The Effects of Lithium Therapy on Thyroid and ThyrotropinReleasing Hormone J'H' Lazarus, Thyroid 8 1

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The 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

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Introduction

• 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

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Lithium 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

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Inositol 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

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Inositol 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

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Stimulates 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

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Effect 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

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Lithium 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

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Iodotyrosine 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

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Reduction 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

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Decrease 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

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Affect 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

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Clinical effects on thyroid function

• Goiter
• Hypothyroidism
• Thyrotoxicosis
• Therapy with exophthalmos

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Goiter

• 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

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Hypothyroidism

• 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

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Thyrotoxicosis

• 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

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Lithium therapy with exophthalmos

• In a bipolar patient who developed thyrotoxicosis
  with severe exophthalmos while taking lithium,
  the eye signs regressed when lithium was
  discontinued

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Effect 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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