Download central hypothyroidism: a diagnosis overlooked?

6 :1
CENTRAL HYPOTHYROIDISM:
A DIAGNOSIS OVERLOOKED?
Abstract
Central hypothyroidism (CH) is an uncommon cause of
hypothyroidism due to failure on the part of hypothalamicpituitary-thyroid regulatory mechanism. Patients with CH
frequently present with multiple other pituitary hormone
deficiencies. In addition to classic CH induced by hypothalamicpituitary tumors or Sheehan syndrome, novel causes include
traumatic brain injury or subarachnoid hemorrhage, bexarotene
(a retinoid X receptor agonist) therapy, neonates being born
to mothers with insufficiently controlled Graves disease and
lymphocytic hypophysitis. Growth Hormone therapy, which may
be used in children and adults, is now also recognized as a possible
cause of unmasking CH in susceptible individuals. In addition,
mutations in genes have been associated with CH. The difficulty
in making a clear diagnosis of CH makes one frequently tend
to overlook this condition. Appropriate doses of levothyroxine
for T4 replacement therapy need to be higher than presently
used empirical doses in patients with CH. It should be adjusted
according to age and other hormone deficiencies to achieve free
T4 concentrations in the upper end of the normal range. Apart
from central hypothyroidism other hormonal deficiencies should
be looked for and suitable replacement therapy be initiated.
INTRODUCTION
“A diagnosis is easy as long as you think of it”
Soma Weiss (1899-1942), U S Physician
Primary hypothyroidism due to failure of thyroid gland leading to
low levels of circulating thyroid hormones and elevated Thyroid
Stimulating Hormones (TSH) with overt clinical features such as
typical facies, dry skin, hoarse slow speech and bradycardia is a
common clinical condition occurring in 10% of women and 6%
of men. It is easily diagnosed with the advent of sensitive (TSH)
assays, another 10% are diagnosed in the sub-clinical stage with
elevated TSH but with normal thyroid hormones. But what is not
so common and what one tends to overlook is a condition where
the TSH is normal or low despite low levels of thyroid hormones
denoting a failure on the part of hypothalamo-pituitary regulatory
mechanism and is referred to as ‘central hypothyroidism’ with
its inherent diagnostic and therapeutic problems. In this article
it is proposed to discuss in brief the aetiopathogenesis, clinical
KJ Shetty, Punit Bedi, Bangalore
presentation, diagnosis and management of this condition.
DEFINITION
Central hypothyroidism (CH) is defined as hypothyroidism due to
insufficient stimulation of the thyroid gland by Thyroid Stimulating
Hormones (TSH), the secretion or activity of which is impaired
at the hypothalamic or pituitary level1. Consequently despite low
thyroid hormones TSH is low or sometimes paradoxically normal.
PREVALENCE
The precise prevalence of CH is unknown but is thought to be
much lower than that of primary hypothyroidism. Considering
that the most frequent course of CH is due to sellar or suprasellar
pathology and that of prevalence of pituitary tumours in the
general population is greater than 10% the true prevalence of CH
might be higher than reported 2. Martino et al found that 15% of
the 300 patient with pituitary adenomas examined in one year had
CH 3. Vern Tijn et al reported the evidence of congenital CH to
be one in 16,404 neonates with 13.5% of them having permanent
hypothyroidism4. Similarly traumatic brain injury, subarachnoid
hemorrhage, Sheehan’s syndrome and lymphocytic hypophysitis
may all cause CH along with deficiency of multiple pituitary trophic
hormones up to several decades
PATHOPHYSIOLOGY
As has already been brought out the primary pathology/
pathophysiology in CH is at the hypothalamo-pituitary level
(HPT axis). The normal function of the HPT axis involves
thyrotrophin releasing hormones (TRH) secreted mainly from
the paraventricular nucleus of hypothalamus in the thyrotrophs of
the anterior pituitary which produces the thyrotrophic secreting
hormones (TSH). The TRH binds to the TRH receptors in the
anterior pituitary and apart from the thyrotrophic effect also
regulates the conjugation of TSH α and β chains and glycosylation
of TSH molecule to control its biochemical activity1 (Fig-1 and Fig2). The mature TSH secreted from the pituitary gland reaches the
thyroid gland where it stimulates the thyroid hormone production
Medicine Update 2010  Vol. 20
Table 1 : Causes of Central Hypothyroidism
Classic causes:
Space-occupying lesions (brain or pituitary; pituitary adenoma, craniopharygioma, etc.)
Radiation
Vascular disease (Sheehan syndrome, etc.)
Nonclassic causes:
Traumatic brain injury or subarachnoid hemorrhage
Drug-induced (bexarotene, carbamazepine, etc.)
Growth hormone therapy
Infection (lymphocytic adenohypophysitis, lymphocytic hypophysitis)
Set point diseases (infant’s born to mothers with inadequately controlled
Graves disease, etc.)
Genetic mutations
Idiopathic
‘tertiary’ if the hypothalamus is disturbed. Due to the close
anatomical functional and complex mechanism of TRH-TSH
secretion and the diagnostic difficulties of determining the
primary insult at either of these locations these terms are now
being abandoned.
CAUSES OF CENTRAL HYPOTHYROIDISM
Fig. 1 : The hypothalamic-pituitary-thyroid axis.
Abbreviations: COA, coactivators; NcoR, nuclear receptor corepressor;TR, thyroid hormone receptor;TRH,TSH-releasing hormone.
Depending upon the frequency with which one would encounter
different underlying causes of CH they are classified as ‘Classic’
if they are common and ‘Non-classic’ when they are uncommon.
Table 1 lists these separately.The relative incidence, the underlying
mechanisms and the clinical and hormonal profile of these
conditions will now be outlined.
CLASSIC (COMMON) CAUSES:
Pituitary Adenoma
This is the most frequent cause of CH accounting for more
than 50% of cases in most of the studies (2, 4, 5) . In a Spanish study
where 45 cases of CH occur annually per 1,00,000 of general
population as many as 61% were due to pituitary adenomas5.
Various patho-physiological mechanisms are implicated in the
causation of CH in pituitary tumors. Mechanical compression of
portal vessels and pituitary stalk caused by expanding adenoma
seems to be the predominant mechanism leading to multiple
hormonal deficiencies including TSH. Apart from the impairment
of blood supply – which may lead to ischemic necrosis of the
pituitary cells, delivery of the hypothalamic releasing hormone,
in this case TRH, may also be impaired. In most cases CH occurs
concurrently with other pituitary hormone deficiencies – a state
of panhypopituitarism but isolated TSH deficiency has also been
reported. In general LH/FSH deficiency occurs first and is noted
in 85% of patients followed by GH (45%), ACTH (62%) and TSH
(60%). ADH and TRL are preserved till the last 6,7 . In fact in most
cases due to pressure on the stalk and interruption of prolactin
inhibitory hormone there is often elevation of prolactin, leading
to mistaken diagnosis of prolactinoma.
Fig. 2 : TRH not only stimulates the secretion of TSH from the
pituitary but also regulates conjugation of the α and β chain of
the TSH molecule and affects glycosylation, which changes the
biological activity of TSH.
and release. The main hormone secreted by the thyroid is T4
which reaches the peripheral organs and is converted to T3 by
deiodinisation. T3 enters the cell nuclei and binds to thyroid
hormones receptors α and β isoforms on targeted genes thereby
regulating gene transcription. At the hypothalamic and pituitary
level the thyroid hormones inhibits production and secretion of
TRH and TSH – the negative feed back, thus establishing H-P-T
axis. CH will result if any factor in this axis is disturbed.
Till recently it used to be the practice to designate CH in to
‘secondary’ when the problem is at the level of pituitary and
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Central Hypothyroidism : A Diagnosis Overlooked?
Pituitary Tumor Apoplexy
Lymphocytic hypophysitis
Untreated macro-adenomas run the risk of infarction, outgrowing
their blood supply, leading to pituitary apoplexy- a catastrophic
event often leading to secondary adrenocortical failure, a life
threatening emergency 8. CH occurred in 54% of patients in one
study needing thyroxin therapy 9.Also these patients need life-long
thyroxin replacement along with other hormones – particularly
cortisone. It is reported that patients with prolactinoma and
macroadenomas treated with dopamine agonists reduced levels
of LH/FSH in 77% and TSH in 41% of patients.
CH is present in 44% of lymphocytic hypophysitis, an auto-immune
inflammatory disease of the pituitary gland. Women are slightly
more affected than men with the difference being greatest during
pregnancy and shortly after delivery16.
Infants born to mothers with Grave's diseases
Transient thyrotoxicosis effects occur in above 1% of babies born
to mothers with either active or previously treated Graves disease
17
. By contrast CH is also observed in neonates born to mothers
with inadequately controlled thyrotoxicosis during the last
trimester of pregnancy18.The incidence of this type of CH is noted
in at least 1 in 35000 neonates. Transient CH has been shown to
become permanent with need for thyroid hormone replacement
therapy. Insufficient TSH secretion due to excessive maternal to
fetal thyroid hormone transfer could inhibit development of
thyroid gland leading to low thyroid hormone levels.
Craniopharyngioma
A common parasellar tumor arising from embryonic squamous
remnants of Rathke’s pouch, they are often large, aggressive and
infiltrating. Gross hypopituitarism and hypothalamic disturbances
are common and CH occurs in more than 90% of cases10.
Empty Sella Syndrome
Growth Hormone Therapy
Primary empty sella syndrome has been reported in (6-20%) of
unselected autopsies. It is more common in obese women with
hypertension. Hypopituitarism occurs in 10-57% with mainly GH
and FSH/LH deficiency and CH occurring occasionally. Secondary
empty sella follows pituitary apoplexy,surgery or radiation therapy
and pan-hypopituitarism with CH is common requiring life long
hormonal replacement.
Sheehan’s Syndrome
Pan-hypopituitarism as a result of ischemic pituitary necrosis
following severe postpartum hemorrhage occurs in 56-84% of
cases and CH has been reported in as many as 90% of them.
Serum TSH levels are often paradoxically elevated due to reduced
biological activity. Also the time from childbirth to onset of
hormone deficiency can very from several days to a few decades13.
Radiation Therapy
External radiotherapy to head and neck might affect the
hypothalamus, pituitary and /or the thyroid gland. CH has been
observed in 20-50% of patients who have been irrhaled for
nasopharyngeal and paranasal tumors. Primary hypothyroidism
due to radiation thyroiditis occurs in another 20% of patients
with a clinical extency of 4.8 to 7 years 14.
NON-CLASSIC CAUSES:
Growth hormone deficiency masks CH and this disorder may
become evident only after administration of GH replacement
therapy 19. A notable reduction in serum T4 levels without
substantial increase in serum TSH was reported in 36% of
euthyroid adults with GH deficiency and T4 replacement therapy
was required.The mechanism of hypothyroidism after GH therapy
remains unclear. GH therapy has been reported to increase
peripheral deiodinisation of T4 to T3 perhaps producing more of
inactive T3. Also, the increased secretion of somatostatin may
block TSH secretion. Whether this effect is mediated by insulin
like growth factor I (IGF1) or is controlled directly by growth
hormone is not known.
Therapy with Retinoid Analogues
Bexarotene is synthetic retinoid analogue which is approved
for treatment of cutaneous T cell lymphoma. In clinical trials
bexarotene therapy was associated with development of CH in
40% of patients with reduction of serum TSH and T4 levels 20. In one
report 19 out of 27 patients receiving bexarotene had symptoms
or signs of hypothyroidism. This drug probably has two effects on
thyroid function: suppression of TSH production and increased
thyroid hormone metabolic clearance by mechanisms moderated
by deiodinisation and non-deiodinisation mechanisms.
Genetic Mutations
Traumatic Brain Injury and Subarachnoid Hemorrhage
Several genetic mutations causing CH have been reported and
these include mutations of TSHB,TRHR, POU1FI, PROP1, HESX1,
LHX3 and LHX4 genes. The commonest among these is TSHB
mutation causing familial isolated TSH deficiency, the inheritance
being autosomal recessive 21. In severe cases of CH typical signs
and symptoms of cretinism without goiter occur. Radioiodine
uptake in the thyroid is poor and increases after administration
of TSH. In the TRH receptor mutation first reported in 1997,
the patient should no TSH or prolactin response to TRH
administration and CH was mild with normal TSH level and the
Several studies have shown a surprisingly high prevalence of
hypopituitarism including CH brought about by traumatic brain
injury (TBI) and subarachnoid hemorrhage (SAH) 2,15. In a long term
follow up the prevalence of hypopituitarism was 28% after TBI and
47% after SAH. Since the signs and symptom of hypopituitarism
might be subtle and could overlap with neurologic and psychiatric
sequelae of TBI and SAH it may remain undiagnosed in many
cases. CH is however observed in 1 - 10% of patients after TBI
and 3-9% after SAH.
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Medicine Update 2010  Vol. 20
Fig. 3 : Proposed algorithm for the diagnosis and confirmation
of central hypothyroidism.
Abbreviations: GH = growth hormone; LAH = lymphocytic
adenohypophysitis; SAH = subarachnoid hemorrhage; SOL = spaceoccupying lesions;TBI = traumatic brain injury
Fig. 4 : Proposed algorithm for the treatment of central hypothyroidism
only manifestation was short stature . Mutations causing multiple
pituitary hormonal deficiencies have been described in HESX1,
SOX3, LHX3 and LHX4 genes. Both hormonal deficiencies and
the clinical presentations differ in different mutations.
22
Several animal models have been studied to gain insight into CH
caused by genetic mutations. In TRH knock-out mice, typical
tertiary hypothyroidism with low serum thyroid hormones and
elevated serum TSH levels were observed. As in humans TRH
testing revealed exaggerated response of serum TSH. However
serum T3 response to increased TSH was significantly impaired
indicating reduced biological activity of serum TSH 22.
DIAGNOSIS OF CENTRAL HYPOTHYROIDISM
Usual screening for hypothyroidism including clinical and
measurement of TSH might not detect CH. The most effective
way to diagnose CH is by measuring serum levels of free T4 (FT4)
and TSH. Subnormal levels of FT4 and inappropriately low level
of serum TSH usually indicates CH (Fig-3) although some patients
with CH have slightly high TSH levels. Several mechanisms have
been suggested to explain the differences and paradoxical values
of TSH: hypoadrenalism raising TSH, decreased secretion of
somatostatin from hypothalamus leading to increased secretion of
TSH and reduced biological and receptor binding activity of TSH.
Administration ofTRH to normal individuals produces a consistent
rise in serum TSH levels with peak values at 15-30 minutes with
notable decrease starting at 60 minutes. In the TRH stimulation
test TSH is measured before and at 15, 30, 60 & 180 minutes
after intravenous administration of TRH (10 mcg per kg of body
weight). Normal responses is defined as TSH greater than 40-50
mIU/L; absent or blunted if less then this and excessive delayed
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responses as TSH > 20.0 - 25.0 mIU/L or a peak response after
60 minutes. Many CH patients show either blunted or delayed
patterns.
Diagnostic value of TRH stimulation test has recently been
reevaluated 23-25.As a result it is now proposed to test the biological
activity of circulating TSH by measuring the increment of serum
free T3 in response to increased TSH. In normal individuals FT3
response to TRH stimulated TSH have been observed to increase
by 29-37% (mean 32%) at 120 minutes after stimulation while
FT4 levels increased by 14%. In CH this response is blunted.
Distinguishing between hypothalamic CH and pituitary CH by
TRH test can be difficult. Also normal TRH tests do not exclude
abnormalities in hypothalamo- pituitary – thyroid axis.
MANAGEMENT OF CENTRAL HYPOTHYROIDISM
Although TRH and TSH administration are theoretically ideal for
treatment of CH they have been abandoned due to high cost,
limited availability and instability of TRH after oral administration.
Almost all patients are treated with levothyroxine with an average
daily dose of 1.6 mcg / Kg body weight generally restores a
euthyroid state in primary hypothyroidism but the optimum dose
or dose range for CH is unclear. FT4 levels need to be kept at
the upper end of normal range rather than within the middle and
lower values. Also levothyroxine therapy needs to be tailored to
the age of the individual. Children require high doses up to 4.0
mcg/ Kg daily whereas in elderly individuals a dose of 1.0 mcg/
Kg would be sufficient. In patients with GH deficiency conversion
of T4 to active T3 may be deficient and increasing the dose and
monitoring FT3 rather than FT4 will be necessary 19 (Fig 4). In
postmenopausal women on estrogen and people on bexarotene
therapy need much higher doses of levothyroxine. Combination
therapy using levothyroxine and liothyronine showed no benefit
Central Hypothyroidism : A Diagnosis Overlooked?
over singly therapy 26.
10. Kendall-Taylor P et al.The clinical metabolic and endocrine features and
the quality of life in adults with childhood-onset craniopharyngioma
compared with adult-onset craniopharyngioma. Eur J endocrinol.2005;
152:557-567.
In many cases of CH measurement of TSH levels cannot be used
to monitor therapy since negative feed back regulation of TSH by
exogenous T4 can remain intact. When basal level of serum TSH is
normal in patients with CH concentration may decrease to very
low levels after treatment 27. Serum levels of FT4 and FT3 along
with plasma cholesterol, CPK, sex hormone binding globulin and
ACE are other peripheral markers which may be used.
11. Cannavo S et al. Abnormalities of hypothalamic-pituitary-thyroid axis
in patients with primary empty sella. J Endocrinol Invest..2002; 25:236239.
12.
Some cases of CH might be reversible and monitoring of pituitary
function would eliminate the need for life long substitution therapy.
For example - surgical excision of pituitary adenoma leads to
improvement of anterior pituitary function and CH in as many
as 35% of patients in whom T4 supplements were discontinued 28.
Similarly CH in neonates born to hyperthyroid mothers is often
transient and requires only short term supplementation.
CONCLUSION
While primary hypothyroidism is fairly common, central
hypothyroidism being much less common is often overlooked.
However its prevalence is probably higher than reported and one
needs to have increased awareness of this condition. It should be
suspected when low TSH levels are associated with subnormal
FT4 levels and further investigations to pinpoint the underlying
cause needs to be carried out.Apart from central hypothyroidism
other hormonal deficiencies will have to be looked for and suitable
replacement therapy for the deficient hormones needs to be
initiated.
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