The disease was first noted in 1786 by Caleb Hillier Parry 1755- 1822, physician from General Hospital, Bath, England. His account was published posthumously in 1825. However Graves’ disease is named after the Irish physician who described several cases in London Medical Journal in 1835. Graves’ disease is also known as Parry’s disease. In Europe, the disease is known as Basedow’s disease. It is the most common cause of thyrotoxicosis (the morbid condition due to over activity of the thyroid gland). The disorder has three major manifestations: Hyperthyroidism with diffuse goiter.
Ophthalmopathy and Dermopathy The three manifestations need not appear together. Indeed one or two never appear, and moreover, the three may run courses that are largely independent of one another. Graves’ disease can occur at any age but is unusual before puberty. It most commonly affects the 30 to 50 year age group. The disease is more frequent in women, the ratio of predominance in women may be as high as 7 : 1. Genetic factors play a role. There is an association between the disease and the genes HLA ( human leucocyte antigen) B8, -DRw3, -Bw36, -Bw46.
Indeed, a 50% concordance is found between identical twins. This means that if one individual in an identical pair of twins is afflicted with Graves’ disease, the likelihood of the other sibling coming down with Graves’ is 50%. Being an autoimmune disease, there is a clinical and immunologic overlap between Graves’ disease and other diseases with prominent autoimmune features. These include Hashimoto’s thyroiditis, pernicious anemia, systemic lupus erythematosus ( SLE), rheumatoid arthritis ( RA), insulin- dependent diabetes mellitus ( IDDM), and Addison’s disease.
Thyroid hormones are important mediators of growth and differentiation. The absence of which leads to cretins in childhood. The hormones are also responsible for the regulation of the various metabolic pathways which are vital for life. They are necessary for the normal function of many organ systems. In the thyroid gland, multiple follicles make, store and release thyroid hormones into the surrounding capillaries. These little vessels then bring the hormones to the rest of the body where they are needed. “Thyroid hormones” refers mainly to two hormones T3 and T4, which are single, amino acids containing iodine.
They are produced via a complicated pathway requiring the presence of iodine. Another hormone called TSH ( thyroid stimulating hormone) which originates from a “master gland” also known as the pituitary gland in the brain, controls the production of thyroid hormones. TSH not only stimulates the thyroid gland to churn out more hormones. If in excess, can cause overwhelming cell growth and division to result in goiter. Most T3 and T4 released into the bloodstream are bound to proteins. Only the “free” component is biologically active and it is this component which decides the manifestations of thyrotoxicosis.
The hormones exert their effects mainly by binding to nuclear receptors in cells to affect expression of genes. In the presence of excess T3 and T4, an increase in number as well as affinity of beta-adrenergic receptors in the heart is noted. These receptors facilitate the action of “fight, flight and fright” hormones ( epinephrine, norepinephrine) which are positively chronotropic ( beat faster) and inotropic ( pump harder) to the heart. This may then lead to cardiac failure in older patients. In fact, mild hyperthyroidism may produce severe disability in patients with underlying heart disease.
Hence, all patients with unexplained cardiac failure or atrial arrhythmias should be examined for thyrotoxicosis. Hyperthyroidism also increases the basal metabolic rate, heat production and oxygen consumption (calorigenic action) of many tissues. Body temperature increases slightly and the patient experiences intolerance to heat. Flushing and sweating are just compensatory mechanism in an attempt to remedy the rising temperature. The cause of Graves’ disease is unknown. In view of the varying manifestations of the disease and the differing courses of its components, it is likely that no single factor is responsible for the entire syndrome.
However, the evidence that Graves’ disease is autoimmune in origin is quite convincing. Hyperthyroidism and goiter are immunologically mediated. It results from the production of auto-antibodies directed against the TSH ( thyroid stimulating hormone)- receptors on the thyroid follicular cells or closely related cell membrane domains. Auto-antibodies are of two types: TSI ( thyroid stimulating immunoglobulins) or TSH- receptor antibodies ( TRAb) which mimic the action of TSH and thereby inducing the hypersecretion of thyroid hormones. TGI ( thyroid growth stimulating immunoglobulins) which initiates the growth of thyroid cells.
The question is what initiates these autoimmune reactions? The answer is not clear but genetic, immune and environmental considerations are important. In genetically predisposed individuals, infection with viruses or bacteria may serve as a trigger. Certain strains of E. coli and Yersinia enterocolitica possess cell membrane TSH receptors. The production of antibodies to these pathogens might cross react with host TSH receptors on thyroid follicular cells to result in hyperthyroidism. Emotional stress is often dismissed as etiologically important.
However, more than once have we seen a temporal relationship between the onset of hyperthyroidism and a major life event such as the death of a close relative. The pathogenesis of Ophthalmopathy is even more obscure. Many hints point toward an immune- mediated attack on retro-orbital tissues. A marked lymphocytic infiltration and swelling of the extra-ocular muscles and fibro-fatty tissue produces proptosis. The symptoms can be divided into those that reflect the associated thyrotoxicosis and those specifically related to Graves’ disease. The symptoms of hyperthyroidism are:
nervousness, emotional liability, inability to sleep, tremors intolerance to heat and excessive sweating palpitations, shortness of breath, and in older patients, chest pains weight loss despite well maintained or increased appetite proximal muscle weakness as seen in difficulty climbing stairs or standing up from squatting position frequent bowel movements may have oligomenorrhea or amenorrhea The symptoms more suggestive of Graves’ disease are: neck swelling red, painful eyes, double or blurring of vision raised plaque-like hyperpigmented and itchy skin lesion on the dorsum of feet and legs.
Again, the signs can be divided into those that reflect the associated thyrotoxicosis and those specific to Graves’ disease. This segment is filled with medical jargon which I will not attempt to explain individually. The signs of hyperthyroidism are: sinus tachycardia, atrial fibrillation, systolic murmurs, cardiac enlargement, cardiac failure warm moist skin, palmar erythema Plummer’s nails ( separation of fingernail from nail bed) widened palpebral fissures, infrequent blinking, failure to wrinkle the brow in upward gaze, lid lag Hyperreflexia The signs seen in Graves’ disease are:
diffuse goiter, with occasional bruit clubbing of fingers and toes resulting in a “drumstick looking” deformities (thyroid acropachy) Ophthalmoplegia and congestive Oculopathy characterized by chemosis, conjunctivitis, peri-orbital swelling and the potential complications of corneal ulceration, optic neuritis and optic atrophy pretibial myxedema characterized by raised, thickened, peau de orange lesions which may be itchy and hyperpigmented found on the dorsum of feet and legs Hyperthyroidism in Graves’ disease is characterized by cyclic phases of exacerbation and remission, each of unpredictable onset and duration.
As mentioned earlier, hyperthyroidism may take a course different from the other two components of Graves’ disease, which are Ophthalmopathy and Dermopathy. The aims of treatment in Graves’ hyperthyroidism are to treat acute disease and attempt to cure if not prolong the period of remission. Treatment may be in the form of nonspecific measures like rest and sedation, which are used in conjunction with specific measures like the use of anti- thyroid drugs, surgery and radioiodine. These 3 major treatments are directed to limiting the quantity of thyroid hormones the gland can produce.
The use of anti- thyroid drugs serves as a chemical blockade to the production of hormone. The effect is only operative as long as the drugs are being used. It does not prevent relapse at some subsequent period. The second approach is by the ablation of thyroid tissue to control hormone production. This is achieved by surgery or radioactive iodine. They can control acute disease and are more likely to prevent future recurrences. However, they sometimes “overdo” the job to cause hypothyroidism within weeks or with the passage of years. Each case must be considered individually.
Besides working by a set of guiding principles, doctors also take into consideration factors like age, sex, wishes of individual patient, coexistent medical or surgical condition, local facilities and experience with the modality of treatment. In general, medication or radioactive iodine is favored as primary therapy. In some situations, the choice is clear cut e. g. in a relapse after Thyroidectomy, radioactive iodine is advised; in pregnancy, surgery and radioactive iodine are contraindicated especially in the 1st and 3rd trimesters for the former, leaving anti- thyroid drugs as treatment of choice.
If the patient is willing to take replacement Thyroxine for life, the simplest approach may be the use of radioiodine. There are arguments for and against giving radioiodine to children and young persons who plan to have children. Previously, clinicians are unwilling to advise its use under the age of 45. This restriction is now rapidly being laxed as there is no convincing evidence that there is significant increase in the incidence of cancers occurring in adulthood secondary to its usage. Radioiodine can ensure that mothers are not taking anti- thyroid drugs during pregnancy and breastfeeding.
Therefore, an argument can be made for using this treatment method for all age groups except when pregnant or breastfeeding. Relapse of Graves’ disease after medical therapy may be managed with a second course, but at this point radioiodine is preferred. During pregnancy and breastfeeding periods, PTU ( propylthiouracil) appears to be the safest drug to use. And surgery is advised in cases with the presence of concomitant suspicious nodule. Each of the 3 major treatments ( anti- thyroid drugs, surgery and radioactive iodine) has their own advantages and disadvantages compared to the others.