Goitre

• Goitre (or goiter) – enlargement of the front and sides of the neck caused by inflammation of the thyroid gland. From Latin ‘guttur‘ (throat, neck) and Old Provençal ‘goitron‘ (throat, gullet)
• Goitre was first been reported in the book Shen Nong Bencao Jing (神农本草经) (the divine farmers classic of materia medica) around 2800 BC. Further descriptions are found in Egyptian texts (1500 BC), Hindu texts (200 BC) and in a frieze depicting the life of Buddha in Gandhara in 3AD.

Exophthalmos (εξόφθαλμο)

• Aristotle studied individuals with exophthalmos and related the condition to the brain and to persons with a reduced mental constitution. He also noted that those with thick and large neck were spirited and rash (toxic rather than non-toxic goitre).
• Plato, Xenophon, and Aristoxenus described Socrates as having exophthalmos, diplopia, and some symptoms compatible with hyperthyroidism [2015;14:167-171].

Goitre and exophthalmos

• Probably the first association between goitre and exophthalmos is found in legal documents. Around 200 AD the Roman jurist Dometius Ulpianus legislated that a slave with goitre and prominent eyes had no work capacity (Si quis natura gutturosus sit aut oculos eminentes habeat, sanus videtur).
• The combination of protruding eyes, goitre, and signs consistent with hyperthyroidism were described in another legal text from the sixth century and a Greek manuscript by Meletius from the seventh century ‘The eyes tend to swell and jump out… make the person uncertain and nervous‘.
• The first medical association is recorded by Avicenna (980–1037) in his million word masterpiece ‘Al-Qanoon‘ in which he gives detailed descriptions of exophthalmos, goiter and symptoms of hyperthyroidism.

• Caleb Hillier Parry (1755–1822) was a general practitioner in Bath, England and was the first to describe, although very briefly, the essential signs/symptoms in diffuse toxic goitre.
• In 1786 he treated Mrs. Grace B, a 37-year-old woman a few months after childbirth who had palpitations, tachycardia, goiter, and prominent eyes. His description is usually taken to be the first on thyroid-associated exophthalmos.
• Over the next 27 years he saw four more patients with similar findings, although these individuals probably did not have exophthalmos. Parry did not associate the combination of findings until 1813 when he finally realized that there was probably ‘some connection between the malady of the heart and the bronchocele [goitre].‘ He made notes on these and a further three patients before suffering a stroke in 1816.
• Despite never practicing clinical medicine again, Parry worked on his copious and detailed collection of notes until his death in 1822. The detailed notes of his clinical observations and many of his experiments were then published by his son in 1825, three years after his death.
• The 1825 collection of notes includes a chapter ‘Enlargement of the Thyroid Gland in Connection with Enlargement or Palpitation of the Heart‘ describing 5 patients with goitre and hyperthyroidism including his 1786 description of Mrs. Grace B:

‘The part swelled was the thyroid gland. The carotid arteries on each side were greatly distended ; the eyes were protruded from their sockets, and the countenance exhibited an appearance of agitation and distress, especially on any muscular exertion, which I have rarely seen equalled.‘ [Parry, 1825:112]

• Despite treatment with ‘bleedings and a preparation of squill and quicksilver‘ Mrs B developed developed anasarca with nightly orthopnoea and Parry determined the patient would soon have ‘paid her debt to nature.‘
• The term ‘Parry disease‘ was suggested by Sir William Osler  – ‘if the name of any physician is to be associated with the disease, undoubtedly it should be that of the distinguished old Bath physician‘ [1898;836-837]

• Robert James Graves (1796-1853), delivered a series of lectures at the University Hospital in Dublin in 1834–1835.
• In his lecture ‘Newly Observed Affection of the Thyroid Gland in Females‘ Graves describes three patients with goitre and palpitations.
• A fourth patient, seen by seen by his colleague Sir William Stokes was a ‘lady aged twenty, affected with some symptoms which were supposed to be hysterical‘ exhibited the additional sign of exophthalmos. This young lady presented with palpitations, swelling of the thyroid and nervousness:

‘the eyeballs were visibly enlarged, to such a degree the eyelids were unable to shut during sleep and when trying to close the eye. When the eyes were open the white of the eyes could be seen in the breadth of several lines around all of cornea.‘ [1835;7:516-517]

• Both Graves and Stokes thought the disorder was a form of heart disease, mainly because the most prominent and disturbing complaint was the rapid and powerful heartbeat.
• The term ‘Graves disease’ was suggested by French physician Armand Trousseau ‘Du Goître Exophthalmique, ou Maladie de Graves.‘ in 1862 ‘il nous faudrait substituer au nom de Basedow celui de Graves . . . serait dit maladie de Graves.’

• Karl Adolph von Basedow (1799-1854), was one of the early authors who gave by far the most complete description of the clinical symptoms of exophthalmos in diffuse toxic goitre.
• In March 1840 he described an association of exophthalmos, tachycardia, and goitre in four cases (Madamme F, G, C and Herr M) monitored over periods of 2, 5, 10 and 11 years. Described locally as the ‘Merseburger Triad‘ and in 1858 as Basedow disease [Hirsch 1858;2:224-225]
• Von Basedow outlined the symptoms of hyperthroidism including intolerance to heat, profound sweating, diarrhea and weight loss in the presence of increased appetite.
• Madame G and Madame F presented with symptoms of florid hyperthyroidism and exophthalmos and during the course of the disease, both were deemed to have become insane with Madame F admitted to a lunatic asylum.

‘There appeared an eminent protrusion of the eye balls, which by the way were absolutely healthy and had a completely full sight. In spite of this the sick woman was sleeping with open eyes and had a frightening appearance.’ Basedow 1840 (Madame G)

• Herr M, was a 50-year-old man who in 1832 began feeling malaise and having diarrhoea. He suffered from ‘a heat of the blood‘, intense sweating, and oppression of the chest. He had a pale puffy countenance with protruding eyes (‘prominent like a crayfish’s eyes‘); the thyroid was enlarged; the patient was emaciated in spite of good appetite and continued to suffer from loose bowels.
• Von Basedow described the connection between these symptoms and tried to explain the pathophysiological mechanisms. He proposed that the exophthalmos was due to an increase of the tissue behind the eye. He hypothesized that ‘dyscrasia of the blood‘ (i.e. mediated via the circulation) caused this tissue swelling and also the goitre. He described pretibial myxedema in two patients with thickened lower legs consisting of a ‘plastic brawn‘ not being impressible and not releasing fluid by puncture. Finally he described pregnancy as a most suitable cure! with symptom amelioration during, and exacerbation following pregnancy recorded in all of his three female patients.
• In 1848, Basedow proposed the name Die Glotzaugen-cachexie [Goggle-eyed cachexia] for the constellation of symptoms he first described in 1840.

• Parry CH. Enlargement of the Thyroid Gland in Connection with Enlargement or Palpitation of the Heart. In: Collections from the unpublished medical writings of the late Caleb Hillier Parry. 1825.
• Flajani G. Osservazione LXVII: Sopra un tumor freddo nell’anterior parte del collo broncocele. In: Collezione d’osservazioni e reflessioni di chirurgia. 1802;III:270-273
• Graves RJ. Newly observed affection of the thyroid gland in females. London Medical and Surgical Journal. 1835;7:516-517
• Basedow KA. Exophthalmos durch Hypertrophie des Zellgewebes in der Augenhöhle. Medicinische Blätter: Wochenschrift für die gesamte Heilkunde. 1840;6:197-204, 220-228
• Trousseau A. Du Goître Exophthalmique, ou Maladie de Graves. In: Clinique médicale de l’Hôtel-Dieu de Paris. 1862;2:614-654 [Trousseau: suggests Graves disease]
• Osler W. The Principles and Practice of Medicine: 3e. 1898;836-837 [Osler: suggests Parry disease]
• Hirsch G. Cardiogmus Strumosus. In: Klinische Fragmente. 1858;2:224-225 [Hirsch: suggests Basedow disease]
• Marketos SG, Eftychiadis A, Koutras DA. The first recognition of the association between goiter and exophthalmos. J Endocrinol Invest. 1983 Oct;6(5):401-3. [PMID 6363510]
• Lindholm J, Laurberg P. Hyperthyroidism, exophthalmos, and goiter: historical notes on the orbitopathy. Thyroid. 2010 Mar;20(3):291-300. [PMID 20187784]
• Papapetrou PD. The philosopher Socrates had exophthalmos (a term coined by Plato) and probably Graves’ disease. Hormones (Athens). 2015 Jan-Mar;14(1):167-71. [PMID 25553768]
• Major RH. Classic Descriptions of Disease: With Biographical Sketches of the Authors. 3e. Thomas; 1945:275-286
• Nabipour I, Burger A, Moharreri M-R, Azizi F. Avicenna, the first to describe thyroid-related orbitopathy. Thyroid 2009;19:7–8. [PMID 19119980]
• Sawin CT. Theories of causation of Graves’ disease. A historical perspective. Endocrinol Metab Clin North Am. 1998 Mar;27(1):63-72. [PMID 9534028]
• Hirsch G. Cardiogmus Strumosus. In: Klinische Fragmente. 1858;2:224-225 [Hirsch: suggests Basedow disease]
• Hennemann G. Historical aspects, about the development of our knowledge of morbus Basedow. J Endocrinol Invest. 1991;14(7):617-624. [PMID 1940068]