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 hypothalamicpituitary 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 thyrotropinreleasing 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 radiationinduced 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 TSHinactivating 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 hypothyroidism cold hands and feet 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.
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