The oldest bibliographical reference known about this condition dates back to Egyptian culture. The Ebers papyrus written around 1550 B.C. –a
22 lines and 108 columns manuscript- described what is currently termed goiter (from the Latin word Guttur: throat) or Struma (from the Latin word Struma: a term used to describe the infl ammation of the “neck gland”). The manuscript even recommended surgical excision as potential treatment, or the intake of some particular salts from a specifi c place in Lower Egypt.
Ibn Sina, also called Abu Ali al-Husayn ibn Abd Allah ibn Sina (980–1037) was a Persian philosopher physician and scientist, commonly referred to in the Western world as “Avicenna”, is accepted and acknowledged as the father of mod- ern medicine. Some of his extensive literary work includes “The book of healing” and “The Canon of Medicine”, also known as the “Canon of Avicenna”. The latter, his most famous book, describes in great detail exophthalmos and goiter, symptoms that today we accept as evidence of thyroid hyperactivity. Another historical docu- ment describing the disease was the work by André Du Laurens [Laurentius] (1558–1609) entitled: “De Mirabili Strumas Sanadi” published in Paris in 1609, followed by other works during the XVII and XVIII Centuries and the fi rst quar- ter of the nineteenth Century, until the Italians Giuseppe Flajani in 1802 and Antonio Giuseppe Testa in 1810 described patients with palpita- tions, apprehension, tremor, nervousness, and psychotic disorders [ 1 , 2 ]. In 1825, Caleb Hillier Parry wrote what is considered the most compre- hensive review on exophthalmic goiter. About 10 years later, Robert James Graves published what according to many people is the fi rst accu- rate description of the disease, and in 1840 Carl Adolph von Basedow published an extensive article about the results of his research about treatment approaches [ 3 – 5]. Although von Basedow described many of the key characteris- tics we currently know, his publication took place 5 years after Robert Graves’s description, despite he had followed his patients’ evolution for several
years. The transcendental importance of the last three authors above mentioned, had established that exophthalmic goiter was indistinctively iden- tifi ed as Parry, Graves or von Basedow disease. Though it is well known that in English- speaking countries the term Graves Disease is commonly used, in most European countries the condition is referred to as von Basedow’s disease. In Germany for instance, the description of the clinical char- acteristics of the disease is attributed to von Basedow; so much so, that the description of the so called Merseburg’s triad –exophthalmos, goi- ter, and tachycardia, similar to the triad described by Robert Graves is attributed to von Basedow- [ 5 , 6 ]. Currently there is little controversy about the fact that Parry was the fi rst to describe the disease, though historically modestly acknowl- edged. According to some of Robert Graves’s biographers, this could be due to the fact that Graves very astutely hired the services of Armand Trousseau, a very infl uential advertiser in France at that time, in addition to the fact that he was the head of Medicine at the Hotel-Dieu hospital in Paris. Trousseau was a strong admirer of Graves, and often quoted his work in his clinical lectures and in his multiple publications. When Grave’s book was translated into French, Trousseau praised the author and in fact, used the term Graves-Basedow Disease for the fi rst time. It should also be noted that most publications about this condition are in English, thus perpetuating the term “Graves’ Disease”. However, the auto- immune hyperthyroid diffuse goiter should in all fairness, and from the historical and descriptive point of view, be called “Flajani-Parry-Gr aves- von Basedow Disease”. Other names used in the medical literature to describe GD are March dis- ease, Parsons disease, Flajani disease and Begbie disease [ 6 , 7 ].
Epidemiology
According to the National Health Institutes (NIH) of the United States of America, autoimmune dis- eases affect approximately 23.5 million people in the country, although the American Autoimmune Related Disease Association (AARDA) estimates that there are about 50 million people affected by
the disease, of which 75 % are women. It is currently stated that there are about 100 types of autoimmune diseases identifi ed, affecting a larger population than the number affected by cancer and heart disease. The numerical differences based on the fi gures identifi ed by the various associations responsible for studying autoimmune diseases are due to defi nitions adopted for each particular disease; for instance, the NIH only involve 24 autoimmune diseases (based on trials with specifi c epidemiological designs); it has been estimated however, that the number of dis- eases with some autoimmune background is close to 150. Autoimmune diseases have a variable rate of presentation and ethnic and geographical dif- ferences have been documented to impact the incidence of particular autoimmune diseases. Some specifi c groups may be at higher risk than others for certain diseases with even some varia- tion among the same populations. Autoimmune disease is highly prevalent in the pediatric popula- tion and adolescents (representing one of the ten most frequent causes of death among children 1–14 years old). Likewise, autoimmune disease is one of the ten most important causes of death among women over 65 years of age, and is the fi fth cause of death among women less than 65. The incidence and prevalence of autoimmune dis- eases has been rising in the last two decades worldwide, with diseases such as Diabetes Mellitus Type 1 (DM1), Celiac Disease (CD), Multiple Sclerosis (MS) and Systemic Lupus Erythematous (SLE) being some of the most frequent. Such a rapid rise in frequency strongly suggests that environmental factors play a key role in such increase, since genes do not change so fast, in such short periods of time. The frequency of autoimmune asymptomatic thyroid syndrome indicates an association between the levels of thyroid autoantibodies [Thyroid Peroxidase (TPO) Autoantibodies and anti-Thyroglobulin (Tg) Autoantibodies] and the presence of focal thyroid infl ammation in biopsy specimens and biopsies of individuals that never showed any evidence of hypothyroidism in their life. Post-mortem analyses show histopathological evidence of autoimmune thyroiditis in over one fourth of adult women; diffuse changes were identifi ed in 5 % of females and in 1 % of males;
furthermore, the prevalence of thyroid antibodies among the healthy population ranges between 10 and 12 %. With regards to hypothyroidism, its fre- quency may vary depending on whether the diag- nosis is considered as subclinical or overt hypothyroidism. The former shows a TSH value above the upper reference limit, with a normal Free T4 (FT4) level (assuming that the hypothalamic- pituitary-thyroid axis is normal, and in the absence of current or recent severe criti- cal disease). The variation in prevalence of sub- clinical hypothyroidism is consistent with the TSH values; for instance, The National Health and Nutrition Examination Survey (NHANES III) used an upper normal TSH level above 4.5 mIU/L; at this cut point, the prevalence of subclinical hypothyroidism was 4.3 % and the prevalence of overt hypothyroidism was 0.3 %. The Colorado thyroid disease prevalence survey used an upper normal TSH level of 5.0 mIU/L, and a prevalence of 8.5 % was reported for subclinical hypothy- roidism while the reported prevalence for overt hypothyroidism was 0.4 %. In the Framingham trial, 5.9 % of females and 2.3 % of males over 60 years of age had TSH values over 10 mIU/L, while in the British Whickham survey, 9.3 % of females and 1.2 % of males had TSH values exceeding 10 mIU/L. The frequency of hypothy- roidism in people 85–89 years old in the Netherlands was 7 % among 558 people evalu- ated. Furthermore, the incidence of hypothyroid- ism in females is established at 3.5 per 1000 individuals per year, and in males at 0.6 per 1000 individuals per year. The risk to develop hypothy- roidism in females with positive thyroid Autoantibodies and elevated TSH is 4 % per year, in contrast with those women that only have one of the two conditions with a risk of 2–3 % per year. For males the risk is higher in either condi- tion, but the rate of development of overt hypothy- roidism is still lower than the rate for women. According to the 20-year follow-up Whickham cohort, the annual average incidence of spontane- ous hypothyroidism (in the 20 years of follow- up), was 3.5 per 1000 in females, and of 0.6 per 1000 in males; the presence of elevated TSH and/ or positive thyroid antibodies was associated with an increase risk of developing hypothyroidism. In
females, the annual risk of spontaneous overt hypothyroidism was 4 % (in women with elevated TSH and positive thyroid antibodies); 3 % if only the TSH was elevated and 2 % when only the thy- roid antibodies were positive. The likelihood of developing hypothyroidism was higher in women with TSH >2.0 mIU/L and elevated anti-TPO val- ues [ 8 – 10 ].
Although GD may present at any age, the inci- dence peak is found between the fi fth and the sev- enth decade of life; the female:male ratio is 5–10:1. The incidence of the disease varies depending on the series reviewed, the geographi- cal area studied, the intake of dietary iodine and gender. Most series report an incidence rate from 15 to 50 per 100,000 people/year of follow-up; however, trials based on the British population report an incidence rate of 80 per 100,000 women/year and of 10 per 100,000 males/year. The prevalence of the disease among the general population is of 0.5–1.0 %. The National Health and Nutrition Survey (NHANES III) showed that in individuals older than 12, the general preva- lence of hypothyroidism was 1.3 %, with a lower prevalence in Hispanics (0.7 %) and a higher prevalence among whites (1.4 %). In “The Nurses’ Health Study” the overall incidence of GD hypothyroidism was 4.6 per 1000 women in 12 years of follow-up. There are limited compar- ative incidence data for males. In the “Rochester Epidemiology Project” trial, the age-adjusted incidence of ophthalmopathy due to GD was 5 times higher in white females than in males −16 per 100,000 patients/year and 2.9 per 100,000 patients/year, respectively- In a cohort trial in Stockholm between 2003 and 2005, the total incidence of hypothyroidism among the popula- tion over 18 years of age was 32.7/100,000 patients/year, of which 75 % had GD [ 10 , 11 ]. Changes in incidence may refl ect improved diag- nostic methods, rather than an actual change in the incidence rates. The higher iodine intake has been considered a factor that impacts the inci- dence of GD among the population in places such as Japan, where the dietary iodine intake may be much higher than in most other countries, with an incidence of 200 per 100,000. Moreover, dietary iodine supplementation in mild to moderately
defi cient populations may increase the number of GD cases. Moreover, it has been shown that in some areas with some iodine defi ciency, supple- mentation is associated with a drop in up to 33 % in the incidence of GD [ 12 ].