blood cells, is one of a number of biologic systems in which an attenuation in production is noted with increasing age or under stressful circumstances. Although several studies have shown that there is no difference in the baseline hematopoietic function of carefully selected healthy old and young adults (Garry et al., 1981; Lipschitz et al., 1984), the process of hematopoiesis and its various components are highly vulnerable to stress and disease in older adults. One aspect of hematopoiesis-erythropoiesis (red blood cell formation)-can be dampened by a wide variety of stressors such as malnutrition, inflammation, and chronic disease (Dallman et al., 1984; Lipschitz, 1994; Lipschitz and Mitchell, 1982).
Hemoglobin is the protein in the red blood cells that transports oxygen throughout the body. Anemia, the condition in which the number of red blood cells and the concentration of hemoglobin in blood is below normal, is the primary manifestation of diminished erythropoietic function. Blood loss, chronic disease, and inflammation are the most common causes of anemia and low hemoglobin in older adults (Lipschitz, 1994). Hemoglobin was measured by spectrophotometry. Table 16.1 displays the hemoglobin levels for participants in the WHAS. A hemoglobin value below 12.0 gm/dL is considered to be low and suggests anemia. In the WHAS, approximately 20 percent of these disabled women had low hemoglobin, including 18 percent of those age 65 to 74 years and 29 percent of those age 85 years and older. The proportion of women who were anemic did not differ by level of disability. From 1 to 3 percent of women in all age and disability categories had levels of hemoglobin consistent with severe anemia (hemoglobin less than 10.0 gm/dL).
The mean corpuscular volume (MCV) is another component of the complete blood count that, in clinical practice, is routinely obtained. The reference range for MCV is approximately 83 to 103 femtoliters (fL). The MCV is a precise, accurate measure that can be used to differentiate among the various etiologies of anemia. Thus, anemia can be classified as microcytic (MCV below 83 fL), normocytic (MCV 83 to 103 fL), or macrocytic (MCV greater than 103 fL). By far the most common cause of microcytic anemia in older adults is iron deficiency as a result of bleeding, usually gastrointestinal. Dietary factors, such as poor dietary intake of folate and diminished intestinal absorption of vitamin B12, are important in the etiology of macrocytic anemia (Davidson and Hamilton, 1978). Other significant causes of macrocytic anemia are liver disease and acquired disorders of bone marrow stem cells (Koeffler and Golde, 1980). Normocytic anemia is associated with a variety of conditions, including such chronic diseases as renal failure and rheumatoid arthritis (Cartwright, 1966).
Table 16.1 shows the MCV distribution for women in the WHAS with and without anemia. The majority of participants with low hemoglobin levels (hemoglobin < 12 gm/dL) were found to have normocytic anemia. However, 23 percent were classified as having microcytic anemia and 6 percent macrocytic anemia. Stratified by age, a noticeably smaller proportion of women with anemia age 85 years and older were found to have microcytic anemia compared with women age 65 to 74 years (14 percent versus 27 percent). The proportion of anemic women with microcytic anemia did not differ by level of disability. Again, as with the general nutritional and health status measures albumin and cholesterol, a much higher proportion of women in the oldest and most disabled groups was found to have macrocytic anemia. Table 16.1 also shows that, even in women without anemia, there was a trend toward a higher MCV with increasing level of disability.
Carbohydrate metabolism is another area in which attenuation in homeostatic control often occurs with aging. A number of studies have demonstrated a progressive, age-associated decline in glucose tolerance (Andres, 1971; Davidson, 1979; Shimokata et al., 1991). This alteration in ability to metabolize energy is believed by many to be a marker for frailty and age-associated decline in health measures.
In the WHAS, 21 percent of these disabled women reported being diagnosed by a physician as having diabetes (Chapter 9, Table 9.1). In comparison, the National Health and Nutrition Examination Survey and other investigators report that approximately 10 percent of people over the age of 65 have been diagnosed as having diabetes; among those age 85 years and older, 25 percent have this diagnosis (Bennett, 1984; Harris et al., 1987; Wilson, 1980). It is known, however, that 50 percent of cases of diabetes are undiagnosed (Harris et al., 1987). Therefore, the WHAS self-reports may be underestimates. Consistent with this possibility, high levels of serum glucose were prevalent among WHAS participants who did not have a history of diabetes. Serum glucose level was assessed using glycohemoglobin, a measure of mean serum glucose over a 3-month period, measured by liquid chromatography. Table 16.1 shows that 30 percent of the women who had no history of diabetes had elevated glycohemoglobin levels above 8 percent (normal = 6 to 8 percent). This proportion did not vary substantially by age or disability level.
Recent studies in insulin-dependent diabetes mellitus have demonstrated that better control of blood glucose slows the progression of the complications associated with diabetes (Diabetes Control and Complications Trial Research Group, 1993). However, by far the most common form of diabetes in older adults is non-insulin dependent diabetes mellitus. Among WHAS participants, 44 percent of women reporting diabetes were found to have markedly elevated glycohemoglobin levels, indicating increased risk for complications. The proportion of diabetics with poor glucose control was considerably lower in women with diabetes age 85 years and older compared with the younger women. This finding might reflect a change in the nature of diabetes at advanced age, that is, more people developing mild diabetes with age or those with diabetes requiring less intensive treatment. There is also likely a survival effect, resulting from higher mortality among those with the most severe diabetes.
The belief that deficiency in hormonal (endocrine) function has a role in age-associated decline in homeostasis and function has had proponents for more than a hundred years (Brown-Sequard, 1889). Because of the relative frequency of diseases affecting thyroid function in older adults (Rae et al., 1993), thyroid function was assessed in the WHAS participants by serum thyrotropin (thyroid stimulating hormone, TSH; measured by immunoassay) and by thyroxine (T4; measured by chemiluminescence assays). TSH, secreted by the pituitary gland, is responsible for a number of thyroid- associated functions, including hormone synthesis, thyroid gland growth, and release of thyroid hormones. Thyroxine, in turn, is the primary hormone produced by the thyroid gland, and its measurement is important to detect overt thyroid dysfunction. In addition, certain subtle derangements of thyroid gland function can be recognized only by serum TSH measurement. In so-called subclinical hypothyroidism, in which serum TSH is elevated in the presence of a normal serum free thyroxine, higher incidences of subsequent overt hypothyroidism (Tunbridge et al., 1977), associated hypocholesterolemia (Arem and Patsch, 1990), and nonspecific symptoms of thyroid hormone deficiency (Cooper et al., 1984) have been reported. On the other hand, in subclinical hyperthyroidism, in which serum TSH level is low despite normal serum free thyroxine, higher risks of atrial fibrillation (Sawin et al., 1994) and decreased bone mineral density (Stall et al., 1990) have been described in older persons. Because both a variety of nonthyroidal illnesses and malnutrition can alter tests of thyroid function, the specificity of low serum thyroxine and TSH levels is relatively low in ill persons, particularly those requiring hospitalization. Therefore, in chronically ill populations, the specificity of a single abnormal thyroxine or TSH value for primary thyroid disease is relatively low.
TSH levels were abnormal in 14 percent of the WHAS cohort; 5.6 percent had low levels of measured TSH and 8.5 percent had elevated measures (Table 16.1). The mean level did not differ by age group but increased with severity of disability. Specifically, 16 percent of women who received help with ADLs had elevated TSH, while only 7 percent of moderately disabled women had elevated TSH.
For the total WHAS cohort, 7 percent of participants had levels of thyroxine outside the reference range. Of these, Table 16.1 shows that 2 percent had elevated levels and 5 percent had depressed levels of measured thyroxin. By age group, mean thyroxine was lower for women age 85 years and older compared with those age 65 to 74 years. Similarly, the proportion of women age 85 years and older with low levels of measured thyroxine was somewhat higher than that in the 65 to 74 age group (9 percent versus 6 percent). Lower levels of measured T4 were noted among women who received help with ADLs compared with the less disabled groups.
As noted above, there was a low prevalence of elevated thyroxine in this population. In fact, almost no women in the oldest age group and the highest disability classification in Table 16.1 had high levels of measured thyroxine.
Serum creatinine is a measure of renal function. The production of creatinine, derived from muscle metabolism, increases as muscle mass increases. Hence, creatinine production generally increases during the first two decades of life and begins to decline during the fifth decade of life as muscle mass begins to decline. However, a concomitant decline in glomerular filtration rate (GFR) with age in healthy individuals tends to offset the decrease in creatinine production to the extent that little change in serum creatinine level is seen in healthy older adults. In general, serum creatinine levels above 1.4 mg/dL are considered abnormal. However, it has been pointed out that this commonly used cutoff could miss renal insufficiency in small older women; for example, estimated GFR (Cochroft-Gault) for a 60 kg woman with a serum creatinine of 1.2 is approximately 30 cc/minute (Lemann et al., 1990). Overall, approximately 9 percent of WHAS participants had serum creatinine levels above 1.4 mg/dL. Mean serum creatinine did not vary across age groups or disability classifications. Nor did the proportion of individuals with high levels of serum creatinine vary greatly by age (7 percent of women age 65 to 74 years, versus 10 percent of those 85 years and older) or disability levels (8 to 9 percent). Twelve percent of participants had serum creatinine levels between 1.2 and 1.4 mg/dL.
Agarwal N, Acevedo F, Leighton, LS, Cayten CG, Pitchumoni CS. (1988). Predictive ability of various nutritional variables for mortality in older people. Am J Clin Nutr 48:1173-1178.
Andres R. (1971). Aging and diabetes. Med Clin North Am 55:835-852.
Arem N, Patsch W. (1990). Lipoprotein and apolipoprotein levels in subclinical hypothyroidism. Arch Intern Med 150:2097- 2100.
Bennett PH. (1984). Diabetes in the elderly: Diagnosis and epidemiology. Geriatrics 39:37-41.
Brown-Sequard CE. (1889). Des effects produits chez l'homme par des injections sous-cutanees d'un liquid retire des testicules frais de cobayes et de chiens. Comptes Rend Soc Biol 41:415-422.
Cartwright GE. (1966). The anemia of chronic disorders. Semin Hematol 17:164-176.
Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. (1984). Lthyroxine therapy in subclinical hypothyroidism: A double-blind, placebo- controlled trial. Ann Intern Med 101:18-24.
Corti MC, Guralnik JM, Salive ME, Sorkin JD. (1994). Serum albumin level and physical disability as predictors of mortality in older persons. JAMA 272:1036-1042.
Corti MC, Guralnik JM, Salive ME, Harris T, Field TS, Wallace RB, Berkman LF, et al. (1995). HDL-cholesterol predicts coronary heart disease mortality in older persons. JAMA 274:538-544.
Dallman PR, Yip R, John SC. (1984). Prevalence and causes of anemia in the United States, 1976 to 1980. Am J Clin Nutr 39:437-445.
Davidson MB. (1979). The effect of aging on carbohydrate metabolism: A review of the English literature and a practical approach to the diagnosis of diabetes mellitus in the elderly. Metabolism 28:688-705.
Davidson RJL, Hamilton PJ. (1978). High mean red cell volume: Its incidence and significance in routine hematology. J Clin Pathol 31:493-505.
Diabetes Control and Complications Trial Research Group. (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-986.
Ettinger WH, Wahl PW, Kuller LH, Bush TL, Tracy RP, Manolio TA, Borhani NO, et al. for the CHS Collaborative Research Group. (1992). Lipoprotein lipids in older people. Results from the Cardiovascular Health Study. Circulation 3:858-869.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). (1994). Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 89:1329-1445.
Garry PJ, Goodwin JS, Hunt WC. (1983). Iron status and anemia in the elderly: New findings and a review of previous studies. J Am Geriatr Soc 31:389-399.
Harris MI, Hadden WC, Knowler WC, Bennett PH. (1987). Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20-74 years. Diabetes 36:523-534.
Jacobs D, Blackburn H, Higgins M, Reed D, Iso H, McMillan G, Neaton J, et al. (1992). Report of a conference on low blood cholesterol: Mortality associations. Circulation 86:1046-1060.
Kannel WB. (1987). Prevention of cardiovascular disease in the elderly. J Am Coll Cardiol 10:25A.
Koeffler HP, Golde DW. (1980). Human preleukemia. Ann Int Med 93:347-356.
Kritchevsky SB, Wilcosky TC, Morris DL, Truong KN, Tyroler HA. (1991). Changes in plasma lipid and lipoprotein cholesterol and weight prior to the diagnosis of cancer. Cancer Res 51:3198-3203.
Lemann J, Bidani AK, Bain RP, Lewis EJ, Rohde RD. (1990). Use of serum creatinine to estimate glomerular filtration rate in health and early diabetic nephropathy. Am J Kidney Dis 16:236-243.
Lipschitz DA, Mitchell CO. (1982). The correctability of the nutritional, immune, and hematopoietic manifestations of protein calorie malnutrition in the elderly. J Am Coll Nutr 1:17-25.
Lipschitz DA,, Milton KY, Thompson CO. (1984). Effect of age on hematopoiesis in man. Blood 63:502-509.
Lipschitz DA. (1994). Anemia in the elderly. In: Hazzard WR, Bierman EL, Blass JP, Ettinger WH, Halter JH, eds. Principles of Geriatric Medicine and Gerontology. New York: McGraw Hill.
Mobarhan S, Trumbore LS. (1991). Nutritional problems of the elderly. Clin Geriatr Med 7:191-214.
Noel MA, Smith TK, Ettinger WH. (1991). Characteristics and outcomes of hospitalized older patients who develop hypocholesterolemia. J Am Geriatr Soc 39:455-461.
Rae P, Farrar J, Beckett G, Toft A. (1993). Assessment of thyroid status in elderly people. Br Med J 307:177-180.
Rudman D, Mattson DE, Nagraj HS, Feller AG, Jackson DL, Caindec N, Rudman IW. (1988). Prognostic significance of serum cholesterol in nursing home men. J Parenter Enteral Nutr 12:155-158.
Rudman D, Feller AG, Nagraj HS, Jackson DL, Rudman IW, Mattson DE. (1987). Relation of serum albumin concentration to death rate in nursing home men. J Parenter Enteral Nutr 11:360-363.
Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PW, et al. (1994). Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 331:1249-1252.
Shimokata H, Muller DC, Fleg JL, Sorkin JD. (1991). Age as independent determinant of glucose tolerance. Diabetes 40:44-51.
Stall, GM, Harris S, Sokoll LJ, Dawson-Hughes B. (1990). Accelerated bone loss in hypothyroid patients overtreated with L-thyroxine. Ann Intern Med 113:265.
Stamler J, Wentworth D, Neaton JD. (1986). Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? JAMA 256:2823-2828.
Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH. (1991). A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med 325:373-381.
Tunbridge WMG, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JD, et al. (1977). Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure. Clin Endocrinol 7:495-508.
Wilson PNF. (1980). Epidemiology of diabetes in the elderly: The Framingham Study. Am J Med (Suppl 15A:3-10, 1982).