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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.


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)


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.


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)


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)


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 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.

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

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;
Gastrointestinal Constipation; Megacolon
 Decreased appetite
Respiratory Snoring Hypoventilation;
 sleep apnea
Cardiovascular Dyspnea Hypertension *;
Bradycardia Pericardial
Nervous system Paresthesia Bradykinesia;
 Numbness Distal sensory loss;
 Unsteadiness Ataxia
 Reduced mentation Dementia;
 Headache; visual
 disturbances +

* Diastolic hypertension.

+ Findings in secondary hypothyroidism

CHF = Congestive heart failure.

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
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,

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

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.

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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(2.) Hickie I, Bennett B, Mitchell P, et al: clinical and subclinical hypothyroidism in patients with chronic and treatment-resistant depression. Aust N Z J Psychiatry 1996; 80:246-252

(3.) Chisholm JC Jr: Hypothyroidism: a rare cause of the bilateral carpal tunnel syndrome--a case report and a review of the literature. J Natl Med Assoc 1981; 73:1082-1085

(4.) Heymann WR: Chronic urticaria and angioedema associated with thyroid autoimmunity: review and therapeutic implications. J Am Acad Dermatol 1999; 40:229-232

(5.) Curnock AL, Dweik RA, Higgins BH, et al: High prevalence of hypothyroidism in patients with primary pulmonary hypertension. Am J Med Sci 1999; 318:289-292

(6.) Klein I, Levey GS: Unusual manifestations of hypothyroidism. Arch Intern Med 1984; 144:123-128

(7.) Cruz MW, Tendrich M, Vaisman M, et al: Electroneuromyography and neuromuscular findings in 16 primary hypothyroidism patients. Arq Neuropsiquiatr 1996; 54:12-18

(8.) Ciompi ML, Zuccotti M, Bazzichi L, et al: Polymyositis-like syndrome in hypothyroidism: report of two cases. Thyroidology 1994; 6:33-36

(9.) Arbelle JE, Porath A: Practice guidelines for the detection and management of thyroid dysfunction. a comparative review of the recommendations. Clin Endocrinol (Oxf) 1999; 51:11-18

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(11.) Waise A, Belchetz PE: Lesson of the week: unsuspected central hypothyroidism. BMJ 2000; 321:1275-1277

(12.) Intenzo CM, Capuzzi DM, Jabbour S, et al: Scintigraphic features of autoimmune thyroiditis. Radiographics 2001; 21:957-964

(13.) Winter WE, Signorino MR: Review: molecular thyroidology. Ann Clin Lab Sci 2001; 31:221-244

(14.) Martino E, Bartelena L, Bogazzi F, et al: The effects of amiodarone on the thyroid. Endocr Rev 2001; 22:240-254

(15.) Markou K, Georgopoulos N, Kyriazopoulou V, et al: Iodine-induced hypothyroidism. Thyroid 2001; 11:501-510

(16.) Wiersinga WM: Thyroid hormone replacement therapy. Horm Res 2001; 56(suppl 1):74-81

(17.) Kabadi UM, Kabadi MM: Serum thyrotropin in primary hypothyroidism: a reliable and accurate predictor of optimal daily levothyroxine dose. Endocr Pract 2001; 7:16-18

(18.) Bunevicius R, Kazanavicius G, Zalinkevicius R, et al: Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999; 340:424-429

(19.) Arafah BM: Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 2001; 344:1743-1749

(20.) Mandel SJ, Larsen PR, Seely EW, et al: Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 1990; 323:91-96

(21.) Haddow JE, Palomaki GE, Allan WC, et al: Maternal thyroid deficiency during pregnancy and subsequent neuropsycho logical development of the child. N Engl J Med 1999; 341:549-555

(22.) Farling PA: Thyroid disease. Br J Anaesth 2000; 85:15-28

(23.) Walch TJ: Enhancing compliance in schizophrenic patients by weekly dosing with levothyroxine sodium. J Clin Psychiatry 1994; 55:543

(24.) Ringel MD: Management of hypothyroidism and hyperthyroidism in the intensive care unit. Crit Care Clin 2001; 17:59-74

(25.) Wall CR: Myxedema coma: diagnosis and treatment. Am Fam Physician 2000; 62:2485-2490

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.
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Author:Peiris, Alan
Publication:Southern Medical Journal
Geographic Code:1USA
Date:May 1, 2002
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