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ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY 269
Case
47
Hypothyroidism: Autoimmune Thyroiditis
Shirley Tai is a 43-year-old elementary school teacher. At her annual checkup, Shirley complained
that, despite eating less, she had gained 16 lb in the past year. Her physician might have attributed this weight gain to "getting older" except that Shirley also complained that she has very
little energy, always feels cold (when everyone else is hot), is constipated, and has heavy menstrual flow every month. In addition, the physician noticed that Shirley's neck was very full. The
physician suspected that Shirley had hypothyroidism and ordered laboratory tests (Table 6-3).
TABLE 6-3
Shirley's Laboratory Values and Test Results
T,
TSH
T, resin uptake
Thyroid antimicrosomal antibodies
3.1 p.g/dL (normal, 5-12 ii.g/dL)
85 mU/L (normal, 0.3-5 mU/L)
Decreased
Increased
L. thyroxine; T3, triiodothyronine; TSH, thyroid-stimulating hormone.
Based on the physical findings and laboratory results, Shirley's physician concluded that Shirley
had autoimmune (Hashimoto's) thyroiditis and prescribed oral administration of synthetic
T4 (c-thyroxine). The physician planned to determine the correct dosage of T4 by monitoring
the TSH level in Shirley's blood.
1101 QUESTIONS
1. How were Shirley's symptoms of weight gain and cold intolerance consistent with a diagnosis
of hypothyroidism?
2. Review the regulation of thyroid hormone secretion by the hypothalamic-anterior pituitarythyroid axis. List the potential mechanisms that could result in decreased secretion of thyroid
hormones. How might you distinguish between these mechanisms as potential causes for her
hypothyroidism?
3. Based on the laboratory results, what is the etiology of Shirley's hypothyroidism? Why was her
T4 level decreased?
4. Why was the triiodothyronine (T3) resin uptake decreased?
5. Why was her thyroid-stimulating hormone (TSH) level increased?
6. Shirley's neck appeared full because she had an enlarged thyroid gland (goiter). If Shirley had
hypothyroidism, why was her thyroid gland enlarged?
7. Shirley is receiving hormone replacement therapy in the form of synthetic T,. How does her
body process this T 4 ? How is synthetic T4 expected to ameliorate her symptoms?
8. How was Shirley's serum TSH level used to adjust the dosage of synthetic T4?
9. What symptoms might Shirley experience if the dosage of T4 is too high?
270 PHYSIOLOGY CASES AND PROBLEMS
ANSWERS AND EXPLANATIONS
1. To understand the symptoms of hypothyroidism, we need to review the actions of thyroid
hormone and then predict the consequences of hormone deficiency. Like steroid hormones,
thyroid hormone acts by inducing the synthesis of new proteins. These proteins are responsible for the various hormone actions, many of which are metabolic. Thyroid hormone increases
both the basal metabolic rate (BMR) and 0 2 consumption (in part because it increases the synthesis of Na+-K- ATPase). Increases in BMR and 0 2 consumption lead to increased heat production. To provide additional substrates for oxidative metabolism, thyroid hormone increases the
absorption of glucose from the gastrointestinal tract and induces the synthesis of key metabolic
enzymes, including cytochrome oxidase, NADPH cytochrome C reductase, a-glycerophosphate
dehydrogenase, and malic enzyme. To supply more 0 2 for aerobic metabolism, thyroid hormone also increases cardiac output and ventilation rate. In adults, thyroid hormone is required
for normal reflexes and mentation. In the perinatal period, thyroid hormone is absolutely
required for normal development of the central nervous system.
Shirley had classic symptoms of hypothyroidism (deficiency of thyroid hormones): her BMR
was decreased, she had gained weight despite stable caloric intake, she was always cold (when
others were hot), and she lacked energy.
2. Refer back to Figure 6-2, which shows how the hypothalamic-anterior pituitary axis regulates
thyroid hormone secretion. The hypothalamus secretes a tripeptide [thyrotropin-releasing hormone (TRH)] that stimulates the thyrotrophs of the anterior pituitary to secrete TSH. TSH (a
glycoprotein) circulates to the thyroid gland, where it has two actions. (1) It increases the synthesis and secretion of thyroid hormones (T 4 and T,) by stimulating each step in the biosynthetic process. (2) It causes hypertrophy and hyperplasia of the thyroid gland.
The system is regulated primarily through negative feedback effects of thyroid hormone on
TSH secretion. Specifically, T3 down-regulates TRH receptors on the thyrotrophs of the anterior
pituitary, decreasing their responsiveness to TRH. Thus, when thyroid hormone levels are
increased, TSH secretion is inhibited. Conversely, when thyroid hormone levels are decreased,
TSH secretion is stimulated.
We can use Figure 6-2 to postulate three potential mechanisms for decreased thyroid hormone secretion: (1) primary failure of the hypothalamus to secrete TRH, which would decrease
TSH secretion by the anterior pituitary; (2) primary failure of the anterior pituitary to secrete
TSH; and (3) a primary defect in the thyroid gland itself (e.g., autoimmune destruction or
removal of the thyroid).
The three mechanisms that cause hypothyroidism are not distinguishable by their effects on
circulating thyroid hormone levels or by their symptoms. In each case, circulating levels of T3
and T4 are decreased, and symptoms of hypothyroidism occur. However, the mechanisms are
distinguishable by the circulating levels of TRH and TSH. In hypothalamic failure (very rare),
secretion of both TRH and TSH is decreased, leading to decreased secretion of thyroid hormones.
In anterior pituitary failure, secretion of TSH is decreased, leading to decreased secretion of
thyroid hormones. In primary failure of the thyroid gland (most common), secretion of thyroid hormones is decreased, but secretion of TSH by the anterior pituitary is increased. In this
scenario, the anterior pituitary gland is normal; TSH secretion is increased because of diminished feedback inhibition by thyroid hormones.
Thus, the most common cause of hypothyroidism (a primary defect in the thyroid gland) is
clearly distinguishable from the second most common cause (a defect in the anterior pituitary) by
their respective TSH levels. If the defect is in the anterior pituitary, TSH levels are decreased; if the
defect is in the thyroid, TSH levels are increased.
3. Shirley's laboratory results supported the conclusion that her hypothyroidism was caused by a
primary defect in her thyroid gland (decreased T, level and increased TSH level). Significantly,
ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY 271
she had increased levels of thyroid antimicrosomal antibodies, which are antibodies to the
peroxidase enzyme in the thyroid gland (see Figure 6-3). The peroxidase enzyme catalyzes the
major reactions in the synthesis of thyroid hormones [i.e., reactions involving oxidation of
1- to 1 2 , organification of 1, into monoiodotyrosine (MIT) and diiodotyrosine (DIT), and coupling of MIT and DIT to form T3 and T 4 ]. Because the circulating antibodies inhibited her peroxidase enzyme, Shirley's thyroid gland did not produce sufficient amounts of thyroid hormones. This form of primary hypothyroidism is called autoimmune thyroiditis (Hashimoto's
thyroiditis).
4. T3 resin uptake was decreased because Shirley's circulating T3 levels were decreased. T3 resin
uptake is determined by mixing radioactive T3 with a synthetic binding resin and a sample of
the patient's blood. The radioactive T3 first binds to thyroid-binding globulin (TBG) in the
patient's blood; any remaining radioactive T3 binds to the synthetic resin (i.e., resin uptake).
The more radioactive T3 that is left over, the greater the resin uptake. Thus, T3 resin uptake is
decreased when circulating levels of TBG are increased (more of the patient's TBG binding sites
are available, with less spillover to the resin) or when the patient's T3 levels are decreased (less
of the patient's own T3 occupies binding sites on TBG; more radioactive T3 binds to TBG and
radioactive T3 resin uptake is decreased).
5. Earlier, we discussed why Shirley's TSH level was increased. Briefly, a primary defect in her
thyroid gland led to decreased blood levels of T4 and T3. As a result, there was less negative
feedback inhibition by thyroid hormones on her anterior pituitary, resulting in increased
TSH secretion.
6. Because Shirley had hypothyroidism, perhaps you are surprised that she had a goiter (enlarged
thyroid gland). In fact, goiter can occur in both hyperthyroidism (hyperactive gland) and
hypothyroidism (hypoactive gland). In Shirley's case, decreased secretion of thyroid hormones
led to increased secretion of TSH. Through its trophic effects on the thyroid gland, TSH caused
hypertrophy, hyperplasia, and enlargement of the gland (even though synthesis and secretion
of thyroid hormones was diminished).
7. Synthetic T4 (or L-thyroxine) is processed in the body just like endogenous T4. In the target tissues, Tg, whether endogenous or synthetic, is converted either to T3 or to reverse T3 (rT 3 ). T3 is
the most active form of thyroid hormone, and rT 3 is inactive. Therefore, this conversion step
in the target tissues modulates how much active hormone is produced.
In Shirley's target tissues, synthetic T4 was converted to T3, which then executed all of the
physiologic effects of thyroid hormones, including increases in BMR, 0 2 consumption, and heat
production, and restoration of normal reflexes and central nervous system function.
If T 3 is the active form of thyroid hormone, you may wonder why it isn't administered
directly. Patients with hypothyroidism are more often treated with T4 because it has a much
longer half-life than T3 and, therefore, it can be taken less frequently.
8. The serum TSH level is used to adjust the dosage of synthetic T4 because TSH secretion is sensitive to feedback inhibition by thyroid hormones. If the replacement dose of T4 is correct, TSH
levels will decrease to normal. If too little T4 is given, TSH levels will remain elevated. If too
much T4 is given, TSH levels will decrease to below normal.
9. Excessive replacement of T., causes the classic symptoms of hyperthyroidism: weight loss despite
adequate food intake, heat intolerance, nervousness, diarrhea, and amenorrhea.
272 PHYSIOLOGY CASES AND PROBLEMS
Key topics
Basal metabolic rate (BMR)
filioriotyrosine (SIT)
Goiter
Hashimoto's thyroiditis
Hypothyroidism
Monoiodotyrosine (MIT ►
Peroxidase
T3 resin uptake
• Thyroid-stimulating hormone ITSH)
Thyrotropin-releasing hormone (TRH)
Thyroxine IT4)
Triiodothyronine (Ta)