DEVELOPMENT OF HYPERTHYROIDISM FOLLOWING PRIMARY HYPOTHYROIDISM

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DEVELOPMENT OF HYPERTHYROIDISM FOLLOWING PRIMARY
HYPOTHYROIDISM

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Case Report

• A 60-year-old male was presented with conscious
  disturbance in Mar 1992. Hyponatremia was noted
  at ER. The diagnosis of primary hypothyroidism
  due to Hashimotos disease was made on the basis
  of low serum T4 (1.1 µg/dL) and T3 (32.6 ng/dL),
  high TSH (153.429 µU/mL) , and positive AMiA
  (16400). Thyroxine was started.

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Case Report

• He received I-131 thyroid uptake and scan in
  April 1992, and the result was 2hr 1.7 (4-12)
  and 24hr 0.78 (15-40). Both thyroid lobes are
  hardly visualized due to very low uptake of
  radioiodine, and the findings suggest
  hypothyroidism.
• With the thyroxine therapy, the T3, T4 and TSH
  levels became normal.

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Case Report

• During the thyroxine therapy, in February 1998,
  he presented with body weight loss. The serum T4
  (13.9 ug/dL), T3 (240.7 ng/dL) were high, and TSH
  (0.024 uU/mL) was low. The thyroxine therapy was
  tapered and discontinued since September, 1998
• I-131 thyroid uptake and scan 2hr 1.31, 24hr
  40.9. Bilateral thyroid lobes are not enlarged
  with diffuse radioactivity.

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Case Report

• Six months later, he was still thyrotoxic with
  elevated serum T4 and T3 levels. Therapy with
  Tapazole was started. He has been euthyroid with
  Tapazole therapy till now.

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Discussion

• Development of hypothyroidism spontaneously or
  after ATD treatment in patients with Graves
  disease is well known and is believed to result
  from concomitant autoimmune thyroiditis ( Wood
  Ingbar 1979 Hirota et al. 1986) or emergence of
  blocking type TSH receptor antibodies (Kasagi et
  al. 1986)

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Discussion

• Development of hyperthyroidism following primary
  hypothyroidism is uncommon and only a few
  documented cases have been reported (Bell et al.,
  1985 Kasagi et al., 1986b Takeda et al., 1988
  Cho et al., 1989 Takasu et al., 1990)

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Discussion

• It is difficult to explain how a patient with
  hypothyroidism, conventionally thought to result
  from thyroid destruction, could subsequently
  develop hyperthyroidism
• Hypothyroidism previous to hyperthyroidism may be
  due to TSH receptor blocking antibodies causing
  reversible hypothyroidism secondary to their
  effects at the TSH receptor, without the
  necessary of there being severe gland destruction

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Discussion

• TSH receptor blocking antibodies have been
  reported in about 10 percent of patients with
  goitrous autoimmune thyroiditis and in about 20
  percent of those with atrophic autoimmune
  thyroiditis
• Among adults in whom these antibodies
  spontaneously disappear during treatment with
  thyroxine, only 40 percent remain euthyroid after
  therapy has been discontinued - (Takasu et al.
  NEJM, 1992)

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Discussion

• TSH receptor blocking antibodies contribute to
  hypothyroidism in about 5 to 10 percent of
  patients with chronic autoimmune thyroiditis
• Alterations of thyroid-related immunoglobulins in
  serum could be considered to explain in thyroid
  status ---- Steel et al.(1985)

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Discussion

• Two cases were reported Takeda et al.(1988), Cho
  et al.(1989) in which TSH receptor antibodies
  from blocking to stimulating type resulted in the
  development of hyperthyroidism after primary
  hypothyroidism

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Takeda et al. Clinical Endocrinology,1988, 28,
341-344
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Cho et al. Acta Endocrinologica, 1985, 120,
447-450
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Discussion

• Takasu et al.(1990) report seven patients with
  hypothyroidism due to Hashimotos disease, who
  developed Graves disease with hyperthyroidism.
  They also report one patient with hypothyroidism
  due to Hashimotos disease, who continued to be
  hypothyroid even in the presence of TSAb

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Conclusion

• Hyperthyroidism following primary hypothyroidism
  is a rare phenomenon and only 36 cases having
  been reported
• Only three cases were documented to have the
  changes of TSH receptor antibodies from blocking
  to stimulating type resulted in the development
  of hyperthyroidism after primary hypothyroidism

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Conclusion

• This phenomenon may be due to alterations of TSH
  receptor antibodies in serum, but the exact
  mechanism is still remained to be elucidated
• We should keep in mind that primary
  hypothyroidism due to autoimmune thyroiditis is
  not always life-long , and even thyrotoxicosis
  may eventually develop

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Antibodies to The TSH Receptor

• TSH receptor-stimulating antibodies stimulate
  cAMP production in thyroid cells and are
  responsible for hyperthyroidism in patients with
  Graves disease
• TSH receptor-blocking antibodies inhibit
  TSH-mediated activation of the receptor and may
  contribute to the development of thyroid atrophy
  and hypothyroidism in some patients with chronic
  autoimmune thyroiditis

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Assays for TSH receptor Antibodies

• Radioreceptor assay, which is based on the
  ability of serum of IgG to inhibit the binding of
  radiolabeled TSH to its receptor (TSH-binding
  inhibitory immunoglobulin, TBII)
• Bioassay, which can be used to measure either
  stimulating or blocking activity

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Assays for TSH receptor Antibodies

• Measurement of TSH receptor-stimulating
  antibodies is based on the ability of serum (of
  IgG) to stimulate adenylyl cyclase and therefore
  increase the production of cAMP by thyroid tissue
  or cultured thyroid cells
• Measurement of TSH receptor-blocking antibodies
  is based on the ability of serum (or IgG) to
  inhibit TSH Stimulation of adenylyl cyclase

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TSH receptor antibodies

• Among patients with Graves thyrotoxicosis, TBII
  tests are positive in 76 to 95
• TSH receptor-stimulating antibodies can be
  detected in the serum of more than 90 of
  patients with Graves thyrotoxicosis
• TSH receptor-blocking antibodies can be detected
  in 10 to 75 of patients with atrophic
  thyroiditis and from 0 to 20 of patients with
  goitrous thyroiditis

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Indications for measurement of serum TSH receptor
antibodies

• Difficult diagnostic conditions
• Thyrotoxicosis in pregnancy
• Subclinical thyrotoxicosis with diffuse goiter
• Euthyroid ophthalmopathy
• Toxic multinodular goiter with cold nodules
• Prediction of relapse of Grave thyrotoxicosis
  when antithyroid drug therapy is to be
  discontinued

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Indications for measurement of serum TSH receptor
antibodies

• Prediction of neonatal thyrotoxicosis in mother
  with Graves disease
• Previous child with neonatal thyrotoxicosis
• Receiving high-dose antithyroid drug therapy in
  third trimester
• Euthryoid, after radioiodine or surgical therapy
• Euthyroid with T4 therapy, after radioiodine or
  surgical therapy

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Indications for measurement of serum TSH receptor
antibodies

• Prediction of transient neonatal hypothyroidism
  in mother with chronic autoimmune thyroiditis
• Previous child with transient neonatal
  hypothyroidism
• Euthyroid receiving T4 therapy