Written by Dr. Sanjana V.B Bhms,dbrm,cdn

Founder & medical director of siahmsr wellness.in

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Reviewed by SIAHMSR medical team.

How common is Graves’s disease [GD]?

 It is most common in people of age group 20 to 50 years. Graves’ disease is more common in women than men. Graves’ disease may occur in children also.

The genetic predisposition accounts for 79% of the risk for GD, while environmental factors for 21%. Graves' disease (GD) is the most common cause of hyperthyroidism in developed Countries.

What are the causes of Graves’s disease?

•          Genes

    It is seen in patients with a positive family history. It is more common in monozygotic twins than in dizygotic twins.

•       Environmental factor    

     Stress, smoking, infection, iodine exposure, and childbirth may trigger Graves’s disease. It is also has been found after highly active antiretroviral therapy (HAART) due to immune reconstitution.

·       Occupational exposure to Agent Orange have been associated with GD.

·        Many studies showed that HCV is associated with thyroid autoimmunity and hypothyroidism, in patients with chronic HCV hepatitis.

How does Graves’ disease develop?

Graves' disease is caused by thyroid stimulating immunoglobulin (TSI), also known as thyroid stimulating antibody (TSAb).

B lymphocytes  of the immune system of your body produce these antibodies within the thyroid cells.

These antibodies bind with thyroid-stimulating hormone (TSH) receptor on the thyroid cell membrane and stimulate the action of the thyroid-stimulating hormone.

It stimulates both, thyroid hormone production and thyroid gland growth, causing hyperthyroidism and thyroid swelling.

What are the Signs and symptoms of Graves’s disease?

 Graves’ disease is often manifested with signs and symptoms of hyperthyroidism or overactive thyroid state.

In younger people, common symptoms include heat intolerance, sweating, fatigue, weight loss, palpitation, diarrhoea, and tremors.

Other problems of overactive thyroid include sleeplessness, anxiety, nervousness, breathlessness, muscle weakness, scanty or absent menses in females, low sex drive etc.

Eye symptoms are also present in Graves’s disease and they include lids swelling, eye pain, conjunctival redness, double vision.

Palpable goiter or thyroid swelling is more common in the younger population.  Up to 10 % of patients may have weight gain.

What is apathetic thyrotoxicosis?

In the elderly people, non-specific signs and symptoms like fatigue, weight loss, and new onset atrial fibrillation as heart complication may appear. This kind of  vague and nonspecific presentation of hyperthyroidism in elderly is also referred as apathetic thyrotoxicosis.

Physical signs of hyperthyroidism include increased pulse rate, systolic hypertension  or high bloodpressure.

The signs of heart failure (like edema, rales, jugular venous distension, increased breath rate), atrial fibrillation may be present.

 Fine tremors of hands , hyperreflexia or increased reflexes on clinical examination, warm and moist skin, redness of palms, hair loss, diffuse palpable goiter with thyroid bruit and altered mental status are other signs of overactive thyroid in Graves’s disease.

Signs of extrathyroidal manifestations of Graves’ disease include :

eyelid retraction, bulging eyeballs, swelling around eyelids, exposure keratitis or inflammations of cornea of eyes.

  Marked thickening of the skin, mainly over tibia which is rare, seen in 2% to 3% of cases.

 Subperiosteal bone formation and swelling in the metacarpal bones of hands may be found in some people [ osteopathy or thyroid acropachy].  Nail signs of degeneration (Plummer nails) and clubbing are very rare.

 How is the diagnosis of Graves’ disease made?

Diagnosis of Graves’ disease starts with a complete history taking and physical examination of the person. Family history is also important.

• Thyroid function tests

TSH, Free T4 (FT4) and Free T3 (FT3) is commonly ordered by you healthcare provider in suspected cases of thyroid overactivity

If free hormone assays are not available, total T4 (Thyroxine) and total T3 (Triiodothyronine) can be ordered.

 Suppressed or below normal TSH with high FT4 or FT3 or both will confirm the diagnosis of hyperthyroid state.

 In subclinical hyperthyroidism, only TSH is suppressed, but FT4 and FT3 are normal.

•    Measurement of TSH receptor antibody (TRAb):

 There are two available assays, the thyroid stimulating immunoglobulin (TSI) and thyrotropin-binding inhibiting (TBI) immunoglobulin or thyrotropin-binding inhibitory immunoglobulin (TBII). It may be high in Graves’ disease.

• Radioactive iodine uptake scan with I-123 or I-131:

 In Graves’ disease, the uptake will be high and diffuse whereas, in a toxic nodule within thyroid , the uptake will be focal known as a hot nodule.        

• Thyroid Ultrasonogram with Doppler:

 The thyroid gland in Graves’ disease is usually hypervascular in ultrasound features  or vascularity is increased within the thyroid gland.

• T3/T4 ratio greater than20 (ng/mcg) or FT3/FT4 ratio greater than 0.3 (SI unit) suggests Graves’ disease and can be used to differentiate Graves’ disease from thyroiditis induced thyrotoxicosis.

·           CT or MRI of orbits can be performed to diagnose Graves orbitopathy in patients who present with eye symptoms without hyperthyroidism or high thyroid hormones in blood.

·       Patient with hyperthyroidism can have changes in   some other laboratory tests producing microcytic anemia, thrombocytopenia, bilirubinemia, high transaminases, hypercalcemia, high alkaline phosphatase, low LDL and HDL cholesterol.

 Early diagnosis and management of Graves' disease can prevent severe cardiac complications such as atrial flutter, atrial fibrillation, and high output cardiac failure.

How Graves’s disease is managed?

Treatment for Graves' disease depends on its symptoms and signsin the affected people.

The options include :

Antithyroid drugs which block thyroid hormone production and release

Radioactive iodine (RAI) treatment of the thyroid gland

Total or subtotal thyroidectomy or removal of thyroid gland through surgery.

All three options have pros and cons, and antithyroid drugs have adverse effcts. It is not easy to state which one is the best option. It is very important to discuss all three options in detail with the patients and make an individualized decision based on other health conditions of the person.

Antithyroid drugs:

 According to NIH, Methimazole (MMI) and propylthiouracil (PTU) are two anti-thyroid drugs available in the USA. Outside USA, carbimazole, a derivative of methimazole which is rapidly metabolized to methimazole, is also available. Adverse effects are associated with some of these drugs and follow up with TFT is mandatory every 6 weeks to adjust the medication dosages[3]. 

RAI Therapy:

It is preferred for non-pregnant adult patients older than 21 years, patients not planning to get pregnant within the next six to 12 months after treatment, patients with risky comorbid conditions for surgery, and patients with contraindications for thioamides.

 It is contraindicated during pregnancy, lactation, coexisting thyroid cancer, in patients with moderate to severe Graves orbitopathy, and for individuals who cannot follow radiation safety guidelines.

Thyroid function tests are needed to be monitored every four to six weeks for six months or until the patient becomes hypothyroid. Once the patient is on a stable levothyroxine dose, TFTs can be repeated every six to 12 months. If hyperthyroidism persists after six months of RAI therapy, it can be considered as treatment failure, and a repeat treatment with RAI may be needed

Thyroidectomy: 

Operation is recommended if  compressive symptoms, co-existing suspicious thyroid cancer, large thyroid nodules (greater than 4 cm), cold nodules, co-existing parathyroid adenoma occur or  very high TRAb, and moderate to severe Graves orbitopathy exist.

It is important to bring thyroid normalcy status soon  in patients with Graves orbitopathy. Patients should be advised to quit smoking if they do.  Treatment depends on the severity of orbitopathy. For patients with mild orbitopathy who undergo RAI treatment, prednisone 0.4 mg/kg/day to 0.5 mg/kg/day should be started one to three days after treatment and continued for one month. It should be tapered slowly over two months.

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References

1.        Hussain YS, Hookham JC, Allahabadia A, Balasubramanian SP. Epidemiology, management and outcomes of Graves' disease-real life data. Endocrine. 2017 Jun;56(3):568-578.
2.        Wémeau JL, Klein M, Sadoul JL, Briet C, Vélayoudom-Céphise FL. Graves' disease: Introduction, epidemiology, endogenous and environmental pathogenic factors. Ann Endocrinol (Paris). 2018 Dec;79(6):599-607. https://pubmed.ncbi.nlm.nih.gov/30342794/
3.        https://www.ncbi.nlm.nih.gov/books/NBK448195/
4.        Diana T, Olivo PD, Kahaly GJ. Thyrotropin Receptor Blocking Antibodies. Horm Metab Res. 2018 Dec;50(12):853-862. [PMC free article] [PubMed]
5.        Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce SH. 2018 European Thyroid Association Guideline for the Management of Graves' Hyperthyroidism. Eur Thyroid J. 2018 Aug;7(4):167-186.
6.        https://pubmed.ncbi.nlm.nih.gov/32107168/
7.        Image courtesy : Designed by Freepik