Central hypothyroidism is an important complication of pituitary
disease and, because TSH levels are not useful, the diagnosis and
therapeutic considerations are difficult.
Central hypothyroidism is defined as a reduction in circulating
thyroid hormone as a result of inadequate stimulation of a normal
thyroid gland by TSH and may be secondary, due to pituitary disease,
or tertiary, due to hypothalamic dysfunction. Causes include all
pathologic processes that affect the hypothalamus or pituitary including
tumors, Sheehan's syndrome, idiopathic hypopituitarism and infiltrative
diseases, such as sarcoidosis, histiocytosis and lymphocytic hypophysitis.
Radiation-induced central hypothyroidism is common in patients irradiated
for pituitary tumors. Tsang et al. retrospectively examined records
of 160 patients who had received radiation for non-functioning pituitary
adenomas 8 to 22 years before and found that 65% required thyroid
replacement therapy, with 23% of patients' hypothyroidism directly
attributable to the radiation therapy received . In addition,
hypothyroidism is common in patients receiving radiation for nasopharyngeal
or paranasal sinus tumors and brain tumors. Constine et al. evaluated
the endocrine function of 32 patients who had received radiation
for brain tumors, including gliomas, medulloblastomas and ependymomas,
from 2 to 13 years before, and found that 65% had low free T4 levels.
The probability of hypothyroidism depended on the amount of radiation
received, with doses of more than 5000 rads (50 Gy) to the pituitary
and hypothalamus necessary for the development of hypothyroidism.
Moreover, the longer the interval since irradiation, the more likely
a patient was to have developed hypothyroidism . Therefore, the
percentage of patients developing hypothyroidism may have been even
higher had the follow-up been longer. In addition, because the onset
of hypothyroidism may occur years after the administration of the
radiation, constant vigilance for the signs and symptoms of hypothyroidism
in this population is imperative and yearly monitoring of thyroid
hormone levels obligatory.
As in primary hypothyroidism, the symptoms of central hypothyroidism
include fatigue, apathy, weight gain, dry skin, constipation and
cold intolerance. Signs include periorbital edema, cool extremities,
delayed relaxation of the deep tendon reflexes and bradycardia.
The signs and symptoms of central hypothyroidism mimic those of
several other common conditions, and this disorder is therefore
difficult to diagnose. A low free T4 or free T4 index and a low
TSH in the setting of pituitary disease and signs and symptoms of
hypothyroidism point in a straightforward manner to the diagnosis
of central hypothyroidism. Unfortunately, however, the TSH is most
commonly in the normal range in cases of central hypothyroidism,
creating a confusing picture. Research has shown that, in some of
these cases, a bio-inactive TSH resulting from abnormal glycosylation
of the TSH molecule [3-6] explains the higher than expected TSH
levels. Therefore, although the serum TSH is measured as normal
in routine assays, performed by immunoradiometric assay (IRMA) or
immunochemiluminometric assay (ICMA), only a small proportion of
the TSH molecules function normally. Although these "normal"
TSH values can confound the diagnosis of central hypothyroidism,
it should be noted that a "normal" or slightly high TSH
is inappropriate when circulating thyroid hormone levels are low,
and that in cases of primary hypothyroidism, the TSH would be expected
to be much higher. Therefore, TSH is not a useful screen for the
diagnosis of this disorder.
The management of central hypothyroidism is further complicated
by the fact that the TSH cannot be used to monitor therapeutic response
to L-thyroxine therapy. When pituitary pathology is not present,
the TSH provides an accurate method of assessing the appropriateness
of circulating thyroid hormone levels for each particular patient.
However, pituitary or hypothalamic pathology often interrupts the
feedback mechanism by preventing normal release of TSH and/or TRH.
The consequences of this are two-fold. First, patients with pituitary
pathology or who have been irradiated cannot be screened for hypothyroidism
with TSH levels alone, as a normal TSH often belies central hypothyroidism.
Moreover, the usually routine monitoring of thyroid replacement
becomes more problematic. Inadequate replacement doses of l-thyroxine
often result in markedly subnormal TSH values. Therefore, TSH values
are not reliable as an accurate reflection of thyroid status, and
a free T4 or free T4 index must be used to adjust the replacement
dose. However, as in primary hypothyroidism, when appropriately
diagnosed and treated, management of central hypothyoidism can result
in prompt resolution of symptoms.