Graves Disease – Hyperthyroidism


Graves Disease is an autoimmune disease characterized by hyperthyroidism due to circulating autoantibodies. It is also the leading cause of hyperthyroidism, a condition in which the thyroid gland produces excessive hormones. It affects up to 2% of the female population, sometimes appears after childbirth, and occurs seven to eight times more often in women than in men. Once the disorder has been correctly diagnosed, it is quite easy to treat. In some cases, Graves’ disease goes into remission or disappears completely after several months or years. Left untreated, however, it can lead to serious complications and even death.


Pathophysiology of Graves disease:

Graves’ disease is an autoimmune disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSH). (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.)

These antibodies cause hyperthyroidism because they bind to the TSHr and chronically stimulate it. The TSHr is expressed on the follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This, in turn, causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter.

The infiltrative exophthalmos frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball.

The “orange peel” skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.

The three types of autoantibodies to the TSH receptor currently recognized are:

  1. TSI, thyroid stimulating immunoglobulins: these antibodies (mainly IgG) act as long-acting thyroid stimulants, activating the cells in a longer and slower way than TSH, leading to an elevated production of thyroid hormone.
  2. TGI, thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles.
  3. TBII, thyrotrophin binding-inhibiting immunoglobulins: these antibodies inhibit the normal union of TSH with its receptor. Some will actually act as if TSH itself is binding to its receptor, thus inducing thyroid function. Other types may not stimulate the thyroid gland, but will prevent TSI and TSH from binding to and stimulating the receptor.

Another effect of hyperthyroidism is bone loss from osteoporosis, caused by an increased excretion of calcium and phosphorus in the urine and stool. The effects can be minimized if the hyperthyroidism is treated early. Thyrotoxicosis can also augment calcium levels in the blood by as much as 25%. This can cause stomach upset, excessive urination, and impaired kidney function.

Signs and Symptoms of Graves disease:

  • – Bone loss
  • – Psychosis, Mania, Agitation
  • – Insomnia
  • – Hand tremor
  • – Excessive sweating
  • – Heat intolerance
  • – Weight loss despite increased appetite
  • – Fine hair and Hair loss
  • – Diarrhea
  • – Palpitations
  • – Arrhythmias (Sinus tachycardia, Atrial fibrillation)
  • – Muscle weakness (due to inflammation of muscles)
  • – Exophthalmos aka proptosis
  • – Goiter (Diffusely enlarged thyroid gland)
  • – Pretibial myxedema (waxy, discolored induration of the skin)

Differential Diagnosis:

  • – Anxiety Disorders
  • – Hashimoto Thyroiditis
  • – Hyperemesis Gravidarum
  • – Pheochromocytoma
  • – Struma Ovarii
  • – Subacute Thyroiditis
  • – Thyroid, Papillary Carcinoma
  • – Thyrotropin-producing pituitary adenomas
  • – Toxicity, Cocaine
  • – Wolff-Parkinson-White Syndrome

Workup for Graves disease:

Laboratory studies:

  • – Ultra-sensitive (third-generation) thyrotropin assays remain the best screening test for thyroid disorders.
    • – With the exception of thyrotropin-induced hyperthyroidism, subnormal or suppressed thyrotropin levels are seen in most patients with thyrotoxicosis.
    • – Free T4 levels or the free T4 index is usually elevated, as is the free T3 level or free T3 index. Subclinical hyperthyroidism, defined as a free T4 or free T3 level within the reference range with suppressed thyrotropin, also can be seen.
    • – On occasion, only the free T3 level is elevated, a syndrome known as T3 toxicosis. This may be associated with toxic nodular goiter or the ingestion of T3. Elevated T3 levels are often seen in early phase Graves disease as well.
    • – Assays for thyrotropin-receptor antibodies (particularly TSIs) almost always are positive.
    • – Detection of TSIs is diagnostic for Graves disease.
    • – The presence of TSIs is particularly useful in reaching the diagnosis in pregnant women, in whom the use of radioisotopes is contraindicated.
    • – Other markers of thyroid autoimmunity, such as antithyroglobulin antibodies or antithyroidal peroxidase antibodies, are usually present.
    • – Other autoantibodies that may be present include thyrotropin receptor–blocking antibodies and anti–sodium-iodide symporter antibody.
    • – The presence of these antibodies supports the diagnosis of an autoimmune thyroid disease.

Imagine Studies:

  • – Radioactive iodine scanning and measurements of iodine uptake are useful in differentiating the causes of hyperthyroidism. In Graves disease, the radioactive iodine uptake is increased and the uptake is diffusely distributed over the entire gland.
  • – Ultrasounds with color-Doppler evaluation have been found to be cost-effective in hyperthyroid patients. A prospective trial showed that thyroid ultrasound findings are predictive of radioiodine treatment outcome, and, in patients with Graves disease, normoechogenic and large glands are associated with increased radioresistance.
  • – Computed tomography scanning or magnetic resonance imaging (of the orbits) may be necessary in the evaluation of proptosis. If routinely performed, most patients have evidence of orbitopathy, such as an increased volume of extraocular muscles and/or retrobulbar connective tissue. These techniques are useful to monitor changes over time or to ascertain the effects of treatment. Careful monitoring is required after using iodinated contrast agents as they may affect ongoing treatment

Histological Findings:

  • – In select cases in which thyroidectomy was performed for the treatment of severe hyperthyroidism, the thyroid glands from patients with Graves disease show lymphocytic infiltrates and follicular hypertrophy, with little colloid present.


Treatment for Graves disease:

  • – Propranolol (β-Blocker)
    • – Inhibits peripheral conversion of T4 to T3.
    • – Also manages tachycardia.
  • – Propylthiouracil (PTU) and Methimazole
    • – Block thyroid hormone production.
    • – PTU is safe in pregnancy*
    • – SE: Both can cause agranulocytosis
  • – Radioactive iodine
    • – Most commonly used treatment
    • – Most Cost effective
    • – Best Long term management & Permanent cure
    • – SE: Hypothyroidism
  • – Surgery (Thyroidectomy)
    • – Expensive
    • – Indications:
      • – A large goiter (especially when compressing the trachea),
      • – Suspicious nodules or
      • – Suspected cancer.
    • – SE: Damages Recurrent laryngeal nerves. Hypoparathyroidism

Graves Ophthalmophathy:

  • – Mild cases: are treated with lubricant eye drops or Non-steroidal anti-inflammatory drops.
  • – Severe cases: threatening vision (Corneal exposure or Optic Nerve compression) are treated with steroids or orbital decompression.




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