The diagnosis and management of hypothyroidism. (Featured CME Topic: Thyroid Dysfunction/Disease).

HYPOTHYROIDISM REFERS TO a metabolic state resulting from a deficiency in thyroid hormone function. It usually arises from primary thyroid disease, but in rare cases it is due to hypothalamic-pituitary disease or generalized tissue resistance to thyroid hormone.' The manifestations of hypothyroidism are well described and can affect virtually any organ. The early recognition of hypothyroidism remains a challenge, especially when the decline in thyroid function is gradual. In some instances, the manifestations of hypothyroidism may be erroneously attributed to the effects of aging in the elderly. Clinical suspicion of hypothyroidism justifies laboratory testing. Screening for abnormalities in thyroid function is recommended by several medical professional organizations; however, the criteria for screening remains controversial. In the presence of conditions which increase the risk of hypothyroidism, a more intensive stance on screening may be justified. The criteria for screening are listed in Table 1.

CLINICAL MANIFESTATIONS

The manifestations of hypothyroidism result from a reduction in metabolic activity and a deposition of glycosaminoglycans. Clinical findings that may be seen in hypothyroidism are listed in Table 2. It is important to note that symptoms may be nonspecific in the early stages of hypothyroidism and do not necessarily occur in sequence. These symptoms may include myalgia, arthralgia, muscle cramps, dry skin, headaches, and menorrhagia. Brittie nails, thinning of hair, pallor, and symptoms of carpal tunnel syndrome may also be seen. The characteristic delayed-relaxation phase of deep tendon reflexes may be noted, along with relative macroglossia. As hypothyroidism becomes more marked, hoarseness, peripheral edema, constipation, dyspnea, and weight gain may be seen. Other manifestations include pericardial effusion, ascites, decreased hearing, diastolic hypertension, galactorrhea, and hypothermia, along with neuropathy, ataxia, and sleep apnea. Psychiatric presentations may include depression, cognitive impairmen t, dementia, personality change, and, rarely, frank psychosis. (2) Hypothyroidism should also be considered in the presence of difficulty in weaning patients off of mechanical ventilators. The presence of goiter suggests primary rather than secondary hypothyroidism.

Several rare or unusual manifestations may prompt the patient to seek medical assistance. Bilateral carpal tunnel syndrome may complicate hypothyroidism. (3) Urticaria has been described in patients with autoimmune thyroid disease. (4) Primary pulmonary hypertension is often complicated by coexisting hypothyroidism. (5) Anemia, coagulopathy with easy bruising, myopathy, and a plethora of rheumatologic symptoms may plague the patient. (6) Anemia in patients with hypothyroidism may represent iron deficiency due to menorrhagia, and in some instances may be due to concomitant vitamin [B.sub.12] deficiency. (6) Macrocytosis is a well-described feature of untreated hypothyroidism.

Myopathy may be a dominant presenting feature in some patients with hypothyroidism. In one study, patients with hypothyroidism underwent electroneuromyography (ENMG) to determine the presence of neuromyopathy. (7) A very high prevalence of abnormal ENMG results (87.5%) was seen in this population, with 46.6% having abnormalities consistent with myopathy, and another 43% with carpal tunnel syndrome. (7) Symptoms such as arthralgia, stiffness, paresthesia, joint swelling, and pseudogout may occur in patients with frank hypothyroidism. (6) Hyperuricemia and serous effusions involving the pleura, pericardium, peritoneum, and synovium have been described. Other autoimmune disorders may coexist or occur with increased frequency in patients with Hashimoto's thyroiditis. These disorders include pernicious anemia, vitiligo, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, chronic active hepatitis, polymyositis-like syndromes, and systemic sclerosis. (6,8)

Dyslipidemia and hyperhomocystinemia have been described in hypothyroidism and may contribute to accelerated atherosclerosis and early manifestations of coronary artery disease. Typically, elevated total cholesterol and low-density lipoprotein (LDL) levels and low levels of high-density lipoproteins have been described. (1)

DIAGNOSIS

The diagnosis of primary hypothyroidism is confirmed by a reduced free-thyroxine ([T.sub.4]) level and elevated thyroid-stimulating hormone (TSH) level. Subclinical hypothyroidism is diagnosed by the demonstration of elevated TSH levels in the setting of normal free-[T.sub.4] levels. (9 10) The diagnosis of secondary hypothyroidism resulting from hypothalamic-pituitary dysfunction is more difficult, since the TSH level may be reduced, normal, or even slightly elevated in this condition." Evaluation of other pituitary hormone levels (prolactin, growth hormone, cortisol, and gonadotropins) and imaging studies (computerized tomography or magnetic resonance imaging of the brain) may need to be considered. (11) A positive antithyroid antibodies test may indicate the presence of Hashimoto's disease, but usually does not influence management in frank hypothyroidism. The presence of antithyroid antibodies may also indicate the coexistence of subclinical or overt polyglandular autoimmune endocrine diseases. (1) The u se of the thyrotropin-releasing hormone (TRH) test has declined, although it may have a role in demonstrating the exaggerated TSH response seen with preclinical hypothyroidism. Its use in differentiating causes of central hypothyroidism (pituitary vs hypothalamic) has been questioned. In many instances, concomitant laboratory abnormalities may provide additional clues to the diagnosis of hypothyroidism (Table 3). Radiologic imaging is usually not indicated, except for hypothy roidism associated with retrosternal goiter. Thyroid uptake measurements and scintigraphic studies (using either technetium 99m or iodine 123) are rarely needed, but may occasionally assist in differentiating autoimmune thyroiditis from other diseases involving the thyroid. (12) In rare cases, histologic evaluation of thyroid tissue biopsies may be required in order to confirm the diagnosis.

ETIOLOGY

Primary hypothyroidism remains the prevalent form of hypothyroidism. A variety of disease states can result in hypothyroidism (Table 4). Primary disorders of the thyroid gland are responsible for most cases of hypothyroidism. (1) These include autoimmune thyroid disease, surgical or radiation-induced reduction in thyroid tissue, and, rarely, infiltration or infection of the thyroid. Recently, several new syndromes of thyroid dysfunction have been described and need to be considered in some patients. (13) These include generalized thyroid-hormone resistance, defective conversion of [T.sub.4] to triiodothyronine ([T.sub.3]), TRH deficiency (autosomal dominant), and TRH- and TSH-inactivating mutations. (13) Molecular diagnosis of these conditions is rarely indicated in the current management of hypothyroidism. Drugs such as iodine (in radiocontrast media) and amiodarone have been associated with the development of hypothyroidism. (14,15)

MANAGEMENT

Many different forms of thyroid replacement therapy have been used in the past. Currently, patients should be treated with levothyroxine. (1,16) The use of generic thyroxine, with its variable bioavailability, may result in the need for additional testing. Since the cost difference between brand-name and generic thyroxine preparations is not substantial, many endocrinologists prefer not to use generic thyroxine. In patients with primary hypothyroidism, the TSH level should be lowered to about the midpoint of the normal range. The average dose of levothyroxine required in adults is approximately 1.0 to 1.7 [mu]g/kg. In young adults without associated illnesses, the starting dose can be estimated from this calculation. The etiology of hypothyroidism may influence the replacement dose of thyroxine needed. Patients who have had a total thyroidectomy or chronic autoimmune thyroiditis may need larger doses than those who have not. Kabadi et al (17) were able to predict the dose of thyroxine required based on the p retreatment ISH level. Following total thyroidectomy for differentiated thyroid cancer, a lower TSH value (eg, <0.1) may be desirable. In the treatment of central hypothyroidism, the goal is to achieve a normal free-[T.sub.4] level, since the TSH level may be unreliable in this setting. Patient education regarding the adverse effects of thyroxine replacement should include advice against "doubling-up" following days in which the usual dose was not taken. Once thyroid function tests and clinical status are stable, thyroid function tests should be monitored approximately every 6 to 12 months.

Patients unable to take thyroxine for several days do not need additional intervention, given the long half-life of thyroxine. Patients unable to take oral thyroxine for more prolonged periods, however, may need daily intravenous supplementation with approximately 80% of the daily oral dose.

The persistence of symptoms while taking thyroxine replacement have raised questions about the role of [T.sub.3] in therapy. Moreover, the increased interest in alternative medicine has resulted in patient inquiries regarding replacement therapy with "more natural" whole thyroid. While the administration of thyroxine leads to normal levels of [T.sub.4] and [T.sub.3], the question of tissue levels achieving normality has been raised by studies of thyroidectomized animals. Using [T.sub.3] for chronic replacement is currently not recommended, due to its short half-life and the wide fluctuations in serum levels. Combined [T.sub.4]-[T.sub.3] preparations are available as desiccated thyroid, with 10 [micro]g of [T.sub.3] and 40 [micro]g of [T.sub.4] in one grain (60 mg), and liotrix, which contains a 4:1 ratio of [T.sub.4] to [T.sub.3]. Most endocrinologists favor levothyroxine therapy over these combined preparations or thyroid extract, due to its more predictable absorption leading to more stable serum levels, a s well as better standardization of the medication. Bunevicius et al (18) reported improved mood and symptom relief when [T.sub.4] was combined with [T.sub.3], compared with thyroxine replacement alone. At the end of that study, patients preferred the combination form of treatment. Given the short duration of the study, additional investigations are needed to confirm these findings and evaluate possible adverse effects from combination therapy before widespread use is recommended. Multiple factors lead to persistent elevation of TSH values in patients treated for primary hypothyroidism (Table 5). (19)

THYROXINE REPLACEMENT IN SPECIAL SITUATIONS

The presence of a normal free-[T.sub.4] level with elevation of TSH values is found in subclinical hypothyroidism. The point at which therapy should be initiated has been controversial. The work-up for this condition should include antithyroid antibodies tests and fasting lipid levels. Patients with positive tests for thyroid antibodies should be treated. Patients whose tests for thyroid antibodies are negative, but whose TSH values are >10 [micro]g/mL, should also be treated. Patients with goiter, elevated lipid levels, pregnancy, ovulatory dysfunction/infertility, or impaired cardiac contractility may also be treated. It is difficult to assess the relationship of mild, subclinical hypothyroidism and general health concerns in some patients, and some physicians will initiate therapy while others advocate follow-up with annual laboratory testing. (10)

The thyroxine dose needs to be increased during pregnancy. (20) A study by Haddow et al (21) indicated that maternal thyroid deficiency during pregnancy could impair neuropsychological development in children. Thyroxine replacement in elderly and/or cardiac patients needs to be initiated at a low dose (eg, 12.5-25 [micro]g daily), with a gradual increase (eg, 12.5-25 [micro]g every 3-4 weeks) and monitoring of thyroid function and clinical status. Patients who need elective surgery can be rescheduled after thyroid function has normalized. (22) Surgery should proceed for patients who need surgery immediately, and they should be given simultaneous replacement therapy with thyroxine. The route of administration and the dose will be influenced by age and concomitant health factors of the patient, such as the presence of cardiac disease. Hypothyroidism may also be associated with postoperative complications. (22)

Thyroid function tests are routinely checked when patients are admitted to the psychiatric ward. Noncompliance with daily thyroxine replacement is often seen in psychiatric patients. The administration of doses once or twice weekly is effective and without side effects; moreover, this method of administration may enhance compliance and decrease the need for hospitalization. (23) Psychiatrists have sometimes used both [T.sub.4] and [T.sub.3] replacement in pharmacologic doses to treat refractory depression and bipolar disease. Further studies are needed to confirm: a) the efficacy of these regimens; b) any synergy between traditional antidepressants and thyroxine therapy; and c) lack of adverse effects, including osteopenia. Pending these studies, the role of adjunctive thyroid-hormone therapy for refractory depression and bipolar disease remains a controversial option. In depressed patients receiving thyroxine treatment for hypothyroidism, it may be reasonable to consider a TSH-level goal closer to the lower limit of the normal range, although this issue also needs to be addressed by additional studies.

MYXEDEMA COMA

Myxedema coma is a severe form of hypothyroidism that is associated with a significant mortality rate. (24) The disorder is most often seen in patients with a history of hypothyroidism who are exposed to stressful conditions, such as surgery or extreme cold. Other events, such as concurrent cerebrovascular accidents, infections (eg, pneumonia), hypothermia, trauma, and the use of medications (eg, analgesics, sedative tranquilizer drugs, general anesthesia, narcotics, amiodarone, and lithium) can also precipitate myxedema coma. (24) The principal clinical features, in addition to the other manifestations of hypothyroidism reviewed earlier, include hypothermia, altered consciousness, delirium, hypoventilation (resulting in respiratory failure and hypercapnia), cardiac dysfunction (bradycardia, decreased cardiac output, and hypotension), constipation, and urinary retention. Periorbital edema, macroglossia, and generalized swelling may be seen. Electrolyte abnormalities, such as hyponatremia, occur in these criti cally ill patients, and are often due to excessive fluid retention. Elevated creatinine phosphokinase levels suggest the presence of rhabdomyolysis. Other laboratory testing abnormalities observed include hypoglycemia, dyslipidemia and anemia. The term myxedema coma may be a misnomer, since patients may have neither coma nor evidence of peripheral, nonpitting edema. (25) It is important to diagnose and treat the patient with myxedema coma aggressively because, if untreated, the disorder has a very high mortality rate. Treatment usually requires admission to a medical intensive care unit and the administration of intravenous levothyroxine. (25) Many patients also require concomitant administration of hydrocortisone until coexisting adrenal insufficiency has been excluded. Associated complications, such as infections, electrolyte disturbances, hypoglycemia, cardiorespiratory problems, hypothermia, and rhabdomyolysis, also require treatment. In spite of aggressive management, studies have suggested mortality rat es between 30% and 60%, especially in the very elderly patient or those with persistent hypothermia or cardiac dysfunction.

TABLE 1.

Screening for Thyroid Disease in Asymptomatic Adults: Recommendations of
Six Professional Organizations (10)

     Organization                  Screen?

American Thyroid Association         Yes

American Association of              Yes
 Clinical Endocrinologists
American College of                  Yes
 Obstetrics and Gynecology

American College of Physicians        ?
US Preventive Services Task Force    No

Royal College of Physicians          No


     Organization                    Specific Recommendation

American Thyroid Association       Women and men over age 35
                                   Screen every 5 years
American Association of            Older patients, especially women
 Clinical Endocrinologists
American College of                Women in high risk groups
 Obstetrics and Gynecology
                                   starting at age 19 years
American College of Physicians     Women over age of 50 years
US Preventive Services Task Force  Insufficient evidence for or
                                    against screening
Royal College of Physicians        Screening of healthy
                                    adults unjustified
TABLE 2.

Clinical Findings in Hypothyrodism

  System          Symptoms              Signs

General           Fatigue/lethargy;     Periorbital edema;
                  Weakness              Pallor
Endocrine         Swelling of thyroid;  Goiter;
                  Menorrhagia           Galactorrhea
Metabolic         Cold intolerance;     Hypothermia;
                  Weight gain           Obesity
Psychiatric       Depression            Depression
Musculoskeletal   Arthralgia; myalgia
Skin              Decreased perspira-   Brittle nails;
                  tion; Hair loss       Reduced skin turgor;
                                        Alopecia/coarse
                                        hair;Carotenemia
Gastrointestinal  Constipation;         Megacolon
                  Decreased appetite
Respiratory       Snoring               Hypoventilation;
                                        sleep apnea
Cardiovascular    Dyspnea               Hypertension *;
Bradycardia                             Pericardial
                                        effusion;
                                        Cardiomegaly/CHF
Nervous system    Paresthesia           Bradykinesia;
                  Numbness              Distal sensory loss;
                  Unsteadiness          Ataxia
                  Reduced mentation     Dementia;
                                        Hyporeflexia;
                                        Pseudomyotonia;
                                        Headache; visual
                                        disturbances +

* Diastolic hypertension.

+ Findings in secondary hypothyroidism

CHF = Congestive heart failure.
TABLE 3.

Laboratory Abnormalities in Hypothyroidism


Thyroid axis  Low total [T.sub.4] level,
              increased TSH level in
              primary hypothyroidism,
              low/normal/mildly elevated
              TSH level in secondary
              hypothyroidism
Chemistry     Low glucose level, low serum
              sodium level
Hematology    Anemia
               Macrocytic (increased MCV)
               Microcytic (decreased MCV)
Lipids        Elevated cholesterol level
Other tests   Elevated creatinine
              phosphokinase (CK-MM)
              level, elevated serum
              myoglobin leve], elevated
              lactate dehydrogenase
              level, elevated liver
              enzyme levels, elevated
              homocysteine levels,
              elevated prolactin levels,
              proteinuria

TSH = Thyroid-stimulating hormone, MCV = mean corpuscular volume.
TABLE 4.

Etiology of Hypothyroidism

Type                      Disorder

Primary hypothyroidism
 Reduced thyroid tissue   Autoimmune thyroiditis
                          [I.sup.151] therapy, External
                          irradiation, Thyroidectomy
 Infiltrative disorders   Neoplasia, leukemia, sarcoidosis,
                          Hemochromatosis, amyloidosis,
                          Mycobacterium tuberculosis
                          infection, Pneumocystis carinii
                          infection, cystinosis
 Reduced efficacy or      Medications
 production of thyroid     Lithium, amiodarone,
 hormone                   iodine/iodinated contrast,
                           medium, antithyroid drugs *,
                           phenylbutazone, sulfonamides
                           interleukin alpha, interleukin-2
                          Thyroid hormone resistance,
                          thyroiditis, iodine deficiency,
                          Inherited defects in biosynthesis
                          Thyroid agenesis/dysgenesis
Secondary hypothyroidism  Hypothalamic/pituitary disease

* Include propylthiouracil, methimazole, perchiorate.
TABLE 5.

Causes of Persistent Elevation of TSH During Thyroid Hormone Replacement
for Hypothyroidism


Problems with medication  Inadequate dose; noncompliance;
                          reduced potency of thyroxine;
                          exposure to light, moisture,
                          air; generic substitution
Decreased absorption      Malabsorption; Concomitant
                          medications; Ferrous sulfate,
                          Sucralfate, Aluminum hydroxide,
                          Cholestyramine, Cation
                          exchange resins
Enhanced metabolism       Drugs; anticonvulsants; *
                          Sertraline; rifampin
Others                    Thyroid hormone resistance;
                          deterioration in thyroid function;
                          pregnancy/estrogen (19)

* Include dilantin sodium and carbamazepine.

Acknowledgments. The authors gratefully acknowledge the assistance of Patsy Ellis and Nancy Milligan of the Mountain Home Veterans Affairs Medical Center Library Service; and the secretarial assistance of Dolores Moore and Ernestine Stewart at East Tennessee State University.

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From the Department of Medicine, East Tennessee State University, Johnson city; and the James H. Quillen veterans Affairs Medical center, Mountain Home. Tenn.

Reprint requests to Alan Peiris, MD, PhD, MRCP (UK), Department of Medicine, East Tennessee State University, PO Box 70622, Johnson city, TN 37614-0622.