GRAVES’ DISEASE IS CHARACTERIZED BY HYPERTHYROIDISM, diffuse goitre, ophthalmopathy and, rarely, dermopathy. Although diagnostic testing is straightforward once Graves’ disease is suspected, physicians need to be aware of heterogeneous and even atypical presentations of the disease, particularly in elderly patients. Because morbidity may be associated with even subtle forms of hyperthyroidism, treatment promoting long-term euthyroidism is necessary. Although all of the available treatments are effective, compliance is best assured by a full discussion of the risks and benefits of each approach. This review focuses on issues of diagnosis and management that will allow the primary care physician to identify patients with Graves’ disease and guide them to recovery.

Graves’ disease is an autoimmune disorder characterized by hyperthyroidism, diffuse goitre, ophthalmopathy and, rarely, dermopathy. Although thyroid-stimulating hormone (TSH) screening has facilitated the diagnosis of this condition, a heightened awareness of heterogeneous and even atypical presentations is necessary. Although all the available treatments effectively normalize thyroid function, each is associated with potentially serious side effects. In guiding the patient to a treatment decision, the physician should not only be aware of the immediate risks and benefits of therapy but should also consider approaches to best preserve the patient’s long-term metabolic health. This review focuses on issues re-lated to the diagnosis and treatment of Graves’ disease that will best help the nonendocrinologist meet these objectives.


The pathogenesis of Graves’ disease is illustrated in Fig. 1. The hyperthyroidism and goitre of Graves’ disease are caused by stimulation of the thyroid by TSH receptor anti-bodies.(1) Production of these antibodies is primarily within the thyroid gland itself,(2) and the immunology underlying this process has been ably described in detail elsewhere.(3) It has been suggested that a genetic clonal lack of suppressor T cells may be responsible for the unregulated production of TSH receptor antibody.(4) Identified predisposing factors for Graves’ disease are outlined in Box 1.

There is substantial evidence linking Graves’ disease and Hashimoto’s thyroiditis. These diseases may cluster in the same family or even coexist in the same patient. Sera of pa-tients with Graves’ disease may contain “Hashimoto’s predominant” antibodies to thyroglobulin and thyroid per-oxidase. Rarely, “Hashimoto’s antibodies,” which bind to the TSH receptor and, instead of stimulating, block TSH action (TSH-blocking antibodies), develop during the course of illness and explain observed improvements in the thyroid status of the patient with Graves’ disease.(5)

One proposed hypothesis for the pathogenesis of ophthalmopathy is that the immune response to a TSH receptor–like protein in orbital connective tissue initiates cytokine formation, promoting production by orbital fibroblasts of hydrophilic glycosaminoglycans, resulting in increased osmotic pressure, extraocular muscle volume, fluid accumulation and clinical ophthalmopathy.(6) However, eye muscle antigens such as the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, G2s and the FOX P1 protein, a winged helix transcription factor, have also been described and their respective antibodies are clinically useful markers of disease.(7) The respective roles of the connective tissue response and eye muscle antibodies in the pathogenesis of ophthalmopathy are the subject of ongoing investigation.

Clinical findings


When thyrotoxicosis, goitre and ocular signs and symptoms coexist, the diagnosis of Graves’ disease appears self-evident. The clinical features are shown in Table 1 (see also Boxes 2 and 3). However, 50% of patients with Graves’ disease may not have clinically detectable ophthalmopathy at presentation,(8) making the diagnosis less obvious. Rarely, findings may predominate in a single organ system (i.e., altered bowel habit, emotional lability, gynecomastia) and distract from the correct diagnosis. Many manifestations of hyperthyroidism, including palpitations and tremor, are due to increased adrenergic tone(9) and may be confused with an anxiety disorder. Elderly patients commonly present in an atypical fashion with only weight loss and anorexia or isolated atrial fibrillation.(10) Elderly patients also tend to have their symptoms for longer periods, have smaller multinodular goitres and do not have ocular signs or symptoms.(11)

The presence of comorbid conditions may also affect the presenting complaint. Worsening emotional lability in a patient with a pre-existing psychiatric disorder, or worsening angina or heart failure in someone with coronary artery disease, may be a clue to superimposed hyperthyroidism. In the patient with diabetes, hyperthyroidism is usually associated with further glucose intolerance or, rarely, hypoglycemia.(12)

Hyperthyroidism may also precipitate an adrenal crisis in pa¬tients so predisposed. The presence of other autoimmune condition(s) in the patient or family members may prompt the diagnosis. Hypokalemic periodic paralysis (especially in Asian males) necessitates a search for precipitating Graves’ disease.13 In the absence of a triiodothyronine (T3) level, there may not be a good correlation between the clinical severity of the disease and the degree of hyperthyroidism.14 Thus, a heightened sensitivity to the heterogeneity of clinical presentation is the best assurance of a prompt diagnosis.

Entire article:

Canadian Medical Association Journal; CMAJ • March 4, 2003; 168 (5)l; by J. Ginsberg, M.D.

Jody Ginsberg, M.D. CMAJ • MAR. 4, 2003; 168 © 2003 Canadian Medical Association or its licensors
CMAJ & Dr. Ginsberg permission granted to publish this article. — 25 April 2007

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