Medical Physiology: Integration Using Clinical Cases
687
tor in the neuromuscular junction. This is typical of antibody-
antigen reactions, in which antigens are removed from the
body (Chapter 18). In Graves’ disease, however, the autoan-
tibodies are highly unusual in that they not only recognize
and bind to the TSH receptor on thyroid follicular cells, but
this binding
stimulates
rather than destroys the receptor.
Therefore, TSIs stimulate the thyroid gland to synthesize and
secrete excess T
4
independently of TSH. The increase in T
4
would be predicted to suppress the secretion of TSH from
the anterior pituitary gland by negative feedback, which is
consistent with the low serum TSH level measured in the pa-
tient’s blood. The elevated serum T
4
probably also suppressed
the synthesis and release of thyrotropin-releasing hormone
(TRH) from the hypothalamus via negative feedback. (Serum
TRH levels are not determined in such situations because
TRH is secreted directly into the hypothalamo-pituitary por-
tal circulation. The actual amount of TRH from the hypo-
thalamus that reaches the systemic circulation is too small for
its measurement in blood in a peripheral vein to be useful.)
The total and free (not bound to plasma proteins) T
4
con-
centrations in the blood of this patient are elevated, confi rm-
ing the diagnosis of hyperthyroidism. Measurement of free T
4
is helpful because most of the circulating thyroid hormone in
the blood is bound to plasma proteins, so measuring the se-
rum T
4
that is not bound to plasma proteins proves that there
is an increase in the amount of biologically active T
4
. The sup-
pressed TSH confi rms that the T
4
is elevated independently of
stimulation from the anterior pituitary gland. This suppression
of serum TSH, as in our patient, is one of the hallmarks of
Graves’ disease and is often used as a screening test for many
disorders of the thyroid gland. Although TSI concentrations
can be measured in the serum in some patients, it is often not
necessary because the diagnosis of Graves’ disease is the most
likely, considering that it represents the majority of patients with
hyperthyroidism.
Although Graves’ disease was by far the most likely di-
agnosis, the physician ordered some additional tests to rule
out other possible causes of the symptoms. Serum electrolytes
were measured because they are important in the generation
and maintenance of membrane potentials (Chapter 6) and
their abnormalities can lead to weakness and palpitations. Se-
rum calcium and parathyroid hormone were measured because
weakness is a common fi nding in primary hyperparathyroid-
ism (Chapter 11). A normal fasting plasma glucose and pH
indicated that diabetes mellitus was probably not the cause of
the patient’s weakness and fatigue. A normal prolactin level
indicated that she does not have hyperprolactinemia, which
can cause abnormalities in the menstrual cycle (see Additional
Clinical Examples in Chapter 17).
Physiological Integration
Thyroid disease is relatively common, particularly in women,
in whom up to 10 percent will develop hyper- or hypothy-
roidism by the age of 60 to 65. Thyroid hormone has a wide
range of effects throughout the body and, therefore, an un-
derstanding of all the organ systems is extremely useful in
understanding the symptoms of thyroid disease.
One of the main effects of thyroid hormone is calorigen-
ic—it increases the basal metabolic rate (BMR). This increase
in metabolic rate is caused by activation of intracellular thyroid
hormone receptors (see Figure 5–4) that are expressed in cells
throughout the body. This leads to increased expression of
Na
+
/K
+
-ATPases as well as the synthesis of other cellular pro-
teins involved in oxygen consumption and metabolic rate in
many tissues (see Figure 3–45). The resultant increase in heat
production by our patient explains the warmness and moist-
ness of her skin and her heat intolerance. It also explains why,
despite eating more, she is losing weight because she is burn-
ing more fuel than she is ingesting.
The nervousness, irritability, and emotional swings are
likely due to effects of thyroid hormone on the central ner-
vous system, although the exact cellular mechanism of this is
not well understood. The symptoms also appear to be due to
an increased sensitivity within the central nervous system to
circulating catecholamines. The muscle weakness is probably
due to a thyroid hormone-induced increase in muscle protein
turnover, local metabolic changes, and loss of muscle mass.
Despite this, there appears to be an increase in the speed of
muscle contraction and relaxation, contributing to the hyper-
active refl exes observed in our patient.
Her thyroid gland is enlarged because TSIs are mim-
icking the actions of TSH to stimulate the thyroid gland to
grow. The enlarged thyroid with increased metabolic activity
explains why a bruit was heard over the thyroid gland. The
thyroid gland has a high blood fl
ow per gram of tissue even
in normal individuals. The increase in thyroid function in
Graves’ disease leads to a marked increase in blood fl ow to the
thyroid—so much so that it is audible with a stethoscope dur-
ing systole in some patients.
Her increased systolic blood pressure and heart rate can
be explained in several ways. First, there are direct effects of
thyroid hormones on the heart, such as an increase in tran-
scription of the myosin genes. Second, as described in Chap-
ter 11, Section C, thyroid hormone has permissive effects to
potentiate the effects of catecholamines on the cardiovascular
system. Finally, the small decrease in diastolic pressure may
result from arteriolar vasodilation and reduced total peripheral
resistance in response to increased tissue temperature and me-
tabolite concentrations (see Figure 12–51).
Increased thyroid hormone can directly inhibit the re-
lease of the pituitary gonadotropins FSH and LH. This can
lead to a decrease in release of gonadal steroids from the ova-
ries, an irregular pattern or complete loss of menstrual periods,
and a lack of ovulation. This explains the lower serum estrogen
levels at the middle of the menstrual cycle in our patient.
The eye fi ndings are among the most striking in many
patients with Graves’ disease (see Figure 19–1). The propto-
sis (bulging out of the eye) is likely due to the autoimmune
component of the disease, rather than to a direct effect of thy-
roid hormone. Supporting this idea is that proptosis can oc-
cur before the development of hyperthyroidism, and excessive
thyroid hormone therapy for hypothyroidism usually does not
cause proptosis. Furthermore, proptosis is caused by infi
ltra-
tion of white blood cells into the extra-ocular muscles behind
the eye, rather than being caused by TSIs. These cells release
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