Title: The Effects of Lithium Therapy on Thyroid and ThyrotropinReleasing Hormone J'H' Lazarus, Thyroid 8 1
1The Effects of Lithium Therapy on Thyroid and
Thyrotropin-Releasing Hormone---J.H. Lazarus,
Thyroid 8 (10) 909 1998 Oct.
- Chimei hospital
- Peir-jer Lin
- 8,Nov,2002
2Introduction
- In 1949, J.F.J. Cade, an Australian psychiatrist,
noticed that guinea pigs that had been given
lithium urate during an investigation into the
role of uric acid in manic patients became less
startled. - In 1967 the occurrence of goiter in patients
receiving lithium was mentioned and these data
were reported in 1968 by Schou and others. - Reviews lithium effect on cellular metabolism,
its effects on thyroid pathophysiology and
thyrotropin-releasing hormone
3Lithium on cell function
- Inhibition action on
- Adenosine monophosphate (ATPase) activity
- Cyclic adenosine monophosphate (cAMP) activity
- Inositol phospholipid metabolism
- Intracellular enzymes
- Stimulates DNA synthesis in thyroid cells
4Inositol phospholipid metabolism
- Uncompetitively inhibit inositol (1,4) P2
1-phosphatase --alteration of many intracellular
inositol metabolites, thus affecting signal
transduction, account for the therapeutic effect
in manic depression - treatment of GH3 cells with 1mM lithium for 7
days reduces basal and TRH-stimulated levels of
inositol 1,4,5-trisphosphate, and this is
associated with a reduction in the number of
cells showing basal calcium oscillations
5Inositol phospholipid metabolism
- The precise relation between intracellular
calcium secretion, lithium, and inositol
metabolism is complex and still unclear - lithium induces end organ resistance to TSH in
intact cells at least partly due to its
inhibition of adenylate cyclase
6Stimulates DNA synthesis
- Lithium stimulates DNA synthesis in thyroid cells
as well as after stimulation by IGF-1 - partly explain the goitrogenic action of lithium
- lithium may be capable of modulating the function
of G (i) -proteins coupled to IGF-1 receptors
during the G (1) phase of the FRTL-5 cell cycle - possibly via activation tyrosine kinase induce
cell proliferation in FRTL-5
7Effect on thyroid physiology
- Lithium is concentrated by the thyroid
- Inhibits the coupling of iodotyrosines to form
iodothyronines - Reduction I-131 release rateand thyroxine release
- Decrease T4 deiodination and conversion to T3
- Lithium on thyroid hormone metabolism in the
mood-stabilizing effects of the drug similar to
other psychotropic agents? - Affects cellular and humoral immunity
8Lithium is concentrated by the thyroid
- It is concentrated in mouse salivary glands,
which also actively concentrate iodide, perhaps
suggesting a common pathway - In human, lithium administration may result in a
reduced, as well as an increased thyroidal
radioiodine uptake. The possible reasons for this
are that lithium causes iodide retention and the
increase in uptake may also be due to TSH
secreted as a result of lithium-induced
hypothyroidism
9Iodotyrosine coupling defect
- Although thyroid hormone synthesis may be
impaired, total iodination is not reduced and the
overall effect is mild - Lithium may alter thyroglobulin structure by
affecting protein conformation and function,
thereby leading to minor iodotyrosine coupling
defect, but no inhibitory effect of lithium on
the biosynthesis or degradation of thyroglobulin
in the rat
10Reduction I-131 release rate and thyroxine release
- The block may be distal to cAMP formation
- Decrease in colloid droplet formation and
degradation of thyroglobulin - Alter tubulin polymerization
- Decrease T4 clearance inhibition of thyroid
hormone secretion, thereby inducing decrease in
type I 5 dediodinase activity
11Decrease T4 deiodination and conversion to T3
- Administration fo lithium to rats for 14 days has
been shown to affect intracellular metabolism of
thyroid hormones in the frontal cortex of the rat
by increasing the type II deiodinase and type III
enzyme - It is still not clear whether these changes in
deiodinase activity result from a direct action
of lithium on the brain or perhaps by a reduction
in serum T4 levels leading in turn to a rise in
5D-II activity - Repeated lithium treatment increase THRa1mRNA in
rat cortex, decrease in the hypothalamus and had
no effect in the cerebellum
12Affect on cellular and humoral immunity
- Enhanced lymphocytes mitogens
- Stimulates interleukin-2
- Inhibits suppressor T cells
- Increase secretion of immunoglobulins
- High proportion of patients receiving lithium as
having detectable antithyroid antibodies, and
lithium therapy is associated with a rise in
these titers - Thyroid autoimmunity may be weakly associated
with subtypes of bipolar disorder
13Clinical effects on thyroid function
- Goiter
- Hypothyroidism
- Thyrotoxicosis
- Therapy with exophthalmos
14Goiter
- Prevalence from 5.6 to 6.1
- Significant thyroid enlargement after 3 months of
lithium treatment in normal female volunteers
after 28 days of lithium therapy - Smooth and nontender
- Clinical, it may develop within weeks or months
to years of lithium treatment - Inhibition of thyroid hormone release that
results in an increase TSH
15Hypothyroidism
- Not different from that seen in other forms of
hypothyroidism - Symptoms appear within weeks of starting lithium
- Female to male ratio about 51
- Prevalence about 3.4
- Risk higher in women with thyroid antibodies
- Unlikely that lithium can significantly induce
the de novo production of thyroid antibody
16Thyrotoxicosis
- Occurred after many years of lithium therapy in
most - Including Graves disease, toxic nodular goiter
and silent thyroiditis - Recent report granulomatous thyroiditis, show
extensive follicular destruction with no
lymphocytic infiltration may directly damage
thyroid cells - Lithium treatment mask underlying hyperthyroidism
17Lithium therapy with exophthalmos
- In a bipolar patient who developed thyrotoxicosis
with severe exophthalmos while taking lithium,
the eye signs regressed when lithium was
discontinued
18Effect on the hypothalamic pituitary axis
- In cross-sectional studies, lithium exaggerated
TSH response to TRH in at least 50 of patients - Basal prolactin concentrations are not raised
- Explanation with feedback effect of reduced
thyroid hormones levels may not valid - Effect on pituitary thyroid hormone receptors may
also a cause - Impairment of HPA axis was temporary, it appears
the HPA axis adjusts to a new level of stat.
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