DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

which T 3
enhances the velocity of contraction. The chronotropic
effect of T 3
is mediated by increases in the pacemaker ion current I f
in the sinoatrial node. Several proteins that comprise the I f
channel
are induced by T 3
, including HCN2 and HCN4. Interestingly, T 3
also
appears to have a direct non-genomic vasodilating effect on vascular
smooth muscle (Hiroi et al., 2006), which may contribute to the
decreased systemic vascular resistance and increased cardiac output
of hyperthyroidism.
Metabolic Effects. Thyroid hormone stimulates the
expression of hepatic low-density lipoprotein (LDL)
receptors and the metabolism of cholesterol to bile
acids, such that hypercholesterolemia is a characteristic
feature of hypothyroidism.
Thyroid hormone has complex effects on carbohydrate
metabolism (Crunkhorn and Patti, 2008).
Thyrotoxicosis is an insulin-resistant state. Post-receptor
defects in the liver and peripheral tissues are manifested
by depleted glycogen stores and enhanced gluconeogenesis.
In addition, the rate of glucose absorption from
the gut is increased. Compensatory increases in insulin
secretion result in hyperinsulinemia. There may be
impaired glucose tolerance or even clinical diabetes,
but most hyperthyroid patients are euglycemic.
However, diabetic patients already on insulin may have
increased insulin requirements in the setting of hyperthyroidism.
Conversely, hypothyroidism results in
decreased absorption of glucose from the gut, decreased
insulin secretion, and a reduced rate of peripheral glucose
uptake. Glucose metabolism generally is not
affected in a clinically significant manner in nondiabetic
patients, although insulin requirements decrease
in the hypothyroid patient with diabetes.
Thyroid Hypofunction. Hypothyroidism, known as
myxedema when severe, is the most common disorder of
thyroid function. Worldwide, hypothyroidism resulting
from iodine deficiency remains an all-too-common problem.
In non-endemic areas where iodine is sufficient,
chronic autoimmune thyroiditis (Hashimoto’s thyroiditis)
accounts for most cases. This disorder is characterized by
high levels of circulating antibodies directed against thyroid
peroxidase and, less commonly, against thyroglobulin.
In addition, blocking antibodies directed at the TSH
receptor may be present, exacerbating the hypothyroidism.
The conditions just described are examples of
primary hypothyroidism, failure of the thyroid gland
itself. Central hypothyroidism occurs much less often and
results from diminished stimulation of the thyroid by TSH
because of pituitary failure (secondary hypothyroidism)
or hypothalamic failure (tertiary hypothyroidism).
Hypothyroidism present at birth (congenital hypothyroidism)
is the most common preventable cause of mental
retardation in the world. Diagnosis and early intervention
with thyroid hormone replacement prevent the development
of cretinism, as discussed earlier.
Common symptoms of hypothyroidism include fatigue,
lethargy, cold intolerance, mental slowness, depression, dry skin,
constipation, mild weight gain, fluid retention, muscle aches and
stiffness, irregular menses, and infertility. Common signs include
goiter (primary hypothyroidism only), bradycardia, delayed relaxation
phase of the deep tendon reflexes, cool and dry skin, hypertension,
nonpitting edema, and facial puffiness. Deficiency of thyroid
hormone during the first few months of life causes feeding problems,
failure to thrive, constipation, and sleepiness. Retardation of
mental development is irreversible if not treated promptly. Childhood
hypothyroidism impairs linear growth and bone maturation. Because
the signs and symptoms of hypothyroidism are nonspecific, diagnosis
requires the finding of an elevated serum TSH or, in cases of central
hypothyroidism, a decreased serum free T 4
. Because physicians
maintain a high index of suspicion, the diagnosis usually is made at
a relatively early stage. Thus, severe hypothyroidism and myxedema
coma are uncommon, except in hypothyroid patients who are noncompliant
with their thyroid hormone replacement therapy or individuals
without access to medical care.
Thyroid Hyperfunction. Thyrotoxicosis is a condition
caused by elevated concentrations of circulating free
thyroid hormones. Increased thyroid hormone production
is the most common cause, with the common link
of TSH receptor stimulation and increased iodine
uptake by the thyroid gland as shown by the measurement
of the percentage uptake of 123 I or 131 I in a 24-hour
radioactive iodine uptake (RAIU) test. TSH receptor
stimulation is either the result of TSH receptor stimulating
antibody in Graves’ disease or somatic activating
TSH receptor mutations in autonomously functioning
nodules or a toxic goiter. In contrast, thyroid inflammation
or destruction resulting in excess “leak” of thyroid
hormones or excess exogenous thyroid hormone intake
results in a low 24-hour RAIU. The term subclinical
hyperthyroidism is defined as those with a subnormal
serum TSH and normal concentrations of T 4
and T 3
.
Atrial arrhythmias, excess cardiac mortality, and excessive
bone loss have been associated with this profile of
thyroid function tests (Biondi and Cooper, 2008).
Graves’ disease is the most common cause of high
RAIU thyrotoxicosis (Brent, 2008). It accounts for
60-90% of cases, depending on age and geographic
region. Graves’ disease is an autoimmune disorder characterized
by increased thyroid hormone production, diffuse
goiter, and immunoglobulin (Ig)G antibodies that
bind to and activate the TSH receptor. This is a relatively
common disorder, with an incidence of 0.02-0.4% in the
U.S. Endemic areas of iodine deficiency have a lower
incidence of autoimmune thyroid disease. As with most
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CHAPTER 39
THYROID AND ANTI-THYROID DRUGS