THE ENDOCRINE SYSTEM

Hyperthyroidism¡ªGraves' Disease

A 34-year-old woman has a 3-month history of nervousness, tremor, palpitations, increased sweating, and discomfort with heat. She had lost 15 pounds despite increased food intake. She also noted muscle weakness and easy fatigability with exercise to which she was ordinarily accustomed. She had missed two consecutive menstrual periods. On physical examination, pulse was 110 beats/min at rest and rose to 150 beats/min with 30 seconds of rapid stair climbing. Blood pressure was 150/60 and respirations were 20/min. Her skin was warm and moist, her speech was rapid, her gaze had a stare quality, and her movements were hyperkinetic. She exhibited a tremor and very rapid reflexes, and she was unable to rise without assistance from a squatting position. The cardiac impulse was hyperdynamic, and the thyroid gland was diffusely enlarged. Laboratory studies showed a total serum T4 level of 26 µg/dl (normal 5 to 12), a free T4 of 4.1 ng/dl (normal 0.8 to 2.4), and a serum TSH of 0.01 mIU/ml (normal 0.5 to 5). A 24-hour uptake of radioactive iodine was 70% (normal 8% to 30%). A pregnancy test was negative. The patient was treated with a thiouracil drug. Four weeks later her symptoms had improved, and serum T4 had decreased to 11 µg/dl. However, after 12 weeks of the same dose of the thiouracil drug, serum T4 had decreased further to 4 µg/dl, and she complained of the recurrence of fatigue, lethargy, and intolerance to cold. Her weight had increased 20 pounds to a level above her usual healthy weight. Resting pulse was 54 beats/min. The thyroid gland, which had begun to decrease in size with drug treatment, had now grown even larger than before treatment.

1. By what mechanisms did an excess of thyroid hormone cause the various symptoms and physical findings this patient exhibited? How did her cardiac output and systemic vascular resistance compare with normal?

2. What genes may have been overexpressed or repressed by the high levels of thyroid hormone?

3. What was her serum level of triiodothyronine (T3) likely to be and why? Would this contribute to her clinical state?

4. Why was her serum TSH so low?

5. Under what circumstances could her serum TSH have been elevated?

6. If her pregnancy test had been positive, how might this have affected her serum thyroid hormone levels?

7. What was the significance of her elevated radioactive iodine uptake?

8. What is the mechanism of action of the thiouracil drug?

9. What resulted at 12 weeks of therapy from continual exposure to the maximal dose of thiouracil drug?

10. What was her serum TSH level likely to be at that point and why?

11. Why did her thyroid gland reenlarge?

[ANSWER]

1. Loss of weight despite normal food intake indicates negative caloric balance caused by energy expenditure exceeding energy intake. An excess level of thyroid hormone has increased the patient's basal or resting metabolic rate, that is, the rate of oxygen

utilization above normal. In addition, thyroid hormone excess has caused a negative nitrogen balance, with the rate of protein degradation exceeding the rate of protein synthesis, so that lean body mass and bone mass have declined along with adipose tissue. The high basal metabolic rate induced by thyroid hormone is accompanied by increased heat production, which causes intolerance to high environmental temperatures and stimulates mechanisms of heat loss, such as sweating and hyperventilation. Nervousness, tremor, rapid reflexes, and tachycardia reflect increased adrenergic nervous system activity. Muscle weakness is caused by a loss of muscle mass that results in enhanced proteolysis. Increased fatigability with exercise is caused by inefficient generation of ATP and reduced stores of creatine phosphate. The patient's cardiac output has been increased through thyroid hormone-induced increases in preload, cardiac contractility, and stroke volume. Systemic vascular resistance is decreased; this is attributable to local vasodilation caused by increased rates of tissue metabolism.

2. Enhanced expression of myosin heavy chain alpha genes and repression of myosin heavy chain beta genes increases the velocity of myocardial contraction. The increase in basal oxygen utilization is partly caused by enhanced expression of the Na+, K+-ATPase gene. Overactivity of the sympathetic nervous system is partly caused by enhanced expression of the beta adrenergic receptor gene.

3. The serum T3 level would be elevated. This is largely attributable to the high serum level of T4, from which most T3 is derived by peripheral conversion. To a lesser extent T3 secretion is increased by the enlarged thyroid gland. T3 is the active metabolite of T4, and it binds with tenfold greater affinity to the nuclear thyroid hormone receptor. Therefore increased T3 accounts for most of the patient's clinical signs.

4. Excess secretion of thyroid hormone almost always results from disease intrinsic to the thyroid gland, and therefore such secretion is autonomous and independent of TSH stimulation of the gland. The resultant high serum T4 and T3 levels inhibit TSH secretion by blocking the effect of TRH on the pituitary thyrotrophs. The serum TSH level is therefore low.

5. The serum TSH level would be elevated only in the rare case in which hypothyroidism was caused by excessive release of TRH or by secretion of TSH from a pituitary neoplasm.

6. Normal pregnancy is accompanied by high levels of estrogenic hormones. Estrogen increases the level of serum thyroid-binding globulin and therefore increases binding capacity. Consequently, total serum T4 rises but free T4 remains essentially normal, and the pregnant woman is basically euthyroid. The negative pregnancy test eliminates this consideration in the patient. In addition, the serum free T4 was clearly elevated.

7. An increased rate of synthesis of T4 requires increased availability of iodide to the thyroid gland. If the total body pool of iodide stays normal, then a larger than normal percentage of that pool must be taken up by the thyroid gland each day to maintain a high level of thyroid hormone synthesis and release.

8. Thiouracil drugs inhibit the enzyme peroxidase, which catalyzes all steps in thyroid hormone synthesis from iodide and tyrosine. In addition to reducing T4 synthesis and release, thiouracil drugs inhibit the enzyme 5' monodeiodinase and thereby decrease the peripheral production of T3 from T4.

9. Although the thiouracil drug was initially beneficial, continued suppression of thyroid hormone synthesis produced a state of hypothyroidism. The basal metabolic rate decreased below normal, leading to inordinate weight gain. Cold intolerance resulted from subnormal thermogenesis. Bradycardia and lethargy resulted from diminished adrenergic nervous system activity.

10. When the patient developed hypothyroidism, the operation of negative feedback caused an elevation in the serum level of TSH. Low serum T4 and T3 levels elicit overstimulation of the pituitary thyrotrophs by TRH.

11. The thyroid gland was initially enlarged because of hyperthyroidism (Graves' disease). The later reenlargement of the thyroid gland during thiouracil therapy reflected the trophic action of excess TSH acting through its thyroid plasma membrane receptor to stimulate DNA, RNA, and protein synthesis.