MANAGING HYPOTHYROIDISM

REGULATION OF THYROID HORMONE LEVELS
    Thyroid hormone levels are regulated by a feedback mechanism beginning with the hypothalamus, which synthesizes and releases the tripeptide thyrotropin-releasing hormone (TRH). Released into the portal circulation, TRH stimulates synthesis and release of the glycoprotein thyroid-stimulating hormone (TSH) by the thyrotroph in the anterior pituitary. TSH stimulates the thyroid to synthesize and release thyroxin (T4), which comprises about 80% of total circulating thyroid hormone, and triiodothyronine (T3), the bioactive form that comprises only about 20% of circulating thyroid hormone. Some 35% of Peripheral T4 is converted to T3 by monodeiodination (by 5'-deiodinase type I, present in almost all peripheral tissues), a process responsible for producing about 80% of total T3 (both active triiodothyronine and inactive reverse triiodothyronine). About 20 times as much T4 is released from the thyroid as T3; and T3 has 4 times the bioactivity of T4. Regulation of conversion of T4 to T3 is a highly-evolved system that regulates metabolic rate very precisely; and the amount of T3 generated from T4 varies with a number of factors including daily caloric intake, level of physical activity, level of stress, and illness.
    Fully 99% of circulating T3 and T4 is bound to serum proteins (thyroid binding globulin [TBg], thyroid binding prealbumin [TBPA], and albumin [Tba]) and circulate in reverse equilibrium with residual amounts of free hormone. Since T4 has greater affinity than T3 for both TBg and TBPA, serum levels of T4 are higher and T4 half-life is longer. Unbound T3 and T4 enter the anterior pituitary where portions of T4 are again converted to T3. The T3 binds to the nuclear receptor in the thyrotroph, which responds to the level of receptor activation by up-regulating or down-regulating TSH secretion. Thus, when levels of circulating T3 and T4 decrease, production of TSH increases to stimulate hormone production and release; but when levels of circulating T3 and T4 increase, TSH is suppressed.

HYPOTHYROIDISM
    A number of situations can lead to underactive thyroid, resulting in levels of T3 and T4 lower than normal and TSH levels higher than normal. Primary hypothyroidism typically presents as chronic lymphocytic thyroiditis, the most common cause of hypothyroidism in the United States since the addition of iodine to table salt. Also known as Hashimoto's thyroiditis, this condition is characterized by autoimmune antibodies to thyroid tissues (antithyroid peroxidase antibodies or antimicrosomal antibodies commonly detectable in the blood) and enlarged thyroid (goiter) with diminished capacity to produce thyroid hormones. The disease is 5 to 10 times more common in women than in men, and it is not uncommon for patients to develop other autoimmune-associated illnesses like diabetes mellitus and pernicious anemia. It affects some 25% of elderly women in the United States, a much greater incidence than in other countries where diets are typically lower in iodine content. Thus, it is conjectured that though supplementing dietary iodine may decrease the incidence of hypothyroidism due to iodine deficiency, it may well increase the incidence of Hashimoto’s thyroiditis.
    Inflammation of the thyroid occasionally follows pregnancy (postpartum thyroiditis) or viral infection (subacute thyroiditis) and can lead to an initial temporary hyperthyroid state where the inflamed thyroid releases excess amounts of thyroid hormones into the blood stream resulting in hyperthyroidism. Once gland is depleted of thyroid hormones, though, hypothyroidism follows and can last for 3 to 6 months until the thyroid gland fully recovers.
    Surgical removal or radiological destruction of the thyroid as treatment for malignancy of the thyroid or surrounding tissues will also terminate thyroid function; and the rare case of birth without a thyroid must be quickly diagnosed in order to supplement and avoid cretinism. Hypothyroidism can also be induced by medications. Of course, like surgical removal and radiological destruction, agents used to treat hyperthyroidism can obviously cause hypothyroidism, specifically propylthiouracil and methimazole. Lithium given for bipolar disorder and amiodarone can both cause hypothyroidism in some cases, and high iodine intake can also reduce thyroid function; so SSKI, Lugol's solution, and seaweed can all become problematic in some patients and/or high doses. Patients on such medications should have regular assessment of thyroid function.

SYMPTOMS
    Though mild hypothyroidism is usually asymptomatic, symptoms become more obvious as the disease progresses and generally reflect slowing of metabolic rate. Symptoms commonly include fatigue, weakness, intolerance to cold, constipation, excessive sleep, dry coarse hair, hair loss, dry skin, muscle cramps, increased cholesterol level, weight gain, depression, decreased concentration, poor hearing, and husky voice. Women may experience dysmenorrhea or amenorrhea, while men may experience erectile dysfunction or loss of libido. Even subclinical hypothyroidism can decrease left ventricular ejection fraction to affect cardiac function significantly over time, and dyslipidemia is a common finding even in subclinical cases.

DIAGNOSIS
    Hypothyroidism is suspected in patients presenting with fatigue, intolerance to cold, constipation, bradycardia, dry flaky skin, and coarse hair; but lab findings are essential to confirm the diagnosis. Though levels of Total T4, Total T3, free T4 and free T3 may be within normal ranges in early disease, they can be expected to drop as the disease progresses. TSH levels will be elevated in all cases of primary hypothyroidism (hypothyroidism caused by an underactive thyroid gland), so this has come to be regarded as the most reliable test of primary hypothyroidism. TSH assay reliability has improved steadily over the past 10 years, so it is now considered very accurate. Patients receiving IV infusions of dopamine or any form of glucocorticoids will frequently have low serum TSH, as these agents inhibit the synthesis and release of TSH.
    Detection of anti-thyroid antibodies is also very significant, in that a patient testing positive for antibodies can almost always be expected to develop hypothyroidism even if TSH, T3, and T4 levels are currently within normal ranges.

Thyroid Product Comparison

Product T4 T3 Comparative Equivalents Levothyroxine (Levothroid, Synthroid, 1 0 0.05 to 0.06 mg1 Levoxyl, Levo-T, Eltroxin) Liothyronine (Cytomel, Triostat) 0 1 15 to 37.5 mcg Liotrix (Thyrolar) 4 1 50 to 60 mcg T4 2.5 to 15 mcg T3 Thyroid Strong 3.1 1 45 mg
Desiccated Thyroid (Armour and others) 2 to 5 1 60 mg Thyrar, SPT

TREATMENT
    Desiccated thyroid and thyroglobulin are derived from beef or pork and are difficult to standardize by iodine content or bioassay; so synthetic derivatives are more reliable in this respect and thus generally preferred in most cases. Significant differences can be observed in bioassay between different brands of the same labeled strength, though; so patients started and regulated on a particular brand should remain on that brand in order to avoid complications.
     Thyroid hormone replacement therapy is currently based on the premise that providing only T4 allows the body to self-regulate the extent of conversion to the active T3. This policy provides more predictable and stable clinical results in most cases, avoiding the chronic intermittent hyperthyroid symptoms associated with the desiccated thyroid products. The use of products that contain both T3 and T4 is generally discouraged for this reason, and the lack of uniformity in T3 and T4 content of the natural products provides further reason to use only pure T4.    
    Though inappropriate for long-term use in hypothyroidism, pure T3 preparations can be appropriate in some cases: Short-term preparation for diagnostic testing or treatment of some thyroid cancers; Rapid correction in severely hypothyroid patients who need immediate results in critical health emergencies; and Adjunctive therapy for depression in some patients, even when not hypothyroid.
     Treatment, except in cases of temporary thyroiditis, is life-long; and since the disease is progressive, dosage adjustments can be expected throughout the life of the patient. Starting doses vary with the individual patient. Since most patients require daily doses between 0.1 and 0.15 milligram of l-thyroxine, healthy young or middle-aged patients can be started on 0.1 milligram daily with laboratory assessment in 4 months, according to many practitioners. Other clinicians prefer a more cautious approach reserved for the elderly patient or the patient with cardiovascular disease, starting with a dose of 0.025 milligram and increasing by 0.025 milligram every 3 or 4 weeks until TSH levels are optimized.
    Frequent assessment is discouraged, since a period of up to 3 months may be required for TSH levels to establish a new baseline in response to therapy on any dose. Four months after initiating therapy or changing dosage is the optimal time for lab assessment. The common therapeutic mistake is made of beginning therapy, assessing in 6 weeks to find TSH still elevated, increasing the dose, reassessing in another 6 weeks to find TSH still elevated, . . . until at 4 months, TSH levels indicate over-treatment.

IMPORTANT INTERACTIONS WITH THYROID HORMONES
Factors Affecting Thyroid Hormone Efficacy
    Ferrous sulfate, aluminum hydroxide, sucralfate, colestipol, and cholestyramine can all interfere with absorption of thyroid hormone, and absorption is significantly better on an empty stomach – 30 minutes before a meal. High-fiber diets (and soy formula fed to infants) can also interfere with absorption, as can short bowel syndrome, jejunal bypass, and cirrhosis.    
    Since estrogen increases TBg levels, pregnancy, oral contraception, or estrogen replacement therapy can affect thyroid hormone efficacy and require dosage adjustment. Infectious hepatitis, nephrosis, acromegaly, and androgen or corticosteroid therapy also affect TBg levels, so close monitoring of thyroid dosage efficacy is recommended for such patients. Since oral doses pass through the liver, other medications affecting the microsomal cytochrome P450 enzyme systems can reduce the efficacy of l-thyroxine doses, most notably carbamazepine, phenytoin, phenobarbital, and rifampin. Amiodarone impairs the ability of the patient to convert T4 to T3.

Other Therapies Affected By Thyroid Hormones        
    The thyroid hormones tend to increase the rate at which clotting factors dependent upon vitamin K are removed from the circulation, so the effects of anticoagulants can be significantly potentiated.    
    Conversion from hypothyroid to euthyroid states increases hepatic blood flow and potentiates the action of microsomal enzymes, so metabolism and elimination of beta-blockers (specifically metoprolol or propranolol) may be enhanced to require dosage adjustment of the beta blocker.
    Theophylline clearance is similarly affected, with hypothyroid states associated with impaired theophylline clearance and hyperthyroid states associated with increased theophylline clearance. Maintenance of euthyroid states in patients taking theophyllines is essential to optimize theophylline therapy and avoid toxicity.
    The therapeutic effects of digitalis glycosides can be similarly diminished by conversion from hypothyroid to euthyroid states as well as by hyperthyroidism (or over-treatment of hypothyroid states).

OVER-TREATMENT
    Over-treatment is all too common, and was particularly so until TSH assay achieved current levels of reliability. Of course, cardiac effects are a primary concern, but recent evidence suggests that over-treatment significantly increases the risks of osteoporosis. Since most of those treated for hypothyroidism are women of postmenopausal age, for whom the risks of osteoporosis are already high, increasing those risks is unacceptable. Fortunately, availability of more accurate TSH assay technology has made it possible to avoid over-treatment and thus, this potential problem.
    Over-treated patients will periodically complain of a fluttering in the chest, and such palpitations are well documented. Ensure that the l-thyroxine dosage is appropriate with TSH assay, and treat the palpitations with a beta-blocker if necessary; but be wary of arrhythmias. The over-treated patient also frequently complains of hair loss, depression, nervousness and agitation, insomnia, tremor, or muscle weakness.

CONCLUSION
    The symptoms of hypothyroidism are common, so most people will experience cold, depression, constipation, and fatigue, particuarly with increasing age. Menstrual irregularities, muscle cramps, fluid retention, weight gain, and changes in libido are also significant problems for which to find a medical remedy. Thus, it is imperative to assess each individual by careful analysis of symptoms and history as well as lab results. T4 is the treatment of choice, is generally well-tolerated, and highly-effective, though continued monitoring (at least on an annual basis) is appropriate for most hypothyroid patients, who will receive life-long treatment. It is important to allow TSH levels to normalize with initial treatment as well as any dosage change, a process that usually requires up to four months for accurate readings.
    With the exception of elderly or cardiovascular patients, treatment should begin with moderate dosage and increased gradually in increments of 0.025mg every 3 to 4 weeks to treat symptoms, as the consequences of over-treatment in this patient group are minimal.

REFERENCES
Tatro, D. Drug Interaction Facts, 1998 Edition Thyroid Hormones, Drug Facts and Comparisons, Electronic Edition, December, 1998.
Hypothyroidism, Medicine Net: http://www.medicinenet.com/Art.asp?li=MNI&ag=Y&ArticleKey=914 Bigos, T.
Thyroid Hormone Therapy, The Bridge Volume 11 Number 1: http://www.clark.net/pub/tfa/vol11no1.htm#hormone Braverman, L.
Treatment Guidelines for Hyper- and Hypothyroidism, Audio CME on Helix: http://cme.silverplatter.com/cgi-bin/nvdeblank.pl?filename=frames.htx&1=ccc/endocrinology/cencme01/&menu=/glaxowellcome.htm