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Systemic complications of Graves’ disease


MRI of the orbits, showing congestion of the retro-orbital space and enlargement of the extraocular muscles (arrows), consistent with the diagnosis of Graves’ ophthalmopathy13


Dr Rafid Al-Ameri*
Endocrine Fellow

Associate Professor Kenneth Ho*

* Faculty of Medicine and Health Sciences, Macquarie University


Graves’ disease is a common cause of thyrotoxicosis, accounting for 60-80 per cent of cases.1 It is an autoimmune disorder characterised by T-cell activation, with B-cell production of immunoglobulin G (IgG) antibodies against TSH receptors (TRAb). These stimulate TSH receptors continuously, causing thyroid hormone hypersecretion and goitrous enlargement.2

Affected people are between 40 and 60 years but may be any age.1 Lifetime risk is 0.5 per cent (males) and three per cent (females).3 While exact aetiology is unknown, environmental factors appear to trigger an autoimmune response in genetically susceptible individuals. Nearly 15 per cent of patients have a first degree relative with the same condition.4 Concordance rate between monozygotic twins is 20 per cent.5

Environmental factors include psychological stress, high iodine intake, postpartum status, infections and smoking.4 It is associated with other autoimmune disorders such as diabetes mellitus type 1, Addison’s disease, celiac disease, myasthenia gravis and vitiligo.2



Mild thyroid disease   Image: Associate Professor Mark Roth


Presentation can be variable. Common symptoms include easy fatigability, palpitations, weight loss with increased appetite, nervousness, insomnia, excessive sweating, diarrhoea and heat intolerance.2 Elderly patients may experience apathy, confusion and reduced appetite.2 It is associated with the following six systemic complications.

  • · Thyrotoxic crisis or ‘Thyroid Storm’6

This is an accelerated thyrotoxic state, occurring in untreated or under-treated individuals. It may be precipitated by sepsis, surgery, trauma and less commonly, during labour, radiation thyroiditis or diabetic ketoacidosis. Patients typically present with fevers, agitation, tremulousness, drenching sweats, cardiac tachyarrhythmia, and congestive heart failure. Abdominal pain and vomiting may manifest early. It has high mortality if not treated quickly.

  • Cardiovascular7

Due to increased metabolic demands of the myocardium during thyrotoxicosis, patients risk precipitating angina and myocardial infarction. Older individuals are at particular risk of cardiovascular complications. Sinus tachycardia is very common and atrial arrhythmias, especially atrial fibrillation is also common. In individuals with pre-existing cardiac conditions, congestive heart failure is a recognised complication.

  • Graves’ Ophthalmopathy2,8

Approximately 50 per cent of Graves’ disease patients experience symptoms of ophthalmopathy which include gritty eyes, photophobia, diplopia, lacrimation and feeling of pressure behind the eye. Ocular involvement and hyperthyroidism can occur simultaneously or within 18 months of each other. Orbitopathy, a more serious ocular complication, may manifest earlier or later than hyperthyroidism. Subclinical involvement is more common, as imaging can detect extra-ocular muscles enlargement in 70 per cent of the patients with Graves’ disease. Common signs are upper lid retraction, swelling, congestion of conjunctivae and proptosis. Graves’ ophthalmopathy can progress into a sight-threatening disease characterised by corneal ulceration and optic nerve compression.2

  • Musculoskeletal system

In longstanding cases, wasting of skeletal muscles, especially proximal groups, is well recognised.7 Bone-related complications include osteoporosis, osteopenia with increased fracture risk.9 Thyroid acropachy is a type of finger clubbing in Graves’ disease.7 It is rare and typically presents in patients with orbitopathy and Graves’ dermatopathy.7

  • Skin10

The skin is commonly moist and hot. Palmer erythema and onycholysis are occasionally evident. Less commonly are pruritis, urticaria or hyperpigmentation. The hair is thin and there is hair loss in 40 per cent of the patients. Graves’ dermatopathy is a specific feature of Graves’ disease that occurs exclusively in patients who have already Graves’ ophthalmopathy. Most commonly it manifests in the lower anterior part of the leg, hence called ‘pretibial myxoedema’. Thickening of skin with nodularity and orange to purplish discolouration are the main features.

  • Reproductive system

Women with Graves’ thyrotoxicosis have anovulatory cycles, presenting with oligomenorrhea, or amenorrhea. Their fertility is reduced and they risk miscarriage during pregnancy.6 Thyrotoxic men may suffer from low testosterone, with reduced libido and erectile dysfunction. Some men may develop gynecomastia.2


Diagnosis of Graves’ disease can be made from clinical presentation associated with elevated free T3, free T4 and suppressed TSH. Presence of TRAb can be confirmatory. Radionuclide scans can differentiate Graves’ from other causes of thyrotoxicosis such as toxic multinodular goitre and thyroiditis.


Choice of treatment depends on factors such as patient age, co-morbidities, presence of ophthalmopathy and patient preference. While propranolol, a beta-blocker, can be used to control the patients’ symptoms, three treatments are available:

  • Anti-thyroid medication

Drugs like ethimazole, carbimazole and propylthiouracil inhibit synthesis and secretion of thyroid hormones. Duration of treatment is 12 to 18 months. Remission rate is variable, but may reach 50 per cent. Side-effects include rash, arthralgia, gastrointestinal disturbance and raised liver enzymes. Agranulocytosis is a rare and serious side-effect.

  • Radioactive Iodine (RAI)

The aim of this therapy is to destroy thyroid tissue through emitting beta particles. Remission can be achieved in 85 per cent of the patients after one year with a single dose of RAI. However, it can worsen Graves’ ophthalmopathy and is contraindicated during pregnancy. It may cause irreversible treatment-related hypothyroidism.

  • Surgery

Thyroidectomy is suitable for patients with large goitres, suspected thyroid malignancy, concomitant hyperparathyroidism or if patients prefer surgery. Potential complications include hypoparathyroidism, and recurrent laryngeal nerve injury.


1. Weetman AP. Graves’ disease. New Eng J Med 2000; 343: 17: 1236-1248.

2. Brent GA. Clinical practice. Graves’ disease. New Eng J Med 2008; 358: 24: 2594-2605.

3. Burch HB, Cooper DS. Management of Graves’ disease: A review. JAMA 2015; 314: 23: 2544-2554.

4. David G, Gardner DS. The Thyroid Gland. In: David S Cooper MPWL, MA (Oxon), MD, editor. Greenspan’s Basic & Clinical Endocrinology. 9th ed: McGraw-Hill Education; 2011, p 198-206.

5. Ferri FF. Graves’ Disease. Ferri’s Clinical Advisor 2016. 1st ed. Philadelphia: Elsevier; 2016, p 557-558.

6. Davies TF. Hyperthyroid Disorders. In: Melmed S, Kenneth S, Polonsky P, Reed Larsen, Henry M Kronenberg, editor. Williams Textbook of Endocrinology, 13th ed. Philadelphia: Elsevier; 2016, p 369-415.

7. Burch HB. Overview of the Clinical Manifestations of Thyrotoxicosis. In: Braverman LEC, David S, editor. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text, 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2013, p 435-439.

8. Bahn RS. Graves’ Ophthalmopathy. New Eng J Med 2010; 362: 8: 726-738.

9. Bauer DC, Ettinger B, Nevitt MC, Stone KL. Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Annals Internal Med 2001; 134: 7: 561-568.

10. Jameson JL. Disorders of the thyroid gland. In: Jameson JL, editor. Harrison’s Endocrinology: McGraw-Hill Education; 2013, p 79.

11. Bahn Chair RS, Burch HB, Cooper DS et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid: official journal of the American Thyroid Association 2011; 21: 6: 593-646.

13. Huy A Tran and Glenn EM Reeves: The influence of hepatitis C infection and interferon-a therapy on thyrotropin blocking and stimulating autoantibodies in Graves’ ophthalmopathy: a case report. Thyroid Research 2009, 2:12 doi:10.1186/1756-6614-2-12 (Open Access)

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