41: Thyroid, Parathyroid, & Adrenal Gland Disorders

General Principles in Older Adults

Subclinical hypothyroidism affects a relatively large number of older persons. Although a small percentage of these cases will progress to overt clinical hypothyroidism each year, individuals with high levels of antimicrosomal antibodies are at greater risk of decline in thyroid function. Several studies have observed beneficial effects of thyroxine (T₄) therapy in patients with subclinical hypothyroidism; no studies have specifically addressed this question in older patients.

Clinical Findings

Older patients with subclinical hypothyroidism may present with few or no complaints. Studies have demonstrated increased intestinal transit time, increased intraocular pressure, higher low-density lipoprotein-cholesterol levels, an increased risk for atherosclerosis, reduced cognitive function, and changes in cardiac performance and congestive heart failure. Older women with atherosclerosis, and an even higher percentage of those with a history of myocardial infarction, have a higher incidence of subclinical hypothyroidism. Treatment with L-thyroxine compared with placebo results in an overall improvement in general well-being. In addition, noninvasive indexes of myocardial contractility also improved, as did memory, psychomotor speed, and serum cholesterol levels. Subclinical hypothyroidism progresses to frank hypothyroidism in 5% to 8% of affected persons each year, with higher rates in those with high levels of antimicrosomal antibodies.

Treatment

Although some physicians advocate replacement therapy for all persons with subclinical hypothyroidism, many believe that treatment is best reserved for those individuals with thyroid-stimulating hormone (TSH) levels >10 mU/L or for those with serum TSH levels between 5 and 10 mU/L with coexisting high levels of antimicrosomal antibodies. If treatment is not initiated, careful follow-up is essential because a percentage of these individuals will develop hypothyroidism each year. The goal of treatment, when initiated, is to normalize serum TSH values as long as the dose of thyroid hormone that is required produces no unwanted clinical effects. Most experts recommend targeting a normal TSH range in older patients, although it should be noted that serum TSH concentrations increase with age and 1 study examining individuals with “extreme longevity” noted serum TSH to be significantly higher in centenarians, with 7.5 mU/L considered to be the true upper limit of normal for those age 80 years and older.

General Principles in Older Adults

Subclinical hyperthyroidism is a term used to identify individuals with suppressed levels of serum TSH with normal levels of circulating thyroid hormones.

Clinical Findings

Subclinical hyperthyroidism may occur as a consequence of thyroid hormone replacement for hypothyroidism. Although still maintaining circulating levels of T₄ within normal range, these individuals are taking higher doses than necessary to normalize serum TSH. Shorter systolic time intervals, atrial fibrillation, and osteopenia are associated with this entity. Epidemiologic data also suggest that this problem affects 1% to 4% of persons older than age 60 years who are not on thyroid hormone therapy. Unfortunately, there is little in the literature to help determine whether treatment is indicated. Most agree that treatment should be initiated if there are clearly associated symptoms, such as a worsening of cardiovascular function or cardiac arrhythmias, excessive wasting of muscle, anorexia, depression, or significant osteoporosis. Atrial fibrillation has been described in 10% of these patients. As with subclinical hypothyroidism, subclinical hyperthyroidism is also associated with an increased incidence of congestive heart failure in older persons. Patients with subclinical hyperthyroidism are at increased risk of both cardiovascular and all-cause mortality.

Treatment

While all agree that individuals receiving excessive thyroid hormone replacement therapy that suppresses TSH should have their dose of thyroid hormone reduced, it is less clear what to do for individuals with subclinical hyperthyroidism who are not on thyroid hormone. Varied outcomes are reported for affected individuals. Of affected individuals, 47% to 61% have normal serum TSH levels on retesting within 1 year without any intervention, while 1.5% to 13% develop hyperthyroidism. It remains unclear exactly when to treat subclinical hyperthyroidism because therapy has the potential for toxicity and expense, and in some patients the problem may resolve on its own. Treatment is best considered on an individual basis with careful follow-up because hyperthyroidism in older adults often presents in a nonspecific manner, and may lead to a decline in functional capacity before or without more classic signs or symptoms of hyperthyroidism. Treatment of subclinical hyperthyroidism may improve bone mineral density and atrial fibrillation if identified. If treatment is selected, ablation therapy with iodine-131 is the preferred modality.

General Principles in Older Adults

Hypothyroidism is a common disease of older adults, with a reported prevalence of 0.9% to 17.5%. Hypothyroidism in older adults most commonly results from an autoimmune thyroiditis. Prior radioiodine treatment and subtotal thyroidectomy are also potential causes. The risk of hypothyroidism is >50% after the first year of radioiodine treatment, with an additional annual incidence of 2% to 4% each year thereafter. Hypothyroidism may also be the natural end point to previous Graves disease. Medications may also lead to hypothyroidism, particularly in persons with autoimmune thyroiditis. The most common medications associated with hypothyroidism include iodine-containing radiographic contrast agents, lithium, amiodarone, and iodine-containing cough medicines. Hypothyroidism may also result from a secondary cause: either a pituitary or hypothalamic abnormality.

Clinical Findings

Many of the presenting complaints are confused with other age-prevalent disorders. This problem is further compounded by the often insidious onset of illness. Fatigue and weakness are common. Whereas younger patients commonly present with weight gain, cold intolerance, paresthesia, and muscle cramps, older patients may not, or they may have these or other classic symptoms such as constipation without a thyroid disorder. Many persons who are later discovered to be hypothyroid are unable to identify exactly when the symptoms actually began. Neurologic findings may include dementia, ataxia, and carpal tunnel syndrome, and a delay in the relaxation of deep tendon reflexes may not be easily apparent in a person of advancing age. Hypercholesterolemia may be more common in both circumstances as well. For these reasons, the examining physician should maintain a high index of suspicion of hypothyroidism when evaluating any older person, especially women and those with a personal or family history of some form of thyroid disease.

Primary hypothyroidism is associated with an elevated serum TSH concentration. Changes in protein binding may reduce the level of total T₄; triiodothyronine (T₃) may be reduced in persons with significant medical illness or malnutrition. Even measures of free T₄ may be misleading; T₄ may be suppressed in individuals with T₃ toxicosis. For these reasons, an increase in serum TSH remains the best way to detect primary failure of the thyroid gland regardless of age. During the recovery phase after an acute nonthyroidal illness, however, an elevation of serum TSH level may not represent true clinical hypothyroidism; in this case, the serum TSH returns to the range of normal within 4–6 weeks. Although uncommon in older adults, hypothyroidism can be secondary to pituitary or hypothalamic failure, with low serum TSH and T₄ levels. TSH >10, female sex, and positive antithyroid antibody are associated with an increased risk of progression to overt hypothyroidism. In patients with TSH <10, testing for antithyroid antibodies can be helpful and favors the treatment with levothyroxine. TSH screening is indicated in those older patients with cognitive problems, goiter or history of thyroid abnormality, hypercholesterolemia, or family history of thyroid illness.

Differential Diagnosis

Many of the presenting signs and symptoms of hypothyroidism in persons of any age resemble findings common to many other age-prevalent disorders, notably congestive heart failure and unexplained ascites resulting from cardiac or hepatic abnormalities. A thick tongue may result from primary amyloidosis. Anemia may result from vitamin B₁₂, folate, or iron deficiency or volume expansion. Depression may be present, and other alterations in cognition may be caused by medication toxicity or dementia.

Treatment

L-Thyroxine is the preferred medication to treat hypothyroidism. In general, consistent use of one of the brand name preparations is suggested to minimize variability that may occur with generic preparations. It is also easier for the older person to identify medication with a consistent color and shape. Older patients generally require a smaller amount of L-thyroxine to normalize their thyroid status, on average, 110 μg/day. Because of the age-related increase in T₄ half-life, approximately 9 days in persons 80 years of age and older, it will take longer to reach a steady state. A longer time between dose increases is necessary to reduce unwanted side effects.

The commonly used adage of “start low and go slow” should be followed when starting any older patient on thyroid hormone replacement therapy. Because many older patients with hypothyroidism may have underlying cardiovascular disease, therapy should start with 25 μg/day, with gradually increasing increments of 25 μg every 4–6 weeks. Individuals with significant cardiac disease may require dose changes as low as 12.5 μg and should even be started at that dose. Once a dosage of 75 μg/day is achieved without side effects, increments of 12.5 μg are advised. The final dose required is the amount of L-thyroxine that reduces the serum TSH into the range of normal and does not have associated side effects.

A euthyroid state may exacerbate cardiac symptoms in patients with significant coronary artery disease. In this circumstance, the use of a β-adrenergic blocking agent may allow a clinically euthyroid state to be reached without induction of symptoms of myocardial ischemia. Monitoring of TSH is necessary to avoid inducing iatrogenic subclinical hyperthyroidism from excessive doses of replacement thyroid hormone.

Prognosis

With early treatment, return to a normal state of health is expected. Complete response to thyroid treatment, however, may take months, and patients will require replacement therapy with thyroid hormone and periodic monitoring with thyroid function tests for life.

General Principles in Older Adults

Myxedema coma is a serious consequence of untreated or inadequately treated hypothyroidism. Although rare, it almost exclusively occurs in older patients. Coma is seen in the most severe cases; more common features include alteration in cognition, lethargy, seizures, psychotic symptoms, and confusion and disorientation. In most cases, the affected individual has had a precipitating event such as a severe infection, cold exposure, alcoholism, or the use of psychoactive medications, sedatives, or narcotics. Early treatment is essential.

Clinical Findings

A history of increased fatigue and somnolence is common, as is a history of treatment of a thyroid disorder or use of narcotic, sedative, or antipsychotic medication. Infections, particularly pneumonia and urosepsis, are common. Physical examination may demonstrate classic signs and symptoms of hypothyroidism, including dry, scaly skin, bradycardia, and edema. Profound hypothermia, as well as hypoventilation and hypotension, may exist. Headaches, ataxia, nystagmus, psychotic behavior, muscle spasms, and sinus bradycardia may precede the coma. There may also be a pericardial effusion, ileus, megacolon, and easy bruising.

Laboratory findings classically include a markedly elevated serum TSH and reduced total and free serum T₄. Hypoglycemia and hyponatremia are common. Autoimmune deficiency states, including diabetes mellitus and adrenal insufficiency, are sometimes associated with hypothyroidism and other autoimmune disorders. Creatine phosphokinase of muscle origin is often elevated as a result of muscle breakdown. Myocardial infarction can occur in the presence of myxedema coma or even be the precipitating event, and may complicate the initiation of thyroid hormone therapy. In rare circumstances, myoglobinuria and rhabdomyolysis may occur. Arterial blood gases usually demonstrate a decrease in partial pressure of oxygen and an increase in partial pressure of carbon dioxide, indicating acute or impending respiratory failure. Anemia is also a common finding and is often normochromic, normocytic, or macrocytic. Cardiomegaly is often seen on chest x-ray film. Evoked potentials may have abnormal amplitude or latency, and electroencephalogram may demonstrate triphasic waves that disappear with thyroid replacement.

Differential Diagnosis

Included in the differential diagnosis are dementia, sepsis, intracranial bleed or tumor, hepatic encephalopathy, congestive heart failure, and hypothyroidism.

Treatment

In most cases, patients with severe illness and coma are started on thyroid hormone replacement based on clinical suspicion before obtaining confirming laboratory data. When deciding on therapy, the following principles should be considered:

1. Myxedema coma has a very high mortality rate if treatment is delayed or is inadequate.

2. The uncertainty of diagnosis before receiving laboratory results must be balanced with empiric therapy, especially if the patient is later found not to be hypothyroid.

3. Supportive therapy must be provided and includes ventilatory support for respiratory failure, antibiotics for infection as indicated, and management of hypothermia by external rewarming. Hypotension may be treated with fluid replacement, although dopamine infusion might be required. Hyponatremia must be treated, although thyroid hormone replacement in itself will result in a decrease in antidiuretic hormone (ADH) and produce a brisk diuresis. Hypoglycemia and anemia will need to be monitored carefully and treated on the basis of individual needs. Care must be taken to prevent aspiration, fecal impaction, pressure sores, and urinary retention.

4. Prompt initiation of thyroid hormone replacement is essential. The initial dose for treatment of myxedema coma is between 300 and 500 μg of L-thyroxine given intravenously. This high dose is necessary to occupy hormone-binding sites that have been left free as a result of significant and prolonged hormone deficiency. In addition, precipitating factors, such as infection, may increase the turnover of T₄, and thus warrant a higher initial replacement dose. High doses can increase myocardial oxygen consumption and the potential for myocardial infarction. Once there is evidence of a clinical response, usually noted by a diuresis and increase in body temperature and heart rate, the daily dose of L-thyroxine should be reduced to 50–100 μg and can be given orally and adjusted as necessary. The use of T₃ or a combination of T₄ and T₃ has been suggested by some clinicians because of the shorter onset of action of T₃ and reduced ability to deiodinate T₄ to the more active T₃ in persons with significant illness and/or malnutrition. Data are not available upon which to make a more definitive recommendation.

5. Because adrenal insufficiency may coexist with myxedema coma, suspicion of cortisol deficiency should be high. A suggestive history, physical examination, or electrolyte abnormalities calls for administration of intravenous glucocorticoids. Initiating glucocorticoid therapy for all patients with myxedema coma is controversial. In life-threatening situations, blood for measurement of plasma cortisol should be drawn, and intravenous stress doses of corticosteroids should be administered and continued until there is laboratory confirmation of adrenal status and a decision can be made to continue, taper, or stop the corticosteroids.

Prognosis

Myxedema coma is a serious condition that occurs largely in older hypothyroid persons. Aggressive supportive therapy and thyroid hormone therapy are essential while possible contributing factors are evaluated and treated as necessary. Close monitoring is required when treatment is initiated to avoid toxicity from the relatively large starting doses of thyroid hormone. Even under the best of circumstances, there is considerable mortality related to delay in diagnosis and presence of coexisting morbidities.

General Principles in Older Adults

Hyperthyroidism is the result of an excessive amount of circulating thyroid hormone either from endogenous production or iatrogenic sources. Clinically, this disorder is accompanied by a broad spectrum of signs and symptoms that vary among individuals and can differ markedly between young and old persons. A greater percentage of affected individuals is older than age 60 years. Several studies of prevalence indicate the presence of hyperthyroidism in 1% to 3% of community-residing older persons. Hyperthyroidism is far more common in women than in men, with estimates ranging from 4:1 to 10:1.

Graves disease remains the most common cause of hyperthyroidism in young persons, and may still be present in older patients. With increasing age, however, more cases of hyperthyroidism result from multinodular toxic goiter. Although multinodular goiters are commonly found in older persons and are not usually associated with clinical disease, they may evolve into toxic multinodular thyroid goiters. A toxic adenoma may cause hyperthyroidism and is usually identified on thyroid scan as a solitary hyperfunctioning nodule with suppression of activity in the remaining portion of the thyroid gland.

Rarely, hyperthyroidism may result from ingestion of iodide or iodine-containing substances. Iodine may be introduced from seafood, although this problem is more common after exposure to iodinated radiocontrast agents and to amiodarone. Up to 40% of patients taking amiodarone will have serum T₄ levels above the normal range as a result of the drug’s effect on T₄ metabolism; far fewer (5%) will develop clinically apparent thyrotoxicosis. The hyperthyroidism can be of rapid onset and severe in magnitude.

Hyperthyroidism must always be considered in the older person who is already receiving thyroid hormone therapy. This is particularly important if the dose is >0.15 mg of L-thyroxine daily, although even smaller doses may be excessive, especially in small individuals of advanced age. Persons taking the same dose of thyroid hormone for many years may become hyperthyroid simply because of an age-associated decline in the body’s ability to degrade T₄.

Although extremely rare, a TSH-producing pituitary tumor may be the cause of hyperthyroidism. Nonsuppressed levels of serum TSH in the presence of increased amounts of circulating thyroid hormone are seen with these tumors. Hyperthyroidism may also rarely result with overproduction of thyroid hormone from a widespread metastatic follicular carcinoma.

Transient hyperthyroidism may occur in patients with silent or subacute thyroiditis as a result of increased release of thyroid hormone into the circulation during the inflammatory phase of the illness. Radiation injury, which may be caused by radioactive iodine therapy for hyperthyroidism, may also result in an outpouring of thyroid hormone.

Hyperthyroidism is usually accompanied by elevated levels of both T₄ and T₃. However, a subgroup of older hyperthyroid individuals have isolated elevations of T₃ alone. T₄ is either within the normal range or may, in fact, be suppressed. This circumstance is referred to as T₃ toxicosis. Although it can occur with any type of hyperthyroidism, it is most commonly seen in older patients with toxic multinodular goiter or solitary toxic adenomas. The diagnosis is made on clinical grounds and measurements demonstrating an elevated level of serum T₃ and a suppressed level of serum TSH. T₄ toxicosis, or an isolated increase in serum T₄ without an elevation in serum T₃, most commonly occurs in a sick older person with hyperthyroidism. Disease or malnutrition interferes in the normal removal of iodine from the 5′ position of T₄ and thus a decreased ability to convert T₄ to T₃.

Clinical Findings

Symptoms & Signs

Clinical findings associated with hyperthyroidism in the older adult vary greatly. In general, the clinical presentation of hyperthyroidism at this time of life differs from the more classic findings noted earlier in life (Table 41–1). The presenting feature may be a decline in functional capacity. There may be increased fatigue, muscle weakness, cognitive changes, loss of appetite, weight loss, cardiac arrhythmias, and congestive heart failure. Eye findings associated with the hyperthyroidism are less commonly noted in older adults. Rather than frequent bowel movements, more commonly there is a resolution of preexisting constipation. Anemia and hyponatremia are often noted and thought to be caused by other coexisting illnesses. Although this relative lack of the classic findings of hyperthyroidism does not occur in every older person with hyperthyroidism, a subgroup develops an apathetic hyperthyroid state. In this circumstance, the patient lacks the hyperactivity, irritability, and restlessness common to young patients who are hyperthyroid and presents instead with severe weakness, lethargy, listlessness, depression, and the appearance of a chronic wasting illness. Often the person is incorrectly diagnosed as having a malignancy or severe depression.

Symptoms less common in older patients include nervousness, increased diaphoresis, increased appetite, and increased frequency of bowel movements. More common symptoms include marked weight loss, present in >80% of older patients, poor appetite, worsening angina, agitation, confusion, and edema.

Similarly, physical findings differ in older patients. Hyperreflexia, palpable goiter, and exophthalmos are usually absent, although lid lag and lid retraction may be present. The pulse rate tends to be slower. Cardiac manifestations are particularly important in the older person who may have coexisting heart disease. An increased heart rate with a related increase in myocardial oxygen demand, stroke volume, cardiac output, and shortened left ventricular ejection time underlie the clinical consequences of palpitations. There is also an increased risk of atrial fibrillation (often with slow ventricular response), exacerbation of angina in patients with preexisting coronary artery disease, and precipitation of congestive heart failure that responds less readily to conventional therapy.

Gastrointestinal problems may occasionally include abdominal pain, nausea, and vomiting. Diarrhea and increased frequency of bowel movements resulting from the effect of the thyroid hormone on intestinal motility can occur, but these symptoms are often absent and constipation is still common. There may be an alteration in liver enzymes, including elevation of alkaline phosphatase and γ-glutamyltranspeptidase levels, which become normal after a return to the euthyroid state. Weakness, especially of proximal muscles, is a major feature of hyperthyroidism in older persons and is often accompanied by muscle wasting and functional decline. Disorders of gait, postural instability, and falling may be noted. Tremor is noted in >70% of older persons with hyperthyroidism. The tremor is usually more coarse than in other common tremors. A rapid relaxation phase of the deep tendon reflex is difficult to identify in the older thyrotoxic individual. Central nervous system (CNS) manifestations may be prominent and include confusion, depression, changes in short-term memory, agitation and anxiety, and a decreased attention span. Other findings associated with hyperthyroidism include worsening of glucose tolerance, mild increases in serum calcium, and osteoporosis resulting from increased bone turnover.

Laboratory Tests

The altered and often atypical presentation of hyperthyroidism in the older patient warrants a high degree of suspicion among clinicians and the initiation of appropriate laboratory studies. Serum free T₄ and a measurement of serum TSH are the preferred tests for diagnosing thyroid dysfunction. The findings of a normal or low serum free T₄ with a suppressed serum TSH raises the possibility of T₃ toxicosis and warrants a measurement of serum T₃ by radioimmunoassay. Although the finding of anti-TSH receptor antibodies confirms the diagnosis of Graves disease, it is rarely necessary to obtain this test.

Special Tests

Thyroid scanning with technetium and measurement of 24-hour ¹³¹I uptake can be useful in distinguishing Graves disease from toxic multinodular goiter. Scanning may also demonstrate the presence of a small, diffusely active goiter that could not be detected on physical examination. Very low ¹³¹I uptake in a patient with elevated circulating thyroid hormone levels suggests exogenous thyroid hormone ingestion, the hyperthyroid phase of painless or subacute thyroiditis, or iodine-induced hyperthyroidism.

Differential Diagnosis

Patients with hyperthyroidism in later life commonly have coexisting illness, and it is important not to attribute all presenting signs and symptoms to the hyperthyroid state itself. The most common differential diagnoses to consider include anxiety, malignancy, depression, diabetes mellitus, menopause, and pheochromocytoma.

Treatment

Therapy should be directed at the specific cause of the hyperthyroid state. Therefore, the underlying cause must be determined to exclude the possibility of one of the transient forms of illness, such as excessive hormone ingestion, iodine exposure, or subacute thyroiditis. The majority of older patients with either Graves disease or multinodular toxic goiter can be treated with antithyroid medications, radioactive iodine, or surgery. The preferred treatment, however, is radioactive iodine.

A useful initial step in treating suspected hyperthyroidism is to administer a β-adrenergic blocking agent such as long-acting propranolol, metoprolol, nadolol, or atenolol. These agents quickly control associated palpitations, angina, tachycardia, and agitation. Caution is advised, however, in persons with congestive heart failure, chronic obstructive pulmonary disease, or diabetes mellitus being treated with insulin.

Once a diagnosis of Graves disease or toxic nodular goiter is confirmed, treatment should be initiated with one of the antithyroid drugs: propylthiouracil or methimazole. These agents impair biosynthesis of thyroid hormone, thus depleting intrathyroidal hormone stores and ultimately leading to decreased hormone secretion. A decline in serum T₄ concentration is usually seen within 2–4 weeks after initiation of antithyroid drug therapy, and the dose should be tapered once thyroid hormone levels reach the normal range to avoid hypothyroidism. In 1% to 5% of patients, the antithyroid medications may result in fever, rash, and arthralgias. A drug-induced agranulocytosis may be more common in older patients and will most likely occur within the first 3 months of treatment, especially in those who receive >30 mg/day of methimazole. Periodic white blood cell count monitoring should be considered, with discontinuation of the antithyroid medication if there is evidence of neutropenia.

Long-term antithyroid medication use can be effective in patients older than age 60 years with Graves disease, who appear to respond fairly quickly and have a greater likelihood of a long-lasting remission. Because these medications rarely will provide a long-lasting effect for those with a toxic multinodular goiter, more definitive therapy is needed once the patient returns to an euthyroid state on medication. The recommended treatment in most older persons with hyperthyroidism is thyroid gland ablation with ¹³¹I. Once the patient achieves a euthyroid status on antithyroid medication, these agents should be stopped for 3–5 days, after which ¹³¹I is given orally. Therapy with β blockers can be maintained and antithyroid agents restarted 5 days after radiotherapy and should be continued for 1–3 months until the major effect of radioiodine is achieved. Although some physicians attempt to calculate a specific dose that will render the patient euthyroid without subsequently developing hypothyroidism, many patients will still develop permanent hypothyroidism. For this reason, most clinicians advocate treating the older person with hyperthyroidism with a relatively large dose of ¹³¹I to ensure ablation of thyroid tissue and thus avoid the possibility of hyperthyroidism recurrence.

After treatment, the patient is closely monitored in order to start replacement doses of thyroid hormone, because hypothyroidism may develop in as few as 4 weeks after treatment. Regardless of dosing regimen used, 40% to 50% of patients will be hypothyroid within 12 months of ¹³¹I administration, with 2% to 5% developing hypothyroidism each year thereafter.

Prior treatment with antithyroid medication prevents the possibility of radiation-induced thyroiditis after ¹³¹I therapy. However, in some circumstances, when clinical and laboratory features suggest a mild case of hyperthyroidism and no cardiac problems are noted, it may be appropriate to treat the hyperthyroid patient with ¹³¹I without antithyroid medication pretreatment. When this option is chosen, the patients should be started on a β-blocker and continue with it until thyroid hormone levels return to normal.

Surgery is not recommended as a primary treatment for hyperthyroidism in older patients. Coexisting illness, particularly cardiac, increases operative risk. In addition, postoperative complications of hypoparathyroidism and recurrent laryngeal nerve damage are significant risks. Surgery may be indicated in the rare patient with tracheal compression secondary to a large goiter.

Atrial fibrillation occurs in 10% to 15% of hyperthyroid patients. Treatment of the underlying disease is essential; cardioversion and anticoagulation are considered on an individual basis. The longer the hyperthyroid period, the less likely is the return to normal sinus rhythm; most benefit is found in those who become euthyroid within 3 weeks. Cardioversion is usually reserved for those patients who still remain in atrial fibrillation after 16 weeks of euthyroidism. Many older individuals with hyperthyroidism who develop atrial fibrillation are at greater risk of thromboembolic events, especially those with a history of thromboembolism, hypertension, or congestive heart failure and those with evidence of left atrial enlargement or left ventricular dysfunction. In the absence of contraindications, anticoagulant therapy should be given with warfarin in a dose that will increase the international normalization ratio to 2.0–3.0. Warfarin should be continued until the patient is euthyroid and normal sinus rhythm has been restored.

General Principles in Older Adults

Multinodular thyroid glands occur more commonly in individuals who have lived in areas of iodine deficiency. Often there is a history of goiter dating to childhood or young adulthood. Very large multinodular goiters, particularly those with a significant substernal component, may compress the trachea and lead to problems of dyspnea and wheezing, or problems with swallowing. All patients with thyroid nodules should be questioned regarding prior exposure to external radiation of the head, neck, and upper thorax. Radiation to these areas markedly increases the risk of thyroid malignancy. Radiation increases the risk of thyroid malignancy as well as benign nodules and parathyroid adenomas. Approximately 16% to 29% of persons who received low-dose radiation to the head and neck as children will develop palpable thyroid nodules; approximately 33% become malignant and clinically detected only after 10–20 years, reaching a peak incidence 20–30 years after radiation exposure.

Clinical Findings

Symptoms & Signs

Thyroid nodules usually remain asymptomatic, being discovered by the patient inadvertently or by the physician during a routine physical examination. On occasion, a thyroid nodule may result in an acute onset of neck pain and neck tenderness. This may be an acute or subacute thyroiditis or hemorrhage into a preexisting nodule. Although a single thyroid nodule is more commonly associated with malignancy than is a multinodular thyroid gland, only 5% of clinically apparent solitary nodules will be malignant. The vast majority of thyroid nodules are benign, and include follicular and colloid adenomas, Hashimoto thyroiditis, and thyroid cysts.

Malignant thyroid neoplasms may be papillary, follicular, medullary, or anaplastic carcinomas; lymphoma; or, in rare cases, metastatic disease to the thyroid. Nonthyroid lesions may appear as nodules on physical examination; these include lymph nodes, aneurysms, parathyroid cysts and adenomas, and thyroglossal duct cysts. The risk that a solitary thyroid nodule will prove to be malignant is increased by a history of radiation exposure, age >60 years, rapid increase in size, hoarseness of the voice suggesting an impingement of the recurrent laryngeal nerve, and hardness on palpation. Age is also a factor in predicting the histologic type of malignancy. The overall histologic distribution of all thyroid cancer is 79% papillary, 13% follicular, 3% Hürthle cell, 3.5% medullary, and 1.7% anaplastic. In patients older than 60 years, papillary carcinoma accounts for 67% of thyroid cancers. Follicular carcinoma peaks in frequency between the fourth and sixth decades of life (mean age at diagnosis: 44 years). Together with Hürthle cell carcinoma, these cancers account for 20% of thyroid malignancies in the older-than-age-60-years population. Medullary carcinoma has a peak incidence during the fifth and sixth decades of life and represents approximately 5% of thyroid cancers in the older adult (Table 41–2). Anaplastic carcinomas occur almost exclusively in older populations and account for approximately 6% of thyroid cancers in older patients. Anaplastic carcinoma is characterized by rapid growth, rock-hard consistency, and local invasiveness. Involvement of the recurrent laryngeal nerve and compression of the trachea are common. Lymphoma and metastatic cancers occur infrequently in the older patient. Lymphoma usually presents with a rapidly enlarging painless neck mass that may cause compressive symptoms. Coexisting Hashimoto thyroiditis is common.

Laboratory Tests

The major objective in evaluating an older person with a thyroid nodule is to rule out the presence of a malignancy. Blood tests of thyroid function will usually be normal unless there is a hyperfunctioning adenoma or toxic multinodular goiter. An elevated serum TSH may be noted in persons with subclinical hypothyroidism and nodular disease, as may result from longstanding Hashimoto thyroiditis. Serum thyroglobulin is often elevated in the setting of thyroid cancer but cannot differentiate malignancy from benign nodules or thyroiditis with any degree of certainty. It is, therefore, more commonly used as a marker for recurrence or metastasis in patients with papillary or follicular carcinoma who have undergone total thyroidectomy. An elevation of serum calcitonin concentration is indicative of a medullary carcinoma, but is not part of the initial evaluation, unless there is a family history of multiple endocrine neoplasia.

Special Tests

Fine-needle aspiration (FNA) of the thyroid remains the best way to obtain tissue for cytologic or histologic examination. FNA is indicated in any patient with a solitary nodule and when there is suspicion of thyroid malignancy based on clinical evaluation, ultrasonography, or thyroid scan. This procedure, when performed by a skilled clinician, has proven to be safe, inexpensive, and capable of determining the presence or absence of malignancy with an accuracy of close to 95%, and even greater accuracy with sonographic guidance. In general, cytopathologic findings from FNA are divided into 4 categories: positive for malignancy, suspicious for malignancy, negative for malignancy, and nondiagnostic. A repeat FNA is indicated for a nondiagnostic but clinically suspicious nodule. Malignant cells found on FNA indicate the need for surgery. The combination of suspicious cytology by FNA and a cold-appearing nodule on thyroid scan also indicates the need for surgical excision of the suspicious nodule. Benign cytology in either a solid or cystic nodule warrants observation. If the FNA is suggestive of a lymphoma, a repeat biopsy using a large-needle or even a surgical biopsy is indicated.

Isotopic scanning is no longer considered the initial diagnostic test in evaluating a suspicious nodule because of its relatively high false-positive and false-negative rates and high cost. Isotope imaging is best used when evaluating a patient with a thyroid nodule who has had a nondiagnostic result from FNA. Because malignant tissue is more likely unable to take up iodine, the identification of a nodule as hot on ¹²³I or technetium scanning makes malignancy in the nodule less likely, although clearly still possible. Scanning may also reveal an apparent single nodule that is, in fact, part of a multinodular thyroid gland, again decreasing the risk of malignancy. The presence of a nonfunctioning or a cold nodule is not proof of a malignancy because 95% of thyroid nodules will prove to be cold; the frequency of malignancy in cold nodules is 5%. Hot nodules associated with normal circulating levels of thyroid hormone and no compressive symptoms should be observed with repeat examinations performed at 6- to 12-month intervals. These nodules may eventually result in hyperthyroidism; thus, clinical correlation is also warranted. High-resolution ultrasonography can detect thyroid lesions as small as 2 mm and can also permit classification of a nodule as solid, cystic, or mixed solid-cystic. It will often identify multinodularity in a gland even when a single nodule is palpated clinically. This technique cannot be used to distinguish with any degree of certainty malignant from benign nodules because there is a great deal of overlap in the characteristics identified using ultrasonography. Ultrasonography is best used to detect recurrent or residual thyroid cancer, as well as to screen persons with a history of radiation exposure earlier in life.

Computed tomography (CT) and magnetic resonance imaging (MRI) are expensive and add little to the initial assessment of malignancy. They may be useful in evaluating the extent of disease in patients found to have anaplastic carcinoma or lymphoma and may provide useful information regarding compression of neck structures and the size and substernal extent of nodules and goiters.

Medullary carcinoma of the thyroid gland can be monitored using blood calcitonin measurements, both in the basal state and after stimulation. Blood levels of carcinoembryonic antigen may also be elevated in patients with residual or recurrent medullary carcinoma.

Differential Diagnosis

The differential diagnosis includes thyroid duct cysts, benign adenomas, toxic thyroid nodule, thyroid malignancy, hemorrhage, and multinodular thyroid gland.

Treatment

Although the basic principles for treating thyroid cancer do not differ significantly between the young and old, older individuals need to be more carefully evaluated for comorbid conditions and risk of surgery. Surgery for thyroid cancer should be performed only by an experienced surgeon. Papillary or follicular carcinoma is usually treated with near-total thyroidectomy because of the high frequency of multicentricity of malignancy and the need to remove functional thyroid tissue to monitor the patient with total-body radioiodine scanning. Thyroid remnants detected postoperatively are ablated with ¹³¹I. At 6 months, and subsequently at yearly intervals, scanning should be obtained and serum thyroglobulin measured to determine whether residual functional tissue exists. If active tissue is found, large ablative doses of ¹³¹I should be administered. This approach has reduced the recurrence rate of both papillary and follicular carcinomas and prolonged survival.

Patients treated for malignancy are treated judiciously with suppressive doses of L-thyroxine as tolerated with the desired objective of reducing serum TSH to below normal as measured by third-generation TSH assays. The administration of suppressive doses of L-thyroxine carries a substantial risk of precipitating or aggravating ischemic heart disease and arrhythmias as well as accelerating bone turnover. The older patient will need to be monitored closely and the dose of thyroid hormone reduced if cardiac symptoms develop. An acceleration of bone loss will occur and necessitate treatment with antibone resorption agents in some circumstances (eg, in osteopenic women). Medullary carcinoma of the thyroid gland is best treated with a total thyroidectomy because the disease is often multicentric. The majority of medullary carcinomas do not respond to ¹³¹I treatment; therefore, palliative therapy is recommended using external irradiation if residual thyroid tissue or recurrent disease is detected. Thyroid lymphoma should be clinically staged using CT or MRI. External irradiation in combination with chemotherapy has been associated with a survival rate close to 100%.

Prognosis

Age at diagnosis is an important factor in predicting cancer aggressiveness and mortality from differentiated thyroid cancer. Individuals diagnosed after age 50 years have a higher rate of recurrence and death (see Table 41–2). The 10-year survival for patients with papillary carcinoma is approximately 97% in those younger than 45 years and <65% for those older than 60 years at diagnosis. The 10-year survival rate for persons with follicular carcinoma is 98% for those younger than 45 years and <57% for those older than 60 years at diagnosis. The older the person is when a follicular carcinoma is diagnosed, the greater the risk of recurrence and death.

The 10-year survival rate for persons with medullary carcinoma is 84% for individuals younger than 45 years and decreases with advancing age. Persons in the seventh decade of life have a high rate of persistent disease even after surgery. Anaplastic carcinoma of the thyroid gland is rarely associated with more than a 1-year survival after diagnosis because of its rapid progression and high propensity to metastasize. Palliative treatment of compressive symptoms may be achieved by surgery followed by high-dose external radiation. Chemotherapy with doxorubicin or cisplatin, or a combination, may be beneficial in combination with surgery and external irradiation.

Advancing age is associated with a reduced metabolic clearance rate of cortisol, but with a compensatory decrease in secretion rate. Consequently, basal levels of serum cortisol are unaffected over the life span. Basal adrenocorticotropic hormone (ACTH) levels are unchanged or slightly increased with age in healthy individuals. Diurnal cortisol rhythm is reported to show a significant age-related phase advance (earlier peak and nadir level) similar to that observed in depressed patients. This is thought to be related to changes in sleep patterns.

The adrenal androgen precursor dehydroepiandrosterone (DHEA) reaches peak blood levels in both men and women by age 20–30 years, and then declines steadily, so that, after age 70 years, levels are <20% of the peak. Although early reports and popular lay literature have attributed a number of antiaging properties to DHEA, more recent studies in which DHEA has been administered for 6–12 months have shown little or no effect on objective measures of physiologic function. Some studies, however, suggest a beneficial effect on mood and sense of general well-being.

The hypothalamic–pituitary–adrenal axis response to known major stimuli remains intact with increasing age. Stimulation tests of this axis using insulin-induced hypoglycemia or metyrapone administration, result in a normal or slightly longer period of cortisol and ACTH secretory response in older persons. Peak cortisol response to stress is also greater, and both cortisol and ACTH levels remain elevated for a longer period in older compared with younger persons. Moreover, dexamethasone causes less inhibition of cortisol in older patients. It is unknown whether this age-related hyperresponsiveness of the pituitary–adrenal axis to stressful situations contributes to age-prevalent illness, including osteoporosis, glucose intolerance, muscle atrophy, and immunosuppression. Adrenal cortical response to exogenous ACTH, measured by circulating cortisol levels, is unaffected by aging.

General Principles in Older Adults

Acute adrenal insufficiency results from a deficiency in cortisol secretion and, in older people, occurs most often as a result of failure of the adrenal gland rather than a pituitary gland disorder. The adrenal gland may be unable to produce an adequate amount of corticosteroids and mineralocorticoids because of an autoimmune process involving the entire adrenal gland or from a replacement of healthy adrenal tissue with tumor or infection, such as in tuberculosis. Adrenal crisis may also result from an increased demand for glucocorticoids in an individual unable to increase output sufficiently. This occurs most commonly as a result of chronic adrenal suppression from exogenous corticoid use and less often from stress from trauma, surgery, hemorrhage, or infection. Rarely, this may result from a sudden increase in the metabolic turnover of corticosteroids, as can occur when a patient with both adrenal insufficiency and hypothyroidism is treated with thyroid hormone. Corticosteroid-induced adrenal suppression can occur after as few as 3–4 weeks of exogenous steroid treatment with doses >15 mg of prednisone or the equivalent dose of other glucocorticoids. In general, individuals on long-term glucocorticoid therapy who have stopped treatment before the return of function of the suppressed adrenal glands or who need a higher dose will have a less clear picture because of the ability of renin and angiotensin to maintain aldosterone function despite suppression of glucocorticoid activity in the adrenal gland.

Clinical Findings

Symptoms & Signs

Patients with adrenal insufficiency often have nausea and vomiting and abdominal pain, and may have an altered mental state and fever. In general, blood pressure is low. Signs of primary adrenal insufficiency may include hyperpigmentation and evidence of dehydration. Older persons commonly have sparse or absent pubic and axillary hair; therefore, this is less commonly noted as a presenting sign in older patients.

Laboratory Tests

Laboratory findings may include hyponatremia or hyperkalemia. Hypoglycemia and elevation of blood urea nitrogen (BUN) and creatinine are common. Eosinophilia may be noted as well. Cultures may be positive if there is an underlying infection. The cosyntropin (ACTH 1–24) stimulation test is abnormal, and plasma ACTH is usually elevated in persons with primary failure of the adrenal gland. With this test, patients are given 0.25 mg of cosyntropin intravenously over 2–3 minutes, and serum cortisol is measured immediately before and 30 and 60 minutes after administration. Under normal circumstances, serum cortisol rises by at least 7 μg/dL to at least 20 μg/dL. Hydrocortisone administration will interfere with the test results, but other glucocorticoids, such as dexamethasone or prednisone, do not interfere with the specific assay for cortisol.

Differential Diagnosis

Although adrenal insufficiency should be considered in any patient who presents with hyperkalemia and hypotension, other possible causes for these findings should be considered.

Other causes of hypotension in particular include sepsis, hemorrhage, and cardiogenic diseases. Renal insufficiency may cause hyperkalemia as may gastrointestinal bleeding, rhabdomyolysis, and medications such as spironolactone and angiotensin-converting enzyme inhibitors. Hyponatremia may occur in hypothyroidism, with diuretic use, in drug and disease states associated with inappropriate ADH secretion, and with malnutrition, cirrhosis, and vomiting. Eosinophilia may be associated with blood dyscrasias, allergies, medication reactions, and parasitic infections. The associated gastrointestinal findings of nausea, vomiting, and abdominal pain may, in fact, be caused by other gastrointestinal tract disorders common during later life. Hyperpigmentation may not be noted in older persons of dark complexion or who have sun-induced skin damage.

Treatment

Replacement of both glucocorticoids and mineralocorticoids is needed in severe cases of adrenal insufficiency. Because hydrocortisone has some mineralocorticoid activity, it is the corticosteroid of choice for patients with mild cases and is effective in doses of 25–37.5 mg orally; two-thirds of the dose is given in the morning and one-third in the late afternoon or evening. If salt-retaining effects from this therapy are insufficient, fludrocortisone is added to the daily regimen in dosages of 0.05–0.3 mg orally each day or every other day. The exact dose required varies with the individual and, therefore, should be clinically adjusted in relation to postural blood pressure changes, level of potassium, and body weight. The dose is reduced if hypokalemia, hypertension, or edema occurs, especially when fluid and electrolyte management is complicated by cardiac disease or renal insufficiency. Underlying factors that may have contributed to the onset of adrenal insufficiency, particularly infections, should be sought. The dosage of hydrocortisone may need to be adjusted upward to a stress dosage as high as 300 mg/day, although usually 50 mg intravenously or intramuscularly every 6 hours will be sufficient, even for the most stressful situations.

Prognosis

With adequate replacement therapy, adrenal insufficiency is a treatable illness. When accompanied by other illnesses, the risk mortality is increased. If the underlying cause is an autoimmune disease, other endocrine problems, such as diabetes mellitus and hypothyroidism, as well as pernicious anemia, may be present.

General Principles in Older Adults

Cushing syndrome is caused by an excessive amount of circulating corticosteroids. In older patients, it most commonly results from exogenous exposure to corticosteroids given for a variety of medical disorders. The most frequent endogenous cause is ectopic production of ACTH by neoplasms, especially small cell carcinoma of the lung and carcinoid tumor. Cushing disease (ie, oversecretion of ACTH by a pituitary tumor) is less common in older than in younger patients, is usually associated with a small benign adenoma, and occurs more often in women than in men. Approximately 15% of cases of endogenous Cushing syndrome are non-ACTH dependent and result from an adrenal adenoma, carcinoma, or bilateral nodular adrenal hyperplasia. Although adrenal adenomas are generally small and produce mostly glucocorticoids, carcinomas tend to be larger on presentation and more commonly produce excessive amounts of both glucocorticoids and androgens, often resulting in virilization and hirsutism.

Clinical Findings

Symptoms & Signs

Although central obesity, thin arms and legs, and a round “moon face” are classic findings, these may be harder to detect in older patients. For example, the “buffalo hump” deposition of fat at the back of the neck may, in older women, be confused with kyphosis resulting from osteoporosis. Thin, transparent skin, bruising, muscle atrophy and weakness, diabetes mellitus, and hypertension are other common findings easily confused with many other age-prevalent disorders. Thirst is less often reported by older adults compared with younger patients. Polyuria may result from increases in blood sugar from glucocorticoid-induced diabetes. Blood glucose is often elevated, and glycosuria may be present. Occasionally, there is a leukocytosis and hypokalemia. Wound healing may be impaired, and changes in mental function, including anxiety, psychosis, and depression, may occur.

Laboratory Tests

A 1-mg overnight dexamethasone suppression test, urine free cortisol, late-night salivary cortisol (2 measurements), or longer low-dose dexamethasone suppression test (2 mg/day for 48 hours) can be used to screen for hypercortisolism, based on its suitability for a given patient. In a 1-mg overnight dexamethasone suppression test, dexamethasone 1 mg is given orally at 11 PM, and serum is collected at 8 AM the next morning for cortisol. A cortisol level <1.8 μg/dL is considered normal and excludes a diagnosis of Cushing syndrome. If there is failure of suppression, further evaluation should include a 24-hour urine collection for free cortisol and creatinine, and late-night salivary cortisol (2 measurements). A 2-mg dexamethasone suppression test using 0.5 mg of dexamethasone administered orally every 6 hours for 48 hours can also be used as a screening test. Serum cortisol is measured 6 hours after the last dose of dexamethasone and cortisol level <1.8 μg/dL is considered normal suppression. Longer low-dose dexamethasone suppression test excludes hypercortisolism with improved specificity compared to 1-mg dexamethasone suppression test.

Once hypercortisolism is confirmed, plasma ACTH should be determined. A level of ACTH below the normal range indicates a probable adrenal tumor; an elevated level indicates overproduction by either the pituitary or an ectopic ACTH-secreting tumor. MRI of the pituitary can identify a pituitary adenoma with considerable accuracy. Selective inferior petrosal venous sampling for ACTH can be done to confirm a pituitary source of ACTH and to help distinguish its origin from other sites. A CT or MRI scan of the chest and abdomen to look for ectopic sources of ACTH is indicated and can localize a tumor of the adrenal glands.

Differential Diagnosis

Hypercortisolism can result from iatrogenic use of steroid medications. Alcoholic patients and those with depression may also have increased levels of cortisol. Abnormal dexamethasone suppression tests have been described in patients with morbid obesity, depression, and a variety of CNS disorders. In these patients, urine free cortisol should be measured and an attempt made to assess diurnal variation in cortisol secretion because these tests are usually within normal limits in the setting of obesity. Hypertension resulting from other causes is common in the older adults, and estrogen replacement therapy may alter normal dexamethasone suppressibility.

Treatment

Cushing disease is best treated by removing the pituitary adenoma responsible for the increase in ACTH secretion. After its removal, the adrenal gland remains unable to respond to normal stimulation for a prolonged time, and there is an altered ability to respond under conditions of stress. Hydrocortisone replacement therapy is necessary until normal pituitary–adrenal axis function returns, often taking as long as 6–24 months. Radiation therapy has also been used to treat Cushing disease, with an approximate cure rate of 25%. For patients who are not surgical candidates, inhibition of adrenal steroid biosynthesis can be useful in controlling symptoms and has been achieved with metyrapone, 500 mg every 6 hours, in combination with aminoglutethimide, 250–500 mg every 6 hours, and ketoconazole, 200 mg every 6 hours. Physiologic replacement doses of a glucocorticoid may be necessary to avoid drug-induced adrenal insufficiency.

Adrenal neoplasms secreting cortisol should be resected when possible and often can be removed laparoscopically. Because the nonaffected adrenal gland is usually suppressed, once again hydrocortisone replacement is indicated until the gland returns to normal function. Metastatic adrenal carcinoma can be managed with the medications just mentioned or with mitotane, 2–10 mg daily in divided doses. Ectopic ACTH-secreting tumors should be surgically resected. If this is not possible, once again, medications may be used to suppress the high levels of cortisol. The somatostatin analogue octreotide has been used to suppress ACTH secretion successfully in as many as 33% of cases in which it has been attempted.

Prognosis

Patients who have hypercortisolism as a result of iatrogenic use of corticosteroids can usually expect a return to normal after discontinuation of the steroid therapy. In hypercortisolism, the best prognosis for total recovery is seen when a benign adrenal adenoma is easily removed. Pituitary adenomas are more difficult to treat and, even in the best of hands, have a failure rate of 10% to 20%. Even those who respond have a 15% to 20% recurrence rate over the next decade. The prognosis of patients with ectopic ACTH-producing tumors depends on the underlying type and degree of tumor involvement.

General Principles In Older Adults

Hyperparathyroidism is a common disorder that affects predominantly postmenopausal women, with an incidence of approximately 2 per 1000 women. At least 50% of patients have no or minimal nonspecific symptoms or signs. Although a primary abnormality in 1 or all of the parathyroid glands may be responsible (primary hyperparathyroidism), suboptimal levels of vitamin D are associated with elevated parathyroid hormone (PTH) levels, although usually with normal or low levels of calcium. PTH concentrations are also influenced by a number of other factors and are higher in older individuals, especially older women; in blacks relative to whites; in those with low calcium; and in obese individuals.

Primary hyperparathyroidism (PHPT) is caused by the inappropriate secretion of PTH, which results in hypercalcemia. The most frequent underlying disease is a single benign parathyroid adenoma. Less commonly, multiple gland involvement or 4-gland hyperplasia may be present. With the availability and more widespread usage of PTH assays, normocalcemic hyperparathyroidism is being increasingly identified. In making the diagnosis of normocalcemic hyperparathyroidism, it is critical to exclude other causes of elevated PTH and normal serum calcium (secondary hyperparathyroidism). These individuals may have isolated hypercalciuria and are predisposed to renal calculi.

Secondary hyperparathyroidism (SHPT) is the result of the parathyroid’s response to hypocalcemia in an attempt to maintain calcium homeostasis. The common causes of SHPT are chronic renal failure, vitamin D insufficiency, malabsorption syndromes, drugs (bisphosphonates, furosemide, anticonvulsants, phosphorus), hypercalciuria caused by renal leak, and pseudohypoparathyroidism type1b. Tertiary hyperparathyroidism (THPT) occurs because of prolonged hypocalcemia leading to parathyroid gland hyperplasia and autonomous oversecretion of PTH resulting in hypercalcemia.

Clinical Findings

Symptoms and Signs

The most common clinical circumstance is an unanticipated finding of hypercalcemia during a routine blood test. Mild nonspecific complaints may include fatigue and generalized weakness. CNS symptoms of depression or mild cognitive impairment may be present. Questioning may disclose increased thirst and polyuria thought to be caused by the antagonistic effect of hypercalcemia on the renal action of ADH. A history of renal calculi, fracture, loss of height, and/or disproportionately low-for-age bone mineral density on dual energy x-ray absorptiometry scan calls for measurement of serum calcium. In SHPT and THPT, patients may have symptoms from the primary disease process. Even if asymptomatic, PHPT patients with calcium stones and or nephrocalcinosis are categorized as having symptomatic disease.

Laboratory Findings

When serum calcium is minimally or only intermittently increased, measurement of ionized calcium can establish the presence of hypercalcemia. Vitamin D deficiency and insufficiency in patients with PHPT may mask hypercalcemia and calcium levels will become increased in most cases after repletion of vitamin D. It is recommended that 1,25-dihydroxyvitamin D₃ (1,25[OH]2) levels be measured in all patients with PHPT. The diagnosis is confirmed by measuring serum intact PTH and correlating to levels of serum calcium. Levels of PTH are almost always elevated above the upper limit of normal or within the normal range but inappropriately high for the level of hypercalcemia. Renal imaging by ultrasound is recommended if kidney stones are suspected. Serum BUN and creatinine should be measured because SHPT is often found in the presence of renal insufficiency. PTH levels tend to rise steadily with the progression of renal disease. A rise of PTH up to the 3-fold normal range is generally accepted as a “physiologic” mechanism of compensating for low 1,25(OH)2, but reverts to normal when vitamin D is repleted.

Once the diagnosis of PHPT is confirmed biochemically, bone mineral density should be measured. Parathyroid adenomas can be localized with a high degree of sensitivity and specificity by means of isotopic scanning with technetium-99m sestamibi. Imaging studies are not appropriate for confirming the diagnosis of PHPT or for screening patients for surgical referral. Selective sampling of veins draining the parathyroid glands for step-up in PTH levels can be done in patients who have had previous parathyroid surgery with failure to identify abnormal parathyroid tissue or if the sestamibi scan is nondiagnostic.

Differential Diagnosis

The finding of hypercalcemia along with low-normal or low serum phosphorus levels suggests the diagnosis of PHPT. Other causes of hypercalcemia are usually associated with a lowered level of PTH and include a number of malignancies with or without bone metastases (squamous cell carcinoma of the lung, breast cancer, renal cell carcinoma, multiple myeloma, lymphoma). Hypercalcemia in many of these malignancies may be mediated by tumor-secreted PTH-related protein. Other causes of hypercalcemia include thiazide diuretics, vitamin D toxicity, sarcoidosis, hyperthyroidism, and familial hypocalciuric hypercalcemia (FHH). FHH has traditionally been diagnosed in families by the presence of hypercalcemia and relative hypocalciuria. The calcium-to-creatinine clearance ratio is of particular value, and is usually below 0.01 in FHH; this ratio is usually above 0.01 in typical PHPT. It is important to ensure that other causes of hypercalcemia and relative hypocalciuria are excluded, including concurrent treatment with thiazide diuretics or lithium.

Treatment

Parathyroidectomy should be offered to patients who meet the criteria for surgery established by the 2008 National Institutes of Health consensus panel (Table 41–3) or who are symptomatic. Older patients are at risk for sudden elevation of serum calcium if they become dehydrated or immobile for whatever reason. The increased risk of fracture in the older woman with significant osteoporosis can be reduced by correction of the hyperparathyroidism. Calcimimetic cinacalcet may be used as a therapeutic trial to determine the effect of lowering serum calcium and the potential benefits of parathyroidectomy in complex cases with significant comorbidity. In the case of parathyroid adenoma, identification and removal of the adenoma will be curative. If parathyroid hyperplasia is found, 3.5 of 4 identified glands must be removed. Intraoperative rapid PTH assay, if available, can confirm that the surgeon has successfully removed the abnormal tissue.

When surgery is not recommended medical monitoring is critical. Recommended surveillance includes annual measurement of serum calcium and creatinine levels, and annual or biannual bone density testing. Vitamin D replacement in patients with suboptimal vitamin D is associated with reductions in serum PTH, and has not resulted in further increases in serum calcium. It would be appropriate to consider vitamin D supplementation in all individuals with PHPT if serum levels are below 50 nmol/L (20 ng/mL) before making any medical or surgical management decisions. Guidelines for calcium intake should be the same as for patients without PHPT.

Medical options for patients unable to undergo parathyroidectomy include antiresorptive treatments, such as bisphosphonates; raloxifene; and calcimimetic cinacalcet. Several randomized control trials have reported that bisphosphonate therapy and estrogen replacement therapy in PHPT decrease bone turnover and increase bone mineral density (BMD), but fracture outcomes have not been evaluated. Very limited data are available in regard to the biochemical and skeletal effects of raloxifene in postmenopausal women with PHPT. If skeletal protection is the primary reason for intervention, bisphosphonates are the drug of choice. If present, vitamin D deficiency should be corrected first, as it increases the risk of hypocalcemia with bisphosphonate therapy. Bisphosphonates should be used cautiously in the presence of renal insufficiency. Only calcimimetic cinacalcet effectively lowers serum calcium and PTH levels during long-term therapy in PHPT, but has not been shown to alter bone turnover or increase BMD. At present, use of this agent in PHPT is limited to management of symptomatic hypercalcemia in patients who are unable to undergo corrective surgery and in whom bisphosphonates are ineffective or are contraindicated.

Goals of medical management in SHPT are the normalization of calcium and skeletal protection. Medical therapy starts with prevention of the development of severe SHPT with close monitoring of serum calcium, phosphate, PTH and vitamin D₃. Principles of managing SHPT in end-stage renal disease include normalization of hyperphosphatemia, regulation of serum calcium, and lowering PTH secretion (calcitriol and calcimimetic administration). Whenever possible, the underlying cause of SHPT should be treated. THPT should be managed by parathyroidectomy especially in the presence of severe metabolic bone disease.