Basic and Clinical Endocrinology 7th International student edition Edition
Susan L. Greenspan MD
Neil M. Resnick MD
Individuals over age 65 comprise the fastest-growing segment of the United States population; each day this group increases by over 1000 people. This increase has led to a remarkable situation—of all the people who have ever lived to the age of 65, more than two-thirds are still alive. Thus, it is becoming increasingly important for the endocrinologist to understand how endocrine physiology and disease may differ in the elderly.
Before considering specific endocrinologic conditions in the elderly, however, it is worthwhile to review some general principles that account for many of the age-related changes in disease presentation in the elderly. First, aging itself—in the absence of disease—is associated with only a gradual and linear decline in the physiologic reserve of each organ system (Figure 23-1). Since the reserve capacity of each system is substantial, age-related declines have little effect on baseline function and do not significantly interfere with the individual's response to stress until the eighth or ninth decade. Second, because each organ system's function declines at a different physiologic rate and because 75% of the elderly have at least one disease, endocrine dysfunction in the elderly often presents disparately, with initial symptoms derived from the most compromised organ system. For example, hyperthyroidism in an elderly patient with preexisting coronary and conduction system disease may present with atrial fibrillation and a slow ventricular response, while in another equally hyperthyroid patient with a prior stroke it may present with confusion or depression; neither patient may tolerate hyperthyroidism long enough for the classic thyroid-related manifestations (eg, goiter) to become apparent. Third, elderly patients often have multiple diseases and take many medications that may mimic or mask the usual presentation of endocrine disease.
THYROID FUNCTION & DISEASE
The prevalence of thyroid disease in the elderly is approximately twice that in younger individuals, with hypothyroidism ranging from 2% to 7% and hyperthyroidism affecting up to 2% of older individuals (Figure 23-2). The Whickham Survey of 21,000 adults in Great Britain and its follow-up study, conducted between 1972 and 1993, reported that the incidence of overt hypothyroidism increased tenfold when its incidence in women in their twenties was compared with that in women age 75 and older. In addition, some
studies suggest that up to 9% of hospitalized elderly patients have overt thyroid disease. Furthermore, “subclinical hypothyroidism”—normal serum levels of thyroid hormones (thyroxine, T4; triiodothyronine, T3) but an elevated level of thyrotropin (TSH)—is more prevalent, with estimates of 4-14% in the elderly, and is higher in women than in men. In the elderly, the progression from subclinical to overt hypothyroidism is roughly 2-3% per year. “Subclinical hyperthyroidism”—normal serum thyroxine with suppressed serum TSH levels—may be found in 2% of elderly subjects. The rate of progression to overt hyperthyroidism is less clear. Finally, the overall prevalence of thyroid hormone use in older adults is approximately 7% (10% in women and 2% in men).
Figure 23-1. Influence of age on physiologic function in humans. (Reproduced, with permission, from Shock NW: Discussion on mortality and measurement. In: The Biology of Aging: A Symposium. Strehler BL et al [editors]. American Institute of Biological Sciences, 1960.)
There are few major age-related changes in the physiology of the hypothalamic-pituitary-thyroid axis (Chapter 7). Serum TSH levels remain constant, and TSH release remains pulsatile, though the nocturnal rise in serum TSH appears to be blunted with age. Balanced decreases in T4 secretion and clearance result in no change in serum T4; T3 resin uptake, free T4, and the free T4 index are also unchanged. There is a slight age-related decline in serum T3, but values usually remain within normal limits. The effect of age on the release of TSH by thyrotropin-releasing hormone (TRH) is less clear, but most recent studies show little clinically relevant change in either sex. The 24-hour radioiodine uptake is also not significantly altered with age. Thyroid antibodies are common in older women (prevalence up to 32%), but their presence does not serve as a specific screening test for thyroid disease.
DISORDERS OF THE THYROID GLAND
Although the United States Preventive Services Task Force and other cost-benefit analyses recommend annual screening thyroid function tests for older women, there is still no consensus among thyroidologists regarding the utility of screening for thyroid dysfunction in the absence of symptoms. The American Thyroid Association recommends that adults be screened by serum TSH determination every 5 years. However, it is reasonable to measure TSH at any time in older individuals who present with“atypical” symptoms of thyroid disease such as exacerbation of cardiac symptoms, change in mental status, falling, or onset of depression. Despite the sensitivity of the TSH assay, further evaluation with a free T4 or free T4 index is often required because up to 98% of elderly subjects with mildly suppressed TSH levels do not have thyrotoxicosis.
With age, the prevalence of Graves' disease decreases (though it remains the most common cause of hyperthyroidism), and the prevalence of multinodular goiter and toxic nodules increases. Elderly hyperthyroid patients tend to present with symptoms or complications related to the most vulnerable organ system—usually the cardiovascular system (atrial fibrillation, congestive heart failure, angina, and acute myocardial infarction) or the central nervous system (apathy, depression, confusion,
or lassitude). The hypercatabolic state also causes muscle wasting, particularly of the quadriceps, thereby increasing the risk of falls. Occasionally, they present with gastrointestinal symptoms, but these differ from those seen in younger patients because they include constipation, failure to thrive, and anorexia and weight loss. Because of degeneration of the sinus node and fibrotic changes in the cardiac conduction system, older patients are less likely than younger ones to present with palpitations (Table 23-1). However, a very low serum TSH concentration is associated with a threefold higher risk of atrial fibrillation in the subsequent decade. Hyperthyroidism is also associated with bone loss and fractures.
Figure 23-2. Percentage with high or low serum TSH in the total United States population, the disease-free (excludes those people who have reported having thyroid disease, goiter, or taking thyroid medications*) and reference population (excludes those people who reported having thyroid disease, goiter, or taking thyroid medications and those who do not have risk factors such as pregnancy or taking estrogen, androgens, or lithium and who are without the presence of thyroid antibodies or biochemical evidence of hypothyroidism or hyperthyroidism**) by age. A: High serum TSH. In the disease-free population, the percentage of people with high serum TSH concentration (> 4.85 ľIU/mL; > 4.85 mIU/L) is slightly lower than that of the total population but significantly higher than the percentage in the reference population. B: Low serum TSH. The percentage of people with low serum TSH in the disease-free population, on the other hand, is significantly lower than the percentage in the total population and similar to the pattern seen in the reference population. Note the elevated prevalence of low TSH in the populations without thyroid disease or risk factors at ages 20-39 years and again after age 79 years. The higher prevalence of individuals with low TSH or high TSH in the total population is related directly to the people reporting thyroid disease, goiter, or taking thyroid medication and probably reflects inadequate management of clinical thyroid disease. (Reproduced, with permission, from Hollowell JG et al: Serum TSH, T4, and thyroid antibodies in the United States population [1988 to 1994]: National Health and Nutrition Examination Survey [NHANES III]. J Clin Endocrinol Metab 2002;87:489. Copyright Š 2002 by The Endocrine Society).
The physical signs of hyperthyroidism also differ in the elderly (Table 23-1). Sinus tachycardia is less frequent; the thyroid feels normal in size or is not palpable in two-thirds of patients; and lid lag is uncommon. Ophthalmopathy is less common, not only because Graves' disease occurs less often, but also because even with Graves' disease ophthalmopathy occurs less frequently in the elderly. However, although they are less common in the elderly, some findings appear to be highly suggestive of hyperthyroidism. These include increased
frequency of bowel movements, weight loss despite increased appetite, fine finger tremor, eyelid retraction, and increased perspiration.
Table 23-1. Percentages of patients with symptoms and physical findings attributable to thyrotoxicosis.1
As in younger patients (Chapter 7), the diagnosis is usually confirmed by standard thyroid function tests, beginning with a depressed TSH level as measured by a sensitive immunoradiometric or chemiluminescent assay. A TRH test is rarely required. There are potential pitfalls, however. Hospitalized elderly patients who are acutely ill (but euthyroid) may have a suppressed serum TSH. Further evaluation of other thyroid function tests should help rule out hyperthyroidism. T3 toxicosis may be more difficult to diagnose because concomitant nonthyroidal illness is common and can depress serum T3. Euthyroid hyperthyroxinemia (also due to nonthyroidal illness) may also cause confusion. Elderly patients may also be taking medications such as propranolol, which may elevate levels of serum T4. Furthermore, iodide-induced hyperthyroidism, known also as the jodbasedow effect, is becoming more common in elderly patients with multinodular goiter because of increased exposure to radiocontrast studies; the resultant hyperthyroidism is generally transient.
Finally, because of screening tests with sensitive TSH assays, “subclinical hyperthyroidism” (normal T4, T3, free T4 with a suppressed TSH) is being recognized more commonly. This is often found in older subjects with autonomous function of a multinodular goiter or nodule. Osteoporosis and atrial fibrillation are complications of subclinical hyperthyroidism that may be an indication for treatment. Recent studies suggest an increase in cognitive impairment and all-cause mortality (especially cardiovascular disease) in patients with subclinical hyperthyroidism. If patients are not treated, careful follow-up is recommended.
Beta-blocking agents are useful in alleviating symptoms, but radioactive iodine is the therapy of choice in elderly patients because it is efficient, uncomplicated, and inexpensive. Antithyroid drugs can be used prior to radioactive iodine treatment to render the patient euthyroid and to avoid radiation-induced thyroiditis, but they are not definitive treatment and are more toxic in this age group. Surgery has a more limited role because of its increased morbidity risk.
Following radioactive iodine treatment, patients become euthyroid over a period of 6-12 weeks. They should receive careful follow-up, because hypothyroidism develops in 80% or more of patients who have been adequately treated. Once hyperthyroidism has abated, the metabolic clearance rate of other medications
may decrease, and doses may require readjustment. Older patients with subclinical hyperthyroidism require follow-up, especially if presented with an iodine load.
Hypothyroidism in the elderly is most often due to Hashimoto's thyroiditis or prior radioactive iodine ablative therapy. The risk for developing hypothyroidism is significantly increased in older women when serum antithyroid antibodies or serum TSH is elevated.
It is easy to overlook hypothyroidism in an older person, because many euthyroid elderly patients have the same symptoms. Moreover, elderly patients with hypothyroidism are more likely than younger patients to present with cardiovascular symptoms (eg, congestive heart failure or angina) or neurologic findings (eg, cognitive impairment, confusion, depression, paresthesias, deafness, psychosis, or coma). Finally, in the older hypothyroid patient, the physical findings are frequently nonspecific, though puffy face, delayed deep tendon reflexes, and myoedema support the diagnosis.
Serum TSH is the most sensitive indicator of primary hypothyroidism and should be checked first. The diagnosis should then be confirmed with a low serum T4 or free T4. Measurement of serum T3 is unnecessary and potentially misleading, because T3 is the form of thyroid hormone most likely to decrease in nonthyroidal illness. Serum TSH should not be used alone to diagnose hypothyroidism because it will not always differentiate symptomatic from “subclinical” hypothyroidism. Furthermore, levels of TSH may be higher at night as a result of the nocturnal rise in serum TSH. Moreover, the pulsatile nature of TSH, resulting in serum TSH slightly above the normal ranges, may lead to a diagnosis of subclinical hypothyroidism in a euthyroid subject. Finally, in hypothyroid patients, serum TSH levels can be reduced to within the normal range by treatment with dopaminergic drugs and corticosteroids. In such patients, determination of free T4 and reverse T3 may help to differentiate those with true hypothyroidism from those with nonthyroidal illness (Chapter 7).
The doses of thyroid hormone required for adequate replacement decrease with age. Elderly patients should be started on approximately 25-50 ľg of levothyroxine, and the dose should be increased by approximately 25 ľg every 4-6 weeks until the serum TSH comes into the normal range. In patients with cardiovascular disease, even lower initial doses can be used (12.5 ľg) and increased at a slower rate. Desiccated thyroid hormone and preparations containing T3 should be avoided because T3 is rapidly absorbed and cleared. The metabolic clearance of other drugs will change as hypothyroidism is corrected, and their dosages may require readjustment. On average, the dose of levothyroxine in the elderly is roughly 1 ľg/kg/d compared with 1.7 ľg/kg/d in young adults. Overtreatment documented by a suppressed serum TSH should be avoided because of the potential adverse effects to the skeleton and cardiovascular system.
It is still not known whether treating “subclinical hypothyroidism” is beneficial for all patients. However, two-thirds of these patients will remain chemically euthyroid for at least 4 years, and absence of antimicrosomal antibodies may identify patients at lowest risk for progression. One cost-benefit analysis reported that it was worthwhile to screen elderly women for subclinical hypothyroidism with serum TSH measurements and that treatment led to symptomatic improvement and decreased cholesterol levels. Recent guidelines from the American Thyroid Association agree with these recommendations. Elderly patients previously treated with radioactive iodine are more likely to progress to overt hypothyroidism.
- Multinodular Goiter
The prevalence of multinodular goiter increases with age. However, if swallowing and breathing are not compromised and thyroid function tests are normal, the goiter can be observed without treatment. Levothyroxine therapy rarely shrinks the gland, and although it may prevent further enlargement, the risk of inducing hyperthyroidism is significant because multinodular goiters may develop areas of autonomous function.
- Thyroid Nodules & Cancer
Thyroid nodules are more common in the elderly. The prevalence of nodules increases with age and is generally higher in women than in men. Furthermore, the prevalence of thyroid nodules detected by ultrasound may be as high as 40% in older women. Ninety percent of these nodules are benign, but the prognosis for elderly patients with malignant nodules may be worse than that for younger patients with malignant nodules. The approach is similar to the workup in a younger patient. The prognosis correlates with the size of the tumor. The outcome in elderly patients may therefore be substantially improved by early evaluation of nodules in patients who are good surgical candidates.
Papillary carcinoma is more common in young and middle-aged patients. However, it has a poorer prognosis in the elderly, possibly because it is detected at a more advanced stage. Follicular carcinoma accounts for 15% of thyroid cancers and usually occurs in middle-aged and older patients. Anaplastic thyroid carcinoma is found almost exclusively in middle-aged and older patients. It presents as a rapidly growing hard mass which is locally invasive, often associated with metastatic lesions, and has a very poor prognosis (Chapter 7).
CARBOHYDRATE INTOLERANCE & DIABETES MELLITUS
AGING & THE PHYSIOLOGY OF CARBOHYDRATE INTOLERANCE
Even healthy elderly individuals demonstrate an age-related increase in fasting blood glucose (1 mg/dL [0.6 mmol/L] per decade) and a more significant increase in blood glucose (5 mg/dL [0.28 mmol/L] per decade) in response to a standard glucose tolerance test. According to the criteria of the National Diabetes Data Group, nearly 10% of the elderly have some degree of glucose intolerance. The possible causes of this intolerance include changes in body composition, diet, physical activity, insulin secretion, and insulin action.
With aging, lean body mass decreases and body fat increases. The percentage of body fat correlates positively with fasting levels of serum glucose, insulin, and glucagon. When obesity (or the percentage of body fat) is taken into account, the basal levels of glucose, insulin, and glucagon are not influenced by age. However, older individuals have impaired glucose counterregulation to hypoglycemia, associated with higher plasma insulin levels and reduced levels of glucagon.
Decreased physical activity and a low-carbohydrate diet impair glucose tolerance. Patients who have type 2 diabetes mellitus may have a combination of insulin resistance, decreased insulin secretion, and increased hepatic glucose production. Lean elderly patients with type 2 diabetes mellitus have a profound impairment in insulin release and a mild resistance to insulin-mediated glucose disposal. In contrast, obese elderly patients with type 2 diabetes mellitus have a significant resistance to insulin-mediated glucose disposal but adequate circulating insulin. In both groups, hepatic glucose output does not appear to be increased (Figure 23-3). Furthermore, there may be gender-related changes in glucose metabolism with age; healthy older men have an impairment in nonoxidative glucose metabolism, but women do not. However, much of the carbohydrate intolerance found in average elderly individuals is caused by diet, drugs, lack of exercise, or environmental factors that may be correctable.
The prevalence of diabetes mellitus increases with age, affecting 16% of persons over age 65 (Figure 23-4). Most diabetes in the elderly is type 2 diabetes. Diabetes may be difficult to diagnose in the elderly because of its often atypical and asymptomatic presentation. For example, polyuria and polydipsia are not present in many elderly patients, because the glomerular filtration rate and thirst threshold decline with age, while the renal threshold for glycosuria increases. Instead, symptoms in these individuals are usually nonspecific (eg, weakness, fatigue, weight loss, or frequent minor infections). These patients may also present with neurologic findings such as cognitive impairment, acute confusion, or depression. Diabetes in the elderly can also predispose to pressure ulcers, falls, incontinence, and a decreased pain threshold.
The American Diabetes Association's Clinical Practice Recommendations for 1998 base the diagnosis of diabetes on a fasting blood glucose greater than 126 mg/dL on two occasions (in the absence of acute illness). A 2-hour glucose tolerance test is needed rarely, if ever. Symptoms of polyuria, polydipsia, and unexplained weight loss and a plasma glucose ≥ 200 mg/dL also are consistent with the diagnosis of diabetes. The ADA also recommends screening adults age 45 and older every 3 years, with more frequent screening for subjects at high risk (family history of coronary heart disease, cigarette smoking, hypertension, obesity, kidney disease, and dyslipidemia). Because the renal threshold for glycosuria increases in the elderly, the diagnosis should not be based on the presence of glycosuria. Increased blood levels of glycosylated hemoglobin or fructosamine support the diagnosis, but these tests are more useful in monitoring treatment.
Since the complications of diabetes mellitus are related to the duration of disease, elderly patients who live long enough will suffer the same complications of nephropathy, neuropathy, and retinopathy as their younger counterparts. The United Kingdom Prospective Diabetes Study (UKPDS) examined the relationship between improved glycemic control and the prevention of complications. Three-thousand and sixty- seven patients with type 2 diabetes mellitus (mean age 54 years) were assigned to intensive therapy (goal of fasting blood glucose < 108 mg/dL) with a sulfonylurea or insulin versus conventional diet therapy. After a median
follow-up of 10 years, they reported that microvascular complications (retinopathy, neuropathy, and nephropathy) were reduced by 25% with intensive treatment. Treatment with insulin and sulfonylureas gave similar results. There was no difference in the incidence of macrovascular complications, but there was a tendency for fewer myocardial infarctions in the intensive therapy group.
Figure 23-3. The pathogenesis of type 2 diabetes mellitus in obese elderly and lean elderly.
Hypoglycemia in the elderly is associated with important sequelae. Sulfonylureas and insulin should not be withheld for fear of hypoglycemia, but patients need to be monitored carefully. Elderly diabetic patients have an impaired counterregulatory response to hypoglycemia. More importantly, the ability to sense hypoglycemia declines, as does the ability to take corrective action. Coupled with the diminished cortical reserve due to the higher prevalence of age-associated conditions such as stroke, lacunes, amyloid angiopathy, and Alzheimer's disease, the older brain is less able to fully recover from hypoglycemic insult.
A reasonable treatment goal in the elderly patient with diabetes mellitus is to maintain the fasting blood glucose below 150 mg/dL (8.3 mmol/L) and the postprandial blood glucose below 220 mg/dL (12.2 mmol/L). Achieving this goal is often difficult and complicated by other medications commonly prescribed for the elderly, eg, thiazide diuretics, phenytoin, and glucocorticoids, which have hyperglycemic effects. Therapy should decrease hyperglycemic symptoms and prevent infections and the potential progression to nonketotic hyperosmolar coma.
Similar to the strategy used in younger patients (Chapter 17), initial therapy should include dietary manipulation, weight reduction for the overweight patient, and an exercise program tailored to the individual's capabilities. If mild to moderate hyperglycemia persists (fasting blood glucose 150-300 mg/dL [8.3-16.7 mmol/L]), an oral hypoglycemic agent should be tried. Chlorpropamide should be avoided because of its long half-life and its propensity to induce both hyponatremia and hypoglycemia. Because of their convenience and potency, second-generation sulfonylureas such as glipizide and glyburide are often used; these drugs increase insulin secretion and the number of insulin receptors and reduce hepatic glucose production. Both have been shown to be well tolerated in short-term trials. Glipizide, which has a shorter half-life
than glyburide, is less likely to cause prolonged hypoglycemia in the elderly, which is poorly tolerated. Glimepiride is approved for use with insulin. It has a rapid onset of action and a more prolonged duration of action. Meglitinides are nonsulfonylurea agents that also increase insulin secretion and may be useful in patients with sulfonamide allergy. However, because of their short half-life, hypoglycemia is less common, but they must be given before each meal. Biguanides (eg, metformin) primarily reduce hepatic glucose production and do not have an effect on insulin secretion. In addition, metformin may decrease peripheral insulin resistance and improve the lipoprotein profile. However, metformin should not be used in patients with renal insufficiency (plasma creatinine ą 1.5 mg/dL [132 ľmol/L] for men, ≥ 1.4 mg/dL [124 ľmol/L] for women), thereby making it an undesirable choice in the elderly. Hypoglycemia is not common. The improvement in glucose control is similar to that achieved with sulfonylureas, but combination therapy with a sulfonylurea may improve glucose control. The side effects of diarrhea, nausea, and anorexia often limit use in the elderly. Alpha-glucosidase inhibitors (acarbose and miglitol) block intestinal α-glucosidase, resulting in a decrease in postprandial hyperglycemia. These agents can be used alone or in combination with sulfonylureas. However, when used alone they are approximately half as efficacious as sulfonylureas in reducing glucose levels. Side effects in the elderly include abdominal discomfort and flatulence. Thiazolidinediones reduce hepatic glucose production and increase peripheral glucose uptake. Data on pioglitazone and rosiglitazone in the elderly are limited. However, since thiazolidinediones can cause fluid retention and exacerbate congestive heart failure, other oral agents are preferable. In summary, there are now several oral agents that can be used alone or in combination in the elderly, but few data are available for these agents in this age group. Side effects, including hypoglycemia, and cost need to be factored into the choice of therapy.
Figure 23-4. Age-specific prevalence of diagnosed diabetes, by race and sex, United States, 1994-1996. (Source: Centers for Disease Control and Prevention, National Center for Health Statistics, Division of Health Interview Statistics, data from the National Health Interview Survey. United States Bureau of the Census, census of the population and population estimates. Data computed by the Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention.)
If the fasting blood glucose remains above 150 mg/dL (8.3 mmol/L) on diet, exercise, and oral agent therapy, insulin should be started in combination with oral agents or by itself. If given alone, the usual initial dose is 15-30 units of NPH (neutral protamine Hagedorn, or isophane insulin) or another intermediate-acting insulin. One daily injection is usually sufficient. Since elderly patients often lack symptoms of hypoglycemia, the fasting, postprandial, and bedtime blood glucose levels must be checked initially even if symptoms are absent. Finally, as in younger patients, it is important to control other adverse factors such as hypertension and smoking, which can contribute to vascular complications associated with diabetes. In addition, the ADA recommends aspirin therapy (81-325 mg/d) for primary prevention in high-risk patients and for secondary prevention in patients with macrovascular disease (eg, history of myocardial infarction, angina, stroke, transient ischemic attack, or peripheral vascular disease). A comprehensive eye examination with yearly follow-ups and preventive foot care are also recommended.
Diabetic ketoacidosis is rarely seen in the elderly. It should be treated cautiously, following a strategy similar to one used in younger patients (Chapter 17 and 24), with particular attention to the correction of electrolytes and water balance.
NONKETOTIC HYPEROSMOLAR COMA
Nonketotic hyperosmolar coma, also known as nonketotic hypertonicity, occurs almost exclusively in the elderly. Predisposing factors include inadequate insulin secretion in response to hyperglycemia and a reduction in the peripheral effectiveness of insulin. Both factors lead to a progressive increase in serum glucose concentrations. The age-related increased renal threshold prevents osmotic diuresis until significant hyperglycemia is present, while an age-related decline in thirst predisposes to dehydration. Blood glucose concentrations
often exceed 1000 mg/dL (55.5 mmol/L) and are coupled with marked elevation of plasma osmolality without ketosis.
This syndrome is frequently seen in elderly patients with type 2 diabetes who are in nursing homes and have limited access to water. However, one-third of such patients have no previous history of diabetes. The most common precipitating event is infection (32-60% of cases); the most common infection is pneumonia. Medications (eg, thiazides, furosemide, phenytoin, glucocorticoids) or other acute medical illnesses can also precipitate this condition. Patients present with an acute confusional state, lethargy, weakness, and occasionally coma. Neurologic findings can be generalized or focal and can mimic an acute cerebrovascular event. Marked volume depletion, orthostatic hypotension, and prerenal azotemia are also usually present.
The average extracellular fluid volume deficit is 9 L. It should be replaced initially with normal saline, especially when significant orthostatic hypotension is present. After 1-3 L of isotonic saline has been administered, fluids can be changed to half-normal (0.45%) saline. Half of the fluid and ion deficits should be replaced in the first 24 hours and the remainder over the next 48 hours.
Intravenous insulin in small doses (10-15 units) should be given initially, followed by a drip infusion of 1-3 units/h. Insulin therapy should not be used in lieu of fluids because it will exacerbate intravascular fluid depletion and further compromise renal function as it shifts glucose intracellularly. Potassium deficits should be corrected when the patient is producing urine. Possible precipitating events—such as acute myocardial infarction, pneumonia, or administration of a medication—must be investigated and treated. Although metabolic abnormalities may improve in 1-2 days, mental status deterioration and confusion may persist for a week or more. Over one-third of patients can be discharged without insulin treatment, but they are at significant risk for recurrence and should be monitored carefully (Chapter 17 and 24).
OSTEOPOROSIS & CALCIUM HOMEOSTASIS
Despite the high prevalence, severe morbidity, and expense of osteoporosis, until recently most of our knowledge was derived from studies of perimenopausal women. Yet it is the older woman who typically experiences the ravages of the disease. Twenty-five percent of women have vertebral fractures by age 70; by age 80, the figure is closer to 50%. Over 90% of hip fractures occur in patients over age 70, and by age 90, one woman in three will have sustained such a fracture. Hip fractures are associated with significant morbidity, an increased risk of institutionalization, and an up to 20% increase in mortality rates. Despite the significant differences between perimenopausal and older women, diagnostic and therapeutic approaches for older women are derived largely from studies of perimenopausal or newly postmenopausal women. The relevance of such studies for older women has only recently been questioned.
The definition of osteoporosis has changed over the years. In 1991, a consensus development conference defined osteoporosis as “a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk.” The World Health Organization issued diagnostic criteria for postmenopausal women based on measurements of bone mineral density or bone mineral content. Osteoporosis is defined as a value of bone mineral density -2.5 SD and below the young adult mean value (Table 23-2). This permits numerical standardization of the definition and establishes criteria for treatment before a fracture takes place.
Factors Affecting Bone Physiology
There are significant physiologic differences between perimenopausal and older women with respect to maintenance of skeletal integrity. While calcium intake is often inadequate in both age groups, calcium absorption declines with age despite an age-related increase in serum levels of parathyroid hormone (PTH). This increase is not due solely to a decrease in renal clearance but may represent secondary hyperparathyroidism from vitamin D insufficiency. When PTH levels are assessed in elderly subjects with normal vitamin D levels, PTH levels are significantly lower than in vitamin D-deficient patients (Figure 23-5).
- VITAMIN D
Vitamin D deficiency is common in the elderly, and vitamin D metabolism changes with age. Up to 15% of healthy elderly residents of communities in the sunny southwestern USA have frank vitamin D deficiency; still more have subclinical vitamin D deficiency; and up to 50% of elderly nursing home residents are deficient in vitamin D. This occurs because elderly individuals have decreased sun exposure and an impaired ability to
form vitamin D precursors in the skin, a decreased dietary intake of vitamin D, and (possibly) an age-related decline in vitamin D receptors in the duodenum. In addition, the ability to convert vitamin D to its active moiety (1,25[OH]2-D3) is impaired with age. Finally, certain vitamin D receptor alleles have been associated with lower bone density and bone loss in some populations, though further investigations of vitamin D metabolism are needed in the elderly in the United States.
Table 23-2. World Health Organization diagnostic criteria for osteoporosis.1
- BONE LOSS AND ARCHITECTURAL CHANGES
The rate of bone loss also differs between perimenopausal and older women. Cortical and trabecular bone are lost rapidly at menopause. Older longitudinal studies suggested that bone loss ceased or slowed in older women. However, longitudinal studies suggest that older women lose an average of 0.7-1% per year at the hip, and femoral bone loss increases with age (Figure 23-6). Vertebral bone density changes assessed by anteroposterior measurements can give a misleading assessment of bone mass as a consequence of nonspecific calcifications from osteoarthritis, sclerosis, aortic calcifications, and osteophytes that interfere with and falsely elevate the measurement. Therefore, measurement of femoral bone density is more reliable in the elderly.
In addition, there are changes in bone geometry; cortical bone remodeling in older women is insufficient to compensate for the loss of bone mineral content (Figure 23-7). There are also qualitative changes in trabecular bone, since an age-related reduction in trabecular bone jeopardizes plate integrity or “connectivity”; trabecular plates not only become perforated and disconnected, but with aging they continue to thin, causing further loss of bone strength and compromising the bone's ability to regain structural integrity with conventional therapy (Figure 23-8).
- RISK FACTORS
Risk factors for fracture differ in perimenopausal and older women. By age 70, approximately 80% of women have a hip bone density that is osteopenic or osteoporotic, compared with 40% of women in their fifties (Figure 23-9). However, there is significant overlap in bone density between older patients who fall and fracture and those who fall and do not fracture (Figure 23-10). Falling is often cited as a major risk factor for hip fracture in older women. Although more than one-third of elderly women fall annually, however, fewer than 5% of falls result in fracture. A fall to the side, a low hip bone mineral density, low body mass index (lean body habitus), and high fall energy have been shown to be significant independent risk factors for hip fracture in community-dwelling elderly (Table 23-3). In nursing home subjects, a fall to the side, low hip bone mineral density, and impaired mobility were independent risk factors. Other factors, including a maternal history of hip fracture, previous hyperthyroidism, inability to rise from a chair, poor depth perception, poor contrast vision, and use of anticonvulsants or long-acting benzodiazepines are also associated with hip fractures in elderly women. Furthermore, with multiple risk factors, the risk of hip fracture increases significantly.
Screening older patients by obtaining a bone mineral density measurement is a comfortable, painless, noninvasive, rapid technique for determining an individual's bone mass and relative fracture risk. In general, the relative risk of spine or hip fracture roughly doubles for every standard deviation decrease in bone mineral density below the mean. Patients may remain dressed and lie on a padded table. Although several methods are available, currently the best technique uses dual-energy x-ray absorptiometry (DXA) of the hip or spine (Figures 23-11 and 23-12). The National Osteoporosis Foundation guidelines suggest obtaining a bone mass assessment in all women age 65 or older regardless of risk factors. For most elderly women, the hip is the single most useful measurement because nonspecific calcifications can lead to falsely elevated measurements in the posteroanterior view of spine.
Similar to the evaluation in a younger individual who presents with bone loss or a fracture, the workup
in an older patient can be designed to exclude secondary causes of osteoporosis. Hyperthyroidism and hyperparathyroidism are both more common in older women, can cause bone loss, and can be clinically silent in older individuals. Because 10% of women over age 65 are receiving thyroid hormone replacement therapy and since thyroid hormone overreplacement results in bone loss in postmenopausal women, true physiologic replacement with a normal serum TSH (if possible) should be the goal of treatment. Osteomalacia may present as nonspecific muscle or skeletal discomfort and is more common in the elderly. In addition, metastatic carcinoma, multiple myeloma, hepatic and renal disease, and malabsorption (especially secondary to gastrectomy)
should be excluded. Glucocorticoid use and antiseizure medications also can cause significant bone loss in the elderly. Biochemical markers of bone turnover reflect bone formation and resorption. Although these markers are associated with the rate of bone turnover even in elderly women, they cannot be used in lieu of a bone mineral density measurement to assess bone mass. Because factors outside the skeleton contribute to fracture risk in the elderly, however, the search for correctable factors must extend beyond those that affect bone density. Particular attention should be devoted to the patient's local environment and medication use.
Figure 23-5. Relationship between serum 25OHD and PTH measured with the Allegro assay (top) and with the CAP assay (bottom).On both figures, the gray area represents the above-normal PTH values with a reference range obtained in the entire group of 280 subjects, whereas the hatched area represents the additional zone of high PTH values with a reference range obtained in the 113 subjects with a serum 25OHD level above 30 nmol/L. The horizontal line is the low level of the reference range (subjects with 25OHD > 30 nmol/L). (Reproduced with permission from Souberbielle J-C et al: Vitamin D status and redefining serum parathyroid hormone reference range in the elderly. J Clin Endocrinol Metab 2001;86:3086. Copyright Š 2001 by The Endocrine Society.)
Figure 23-6. Longitudinal annual percentage change in bone mineral density (BMD) (g/cm2, mean ą standard error of the mean) of the total hip, femoral neck, trochanter, intertrochanter, and spine in 85 healthy women over age 65 (mean age 77 years) followed for 1 year. (*, p< 0.05 difference from zero.) (Modified, with permission, from Greenspan SL et al: Femoral bone loss progresses with age: A longitudinal study in women over age 65. J Bone Min Res 1994;9:1959.)
Figure 23-7. Schematic representation of cortical bone remodeling with age in males and females. Note that with age-related bone loss, bone is remodeled in men to increase its diameter and partially offset the loss of strength. In women, bone diameter changes little with age, so that bone strength decreases proportionately more than in men. (Reproduced, with permission, from Ruff CB, Hayes WC: Sex differences in age-related remodeling of the femur and tibia. J Orthop Res 1988;6:886.)
Figure 23-8. Possible effects of osteoporotic treatment regimens on trabecular bone. Left panel: Normal trabecular bone mass and architecture. Treatment resulting in anabolic effects on bone volume may restore normal bone volume and architecture in thin trabeculae (A, B). If trabecular integrity is disrupted before treatment, similar effects on bone volume may not reverse architectural abnormalities (C, D), particularly if treatment impairs the repair of microfractures (E, F). (Modified and reproduced, with permission, from Kanis JA: Treatment of osteoporotic fracture. Lancet 1984;1:27.)
Older patients presenting with skeletal discomfort should be evaluated by radiography to rule out a fracture. Vertebral osteoporosis usually presents with anterior wedging, involvement of more than one vertebra, prominent vertebral trabeculae, and vertebral deformities usually occurring below T6 (Figure 23-13). Worrisome signs suggesting that skeletal involvement is not due to osteoporosis alone include nerve root compression, posterior wedging, isolated vertebral involvement (especially above T4), and pedicle destruction. Furthermore,
older individuals may complain of persistent groin pain with weight-bearing, while plain radiographs of the hip reveal no fracture. A bone scan may be necessary to confirm the diagnosis of hip fracture.
Figure 23-9. Prevalence of low femur bone mineral density (BMD) by age for non-Hispanic white women: light color, osteopenia; dark color, osteoporosis. (Source: CDC/NCHS III, phase 1, 1988-91.)
Because the factors that affect bone physiology—the rate of bone loss, the structure of remaining bone, and the risk of fracture—are substantially different in perimenopausal and elderly women, interventions appropriate for perimenopausal women may be inappropriate for older women. Studies of older individuals that use bone density—or preferably fracture—as an end point provide the best data.
Figure 23-10. Femoral neck bone mineral density (BMD) (g/cm2) versus age (years) in fallers with and without hip fracture (Fx). The lines represent 2 SD less than peak bone mass (theoretical fracture threshold) for women (dots and lower dashed line) and men (boxes and upper dashed line). Mean (ą SD) femoral neck peak bone mass for women, 0.895 (ą 0.100) and for men, 0.979 (ą 0.110) g/cm2. (Reproduced, with permission, from Greenspan SL et al: Fall severity and bone mineral density as risk factors for hip fractures in ambulatory elderly. JAMA 1994;271:128.)
Controversy surrounds the use of calcium supplementation in perimenopausal women, and few data are available regarding its use in older women. Theoretically, calcium supplementation seems appropriate because calcium intake in the elderly is low and the ability to adapt to a low-calcium diet declines with age. The National Academy of Sciences recommends 1200 mg per day of elemental calcium in divided doses. A reduction in hip fractures and improvement in bone density has been demonstrated in very elderly women (mean age 84) treated with vitamin D, 800 IU, and calcium, 1200 mg daily. Calcium carbonate supplements should be given in divided doses with meals to improve absorption
in the elderly, who may suffer from achlorhydria. Calcium citrate can be used as an alternative in such patients. A potential problem with prescribing high doses of calcium in the elderly includes inducing or exacerbating constipation. In addition, since compliance with other drug regimens decreases as the number of drugs increases, calcium tablets may be taken at the therapeutic expense of more important medications. Finally, because supplementary calcium does interfere with absorption of zinc, elderly patients receiving calcium supplementation should be encouraged to take a multivitamin containing zinc. Calcium absorption is not impaired by psyllium.
Table 23-3. Multiple logistic regression of factors associated with hip fracture in ambulatory elderly individuals.1
- VITAMIN D
There are few data to support the use of vitamin D or its metabolites in the treatment of osteoporosis, and results are equivocal. There is a small therapeutic ratio for vitamin D; toxicity from hypercalcemia can occur with doses as low as 50 ľg (2000 IU), especially in individuals who are also taking a thiazide diuretic and calcium supplementation. However, because vitamin D deficiency is common in the elderly and vitamin D is needed for calcium absorption and mineralization of bone and also improves muscle strength, a single daily multivitamin which contains 400 IU is beneficial and will provide a normal vitamin D level even in institutionalized elderly persons. The current recommendation from the National Academy of Sciences is 400-800 IU/d (10-20 ľg/d). Clinical trials utilizing calcitriol (1,25-dihydroxy vitamin D3) as a therapeutic option for osteoporosis have reported conflicting results, though one trial found a threefold reduction in
vertebral compression fractures. The potential for complications such as hypercalcemia, nephrolithiasis, and nephrocalcinosis are unknown, and this therapy is currently still under investigation.
Figure 23-11. This patient has a total hip bone mineral density (BMD) of 0.330 g/cm2 (black circle on the reference database graph) as measured by dual-energy x-ray absorptiometry, a femoral neck T score of -4.69 and a total hip T score of -5.02. The reference database graph displays age- and sex-matched mean BMD levels ą 2 SD (shaded areas) derived from the third National Health and Nutrition Examination Survey. T score indicates the difference in SD between the subject's BMD and the predicted sex-matched mean peak young adult BMD; Z score, the difference in SD between the subject's BMD and the sex- and age-matched mean BMD; and % of mean, the subject's BMD as a percentage of the mean peak young adult BMD- or age-matched BMD level. (Adapted from bone densitometry report, QDR-4500C bone densitometer, Hologic Inc, Waltham, Massachusetts.)
Figure 23-12. This patient has a lumbar spine (L1-L4) bone mineral density (BMD) of 0.410 g/cm2 (cross on the reference database graph) measured by dual-energy x-ray absorptiometry and a T score of -5.79. The reference database graph displays age-and sex-matched mean BMD levels ą 2 SDs (shaded areas) derived from a normative database from the manufacturer, Hologic Inc, Waltham, Massachusetts. T score indicates the difference in SD between the subject's BMD and the predicted sex-matched mean peak young adult BMD; Z score, the difference in SD between the subject's BMD and the sex- and age-matched BMD level; and % of mean, the subject's BMD as a percentage of the mean peak young adult BMD- or age-matched BMD level. (Adapted from bone densitometry report, QDR-4500C bone densitometer; Hologic Inc, Waltham, Massachusetts.)
Figure 23-13. Lateral thoracic radiograph demonstrating a thoracic anterior wedge fracture. (Reproduced, with permission, from Clinical Crossroads: A 73-year-old woman with osteoporosis. JAMA 1999;281:1531.)
Although the rationale for exercise therapy is sound, few data are available on results of exercise in elderly women. One study prescribed exercise for older women and found that forearm bone mineral content increased in those who continued exercising during a 3-year trial. Middle-aged women (mean age 60) participating in high-intensity strength training for 1 year had improvements in femoral bone mass, muscle strength, balance, and activity level compared with controls. Walking—generally 30 minutes three times a week—is often suggested for frail individuals.
- ESTROGEN AND SELECTIVE ESTROGEN RECEPTOR MODULATORS
There is considerable evidence that estrogen therapy, if initiated at menopause, slows bone loss, temporarily increases bone mass, and may prevent osteoporotic vertebral and hip fractures. If therapy is continued, its efficacy is sustained at least until age 70. In addition, some studies have shown that estrogen will increase femoral
bone mass. Fewer data are available about elderly persons taking newly prescribed estrogen. Four studies have reported a positive effect of estrogen on bone mass in older women. The observational study of osteoporotic fractures noted a 50% reduction of hip fractures in older women who were currently taking estrogens and had been doing so for a mean period of 14.5 years. Administration of conjugated estrogens at a dose of 0.625 mg daily (or the equivalent synthetic estrogen dose) has been the standard recommendation to maintain bone mass. However, in older women, doses as low as 0.3 mg/d may be beneficial to skeletal health while minimizing adverse effects such as mastalgia or the return of uterine bleeding.
For women with an intact uterus, combined cyclic regimens with estrogen and progesterone may provoke return of menses and are less well tolerated. Despite the need for gynecologic surveillance and possible endometrial sampling to prevent uterine cancer, older women are more tolerant of combined continuous therapy regimens with estrogen and progesterone, which generally provide an atrophic endometrium within 1 year. Similar to younger women, older women receiving estrogen therapy require annual mammograms (Chapter 13).
Estrogen's protective effect against cardiovascular disease is in doubt. There are few data to support the suggestion that a cardiovascular benefit will accrue when estrogen is newly prescribed to elderly women, in whom the prevalence of heart disease is already high. Moreover, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI) raised doubts about the cardiovascular benefit to women with established heart disease. And furthermore, because of the possible increased relative risk of breast cancer in older women who have taken estrogen for more than 5 years, physicians must assess all the individual risks and benefits for each patient (see Chapter 13).
Selective estrogen receptor modulators (SERMs) have estrogen agonist and antagonist actions. Raloxifene has been approved for the prevention and treatment of postmenopausal osteoporosis. Although improvements in bone mineral density are less with raloxifene than estrogen replacement therapy, studies demonstrate a reduction of approximately 50% in vertebral fractures with no mastalgia, vaginal bleeding, or increased endometrial thickness. Early studies demonstrated a reduction in cholesterol and protection against breast cancer. Raloxifene has not been shown to reduce nonvertebral or hip fractures.
- OTHER THERAPEUTIC OPTIONS
Bisphosphonates—nonhormonal agents that inhibit bone resorption—effectively prevent osteoporosis. The aminobisphosphonate alendronate has been shown to increase bone mass at the spine (10%) and hip (6-8%) over 3 years in prospective clinical trials in postmenopausal women. Fractures of the spine, forearm, and hip were reduced by approximately 50%. Improvements have also been demonstrated in older women residing in long-term care facilities. Risedronate, another bisphosphonate, has been shown to improve bone mass and reduce vertebral and hip fractures. When taken properly, these medications are well-tolerated—an important factor in choosing therapeutic alternatives for the elderly. Furthermore, alendronate and risedronate can be administered once per week. Prospective studies with etidronate showed a benefit for the spine, but results were not consistent for the hip. Although calcitonin is an approved therapy for osteoporosis, few data are available about its effect on the incidence of fractures. It is expensive and when given by injection is poorly tolerated by the elderly. Nasal calcitonin has been shown to reduce fractures of the spine—but not of the hip—with no improvement in hip bone density. Fluoride therapy causes significant toxicity in one-third of patients and has been associated with an increase in nonvertebral fractures. Although thiazide diuretics have been associated with decreased hip fracture risk in several cross-sectional epidemiologic studies, the results are inconsistent, and the optimal dose and duration are unclear. However, a slight increase in both falls and fractures was noted in the only randomized study of thiazide use, the SHEP trial for hypertension in the elderly. For glucocorticoid-induced bone loss, alendronate and risedronate are the only approved bisphosphonates, but other agents are under investigation.
Parathyroid hormone (1-34), the first anabolic agent, has been shown to significantly increase bone density (9.7% for spine bone density in 18 months) and reduce vertebral and nonvertebral fractures in postmenopausal osteoporotic women. This is given as a subcutaneous daily injection and can be combined with antiresorptive agents. Vertebroplasty and kyphoplasty are interventions in which polymethylmethacrylate (vertebroplasty) or polymethylmethacrylate in a balloon (kyphoplasty) are placed in compressed vertebrae for patients with intractable pain from vertebral fractures. There are no controlled trials with these interventions, and it is not known if the procedures will strengthen or weaken adjacent vertebrae.
Summary of Management Recommendations
In summary, there is ample reason to question the validity of extrapolating data from studies of perimenopausal women when formulating a treatment plan for older women. However, given the prevalence of the problem, it is reasonable to recommend an adequate
daily intake of vitamin D (10 ľg, or 400 IU) contained in one multivitamin tablet), an adequate daily intake of calcium (totaling 1200 mg), and judicious participation in an individually tailored exercise program. The use of bisphosphonates, estrogen replacement therapy, SERMs, parathyroid hormone, or other treatment needs to be individually considered.
Perhaps more importantly, the risk of falls should be addressed. The risk can be reduced by reviewing medications (including nonprescription agents) and discontinuing (when possible) those with adverse effects on cognition, balance, or blood pressure. Common offenders include long-acting benzodiazepines, tricyclic antidepressants, antipsychotics, antihypertensives, and agents with anticholinergic side effects. It is also important to correct reversible sensory losses and medical conditions and to educate patients about hazards in their environment, such as throw rugs, extension cords, and poorly illuminated stairways, that could lead to falls and fractures. For patients with gait disorders, physical therapy should be considered.
Patients who have recently sustained a hip fracture should receive the same evaluation and consideration as those without a fracture. Because there is a significant overlap in bone density measurements between those that fracture and those that do not (Figure 23-10), a hip fracture should not serve as a reason to omit evaluation or treatment (see also Chapter 8).
The prevalence of hyperparathyroidism increases with age. While its incidence is less than 10 per 100,000 in women under age 40, the incidence increases to 190 per 100,000 in women over age 60. As a result, over half of all cases of hyperparathyroidism occur in individuals over the age of 65. Most cases are mild. Detection is by routine screening of serum calcium, and few or no symptoms are present. However, with relatively minor elevations of serum calcium (up to 11-12 mg/dL [2.8-3 mmol/L]), some elderly subjects may experience weakness, fatigue, depression, and confusion. Failure to thrive and constipation are commonly seen; renal, gastrointestinal, and skeletal complications occur less often. Other causes of hypercalcemia in the elderly—especially multiple myeloma, malignancy, vitamin D intoxication, and thiazide diuretics—must be considered in the differential diagnosis.
For symptomatic patients with serum calcium levels above 12 mg/dL (3 mmol/L) and elevated serum parathyroid hormone levels, parathyroidectomy is well tolerated and is the treatment of choice. For those with more modest elevations, treatment recommendations are less simply stated because it is difficult to differentiate symptoms and signs due to the disease from those seen in older individuals without hyperparathyroidism. Moreover, asymptomatic individuals—especially those with levels of serum calcium under 11 mg/dL (2.8 mmol/L)—have been known to remain asymptomatic for over a decade. Until more data become available, the decision to treat asymptomatic individuals surgically should be made on an individual basis.
In patients whose symptoms may be due to hyperparathyroidism, it is worthwhile to observe the response to medical therapy before considering surgery. In women, a course of estrogen may be effective. Ethinyl estradiol (30-50 ľg/d) or conjugated estrogens (0.625-1.25 mg/d) reduce serum calcium by an average of 0.8 mg/dL (0.2 mmol/L), diminish urinary calcium excretion, and antagonize the skeletal effect of PTH. In men and in women with higher elevations of serum calcium, oral phosphates can be used, but they are less well tolerated in the elderly because of their gastrointestinal side effects and the potential for ectopic calcification. Furosemide is a less satisfactory alternative in frail elderly patients because it increases the risk of dehydration and resultant hypercalcemia. On the other hand, parathyroidectomy procedures in elderly patients have similar outcomes compared with younger patients with respect to cure rate, morbidity, mortality, and patient satisfaction. A more recent option for geriatric patients includes a limited or targeted parathyroidectomy and uses preoperative localization and intraoperative measurement of parathyroid hormone rather than the conventional approach of visualization of all glands. This not only improves the success rate but simplifies the surgical procedure as well.
CHANGES IN WATER BALANCE
With age, major changes in renal function and homeostatic mechanisms result in significant changes in water balance. Renal blood flow, cortical mass, the number of glomeruli, and tubular function all decline with age, though medullary mass is preserved. Clinically, however, the most relevant change is the age-related decline in creatinine clearance, which is largely due to relative hypertension in the elderly. Because of the decrease in muscle mass associated with aging, however, serum creatinine levels are unchanged and may not accurately reflect the extent of renal functional impairment.
Extrarenal modulators of water balance also change significantly with age. Although there are no changes
in the basal level, half-life, volume of distribution, or metabolic clearance of vasopressin, the stimulated responses of vasopressin are significantly altered. Hyperosmolar stimuli increase serum vasopressin levels in older subjects to five times those achieved in younger subjects. On the other hand, the normal vasopressin increase observed in response to overnight dehydration and postural change is impaired in the elderly. Additionally, basal and stimulated levels of serum renin and aldosterone decline with age. In contrast, basal levels of atrial natriuretic factor are three times higher in healthy elderly individuals than in young controls. These elevated levels of atrial natriuretic factor may help identify patients at risk for the development of congestive heart failure. Finally, the thirst sensation appears to be somewhat impaired in healthy elderly individuals and is more impaired in those who are frail.
In addition to physiologic changes, many diseases and drugs further increase the vulnerability of the elderly to changes in water balance. These include kidney disease, hypertension, and congestive heart failure as well as medications that alter water balance (eg, narcotics, diuretics, lithium, chlorpropamide, carbamazepine, amphotericin B, intravenous hypotonic fluids, and hypertonic contrast agents).
The incidence of hypernatremia in elderly patients admitted to the hospital ranges from 1% to 3% and is higher for institutionalized elderly patients. Signs and symptoms are usually nonspecific, eg, lethargy, weakness, confusion, depression, and failure to thrive. The cause is usually multifactorial, including impaired thirst mechanism, renal disease, sedative-induced confusion, use of restraints, reduced access to free water intake, excess water loss due to fever, and decreased response to vasopressin.
As in younger patients, initial therapy involves correcting the volume deficit with isotonic saline and then correcting the water deficit with half-normal (0.45%) saline. Roughly 30% of the deficit should be corrected within 24 hours and the remainder within the next 24-48 hours.
The prevalence of hyponatremia is approximately 2.5% in the general hospital setting—higher in geriatric units—and rises to 25% in nursing home settings. Presenting symptoms and signs are often nonspecific and include lethargy, weakness, and confusion. The mechanisms predisposing to hyponatremia include the exuberant response of vasopressin to osmolar stimuli, a decreased ability to excrete a water load, and the sodium-wasting tendency of the older kidney. Furthermore, elderly patients often use medications and have diseases that impair free water excretion. Common hyponatremic syndromes in the elderly include the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and thiazide-induced hyponatremia. In the geriatric rehabilitation hospital, approximately half of patients with hyponatremia have SIADH. Furthermore, hyponatremia has been reported with selective serotonin reuptake inhibitors in the elderly.
The treatment of hyponatremia in the elderly does not differ from that in younger patients (Chapter 5 and Chapter 24).
Hyporeninemic hypoaldosteronism usually occurs in elderly patients with diabetes and mild renal insufficiency. Patients are usually asymptomatic, and hyperkalemia and acidosis are found on routine screening. On the other hand, symptoms of hyperkalemia (eg, heart block) may be provoked by administration of a beta-adrenergic blocking agent, which further compromises extrarenal regulation of potassium homeostasis. After other causes of persistent hyperkalemia are ruled out, patients respond well to administration of small doses of fludrocortisone (0.05 mg/d) or furosemide combined with restriction of potassium.
GLUCOCORTICOIDS & STRESS
Cortisol levels increase 20-50% with age. There is an increase in the nocturnal level of cortisol, an age-related morning increase in cortisol in women (not men), and an advancement in the circadian rhythm (Figure 23-14.
In healthy elderly individuals, dynamic testing of the hypothalamic-pituitary-adrenal axis is normal; expected responses to insulin-induced hypoglycemia, metyrapone, dexamethasone, ACTH, and CRH are preserved (Figure 23-15).
Figure 23-14. Upper panels: Age-related changes in 24-hour mean cortisol levels in men and women. The coefficient of correlation for the linear regression was r = 0.29 in men (P < .002) and r = 0.50 in women (P < .0001). Sex differences in the slope of the regression failed to reach significance. Lower panels: Mean 24-hour cortisol profiles in men and women 50 years of age and older (n = 25 and n = 22, respectively; blue lines) compared with those in 20- to 29-year-old subjects (n = 29 and n = 20, respectively; gray lines). The shading at each time point represents the SEM. (Reproduced, with permission, by van Cauter E, Leproult R, Kupfer DJ: Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 1996;81:2468. Copyright Š 1996 by The Endocrine Society.)
DISORDERS OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
- Abnormal Response to Stress
In contrast to the normal responses in the elderly to dynamic testing of the hypothalamic-pituitary-adrenal axis, increased stress elicits abnormal responses. For example, although serum cortisol levels increase to the same extent in young and old patients undergoing elective surgery, the increase may be protracted in the elderly. Patients with diabetes mellitus and hypertension have also been found to have an exaggerated and prolonged response to CRH stimulation. Older patients with Alzheimer's disease may also have a delayed and prolonged response to CRH stimulation. It is not known if these elevated cortisol levels contribute to the increased hypertension, glucose intolerance, muscle atrophy, and impaired immune function observed in the elderly. However, an elevated urinary cortisol level is an independent predictor of osteoporotic fractures in the elderly.
- Adrenal Hypersecretion
While adrenal hypersecretion (Cushing's syndrome) is uncommon in the elderly, it is easily overlooked because it mimics normal aging processes. Signs such as hypertension, glucose intolerance, weight gain, and osteoporosis are less specific in elderly than in younger patients, but as in younger patients the diagnosis is
established or excluded using the usual criteria (Chapter 9).
Figure 23-15. Mean values for groups A, B, and C of plasma ACTH (upper panel), F or cortisol (middle panel), and DHEA (lower panel) before and up to 120 minutes after bolus intravenous injection of ovine CRH (1 ľg/kg). Group A, 21-49 years, mean age 35.2 years, n = 19. Group B, 50-69 years, mean age 60.7 years, n = 15. Group C, 70-86 years, mean age 77.1 years, n = 15. (Reproduced, with permission, from Pavlov EP et al: Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone to ovine corticotropin-releasing hormone in healthy aging men. J Clin Endocrinol Metab 1986;62:767.)
- Adrenal Insufficiency
Symptoms of adrenal insufficiency in younger patients—eg, failure to thrive, weakness, weight loss, confusion, and arthralgias—are common complaints in adrenally intact elderly patients; the most specific sign of adrenal insufficiency in the elderly is hyperpigmentation. The laboratory findings of adrenal insufficiency are similar to those found in younger patients and include azotemia, hypoglycemia, hyponatremia, hyperkalemia, and eosinophilia. Because the metabolic clearance rate of cortisol decreases with age, older patients generally require lower replacement doses of cortisol (Chapter 9).
CHANGES IN REPRODUCTIVE FUNCTION IN MEN
Overall, while sexual activity decreases with age, there are conflicting reports about the physiologic changes in the hypothalamic-pituitary-testicular axis. Longitudinal studies demonstrate an age-related decrease in testosterone and free testosterone and a higher frequency of hypogonadal values (Figures 23-16 and 23-17). Some studies suggest that circulating testosterone and bioavailable testosterone fall with age by 40-65% and are even lower in institutionalized elderly. A decrease in the number or responsiveness of testicular Leydig cells is likely because serum FSH and LH increase with age, and the testosterone response to human chorionic gonadotropin (hCG) decreases. On the other hand, with age there is probably a decrease in the ratio of circulating bioactive to immunoreactive LH. Finally, pituitary changes are suggested by a decreased gonadotropic response to luteinizing hormone-releasing hormone (LHRH) stimulation.
The clinical relevance of these changes is not clear. The correlation between sexual activity and the age-related hormonal changes described is weak. There are decreased concentrations of spermatozoa in the ejaculate of older men, sperm motility and the volume of ejaculate decrease with age, and the proportion of abnormal spermatozoa also increases. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) are steroids of adrenal origin that decrease with age. Levels do not correlate with cognitive function or decline, and DHEA supplementation has not been shown to be beneficial. However, studies in the elderly are ongoing.
Erectile dysfunction (impotence) becomes more prevalent with age, but an endocrinologic cause becomes
less likely. The prevalence of erectile dysfunction in men under age 45 is 5%; the prevalence in men over age 75 is 50%. However, over 90% of men in the latter group have coexistent medical conditions or are taking medications that contribute to the problem. Furthermore, up to 30% of men over age 76 develop erectile dysfunction following prostatectomy, compared with 3-11% in younger age groups. Often there are multiple overlapping causes of erectile dysfunction—psychosocial, neurovascular, metabolic (diabetes mellitus), medication-related, and vascular—in the same individual.
Figure 23-16. Longitudinal effects of aging on date-adjusted testosterone (T) and free testosterone index (free T index). Linear segment plots for total T and free T index versus age are shown for men with T and sex hormone-binding globulin (SHBG) values on at least two visits. Each linear segment has a slope equal to the mean of the individual longitudinal slopes in each decade, and is centered on the median age, for each cohort of men from the second to the ninth decade. Numbers in parentheses represent the number of men in each cohort. With the exception of free T index in the ninth decade, segments show significant downward progression at every age, with no significant change in slopes for T or free T index over the entire age range. (T, testosterone; SHBG, sex hormone binding globulin; T/SHBG, free T index.) (Reproduced, with permission, from Harman SM et al: Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001;86:724. Copyright Š 2001 by The Endocrine Society.)
Figure 23-17. Hypogonadism in aging men. Bar height indicates the percentage of men in each 10-year interval, from the third to the ninth decades, with at least one testosterone (T) value in the hypogonadal range, by the criteria of total T < 11.3 nmol/L (325 ng/dL) (shaded bars), or T/SHBG (free T index) < 0.153 nmol/nmol (striped bars). Numbers above each pair of bars indicate the number of men studied in the corresponding decade. The fraction of men who are hypogonadal increases progressively after age 50 by either criterion. More men are hypogonadal by free T index than by total T after age 50, and there seems to be a progressively greater difference, with increasing age, between the two criteria. (T, testosterone; SHBG, sex hormone binding globulin; T/SHBG, free T index.) (Reproduced, with permission, from Harman SM et al: Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001;86:724. Copyright Š 2001 by The Endocrine Society.)
The evaluation of erectile dysfunction in the elderly is similar to that in younger individuals (Chapter 12), though more emphasis must be placed on the effects of drugs (both prescribed and nonprescribed) and vascular causes, and a search for multiple causative factors should be undertaken.
BENIGN PROSTATIC HYPERPLASIA
Although the pathogenesis of benign prostatic hyperplasia is incompletely understood, testicular androgens are believed to play a permissive role in the development of
prostatic adenomas. This mechanism provides the rationale for the use of antiandrogens in the treatment of benign prostatic hypertrophy. Antiandrogen treatment has been investigated using luteinizing hormone releasing hormone (LHRH) agonists (nafarelin, leuprolide, buserelin), androgen receptor inhibitors (cyproterone acetate, flutamide), and 5α-reductase inhibitors (finasteride). Overall, these agents result in a 25-30% reduction in prostate size, but their effects on the voiding symptoms associated with benign prostatic hypertrophy have been modest, variable, and less immediate and substantial than observed with alpha-adrenergic blockers. For instance, finasteride reduces symptoms by half in only one-third of men, and statistically significant effects in the largest trial occurred only after 11 months. One trial showed that finasteride reduced the incidence of both urinary retention and surgery, but 15 men would need to take finasteride for 4 years to prevent such an event in just one of them. Moreover, each of these agents must be continued indefinitely to maintain prostate size reduction, yet many men may find such therapy difficult and undesirable as well as expensive, and the long-term side effects are largely unknown. The LHRH agonists and cyproterone acetate cause impotence; androgen deprivation therapy results in bone loss; flutamide induces gynecomastia, and one report describes serologic as well as histologic evidence of flutamide-induced hepatotoxicity in a small number of patients. Since finasteride decreases dihydrotestosterone while maintaining the circulating levels of testosterone, undesirable antiandrogenic side effects are lower. Finasteride causes a significant decrease in the level of prostate-specific antigen, a serum marker increasingly used for the clinical detection of prostate adenocarcinoma, the most common cancer in men. Thus, if PSA levels fail to decline in a man compliant with therapy, investigation for prostate cancer should be initiated. Since the effect of finasteride on prostate cancer development and progression is unknown, it is unclear whether any antitumor benefit will mitigate finasteride's interference with the use of PSA as a tumor marker.
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Carbohydrate Intolerance and Diabetes Mellitus
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Osteoporosis and Calcium Homeostasis
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Changes in Water Balance
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Glucocorticoids and Stress
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Reproductive Function in Men
Abbasi AA et al: Low circulating levels of insulin-like growth factors and testosterone in chronically institutionalized elderly men. J Am Geriatr Soc 1993;41:975.
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McConnell JD et al: The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998; 338:557.
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