Graves' disease

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Graves' disease
Classification and external resources
ICD-10E05.0
ICD-9242.0
OMIM275000
MedlinePlus000358
eMedicinemed/929 ped/899
MeSHD006111
 
  (Redirected from Graves-Basedow disease)
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Graves' disease
Classification and external resources
ICD-10E05.0
ICD-9242.0
OMIM275000
MedlinePlus000358
eMedicinemed/929 ped/899
MeSHD006111

Graves' disease (or Basedow-Graves disease) is an autoimmune disease. It most commonly affects the thyroid, frequently causing it to enlarge to twice its size or more (goiter), become overactive, with related hyperthyroid symptoms such as increased heartbeat, muscle weakness, disturbed sleep, and irritability. It can also affect the eyes, causing bulging eyes (exophthalmos). It affects other systems of the body, including the skin, heart, circulation and nervous system.

It affects up to 2% of the female population, sometimes appears after childbirth, and has a female:male incidence of 5:1 to 10:1.[citation needed] Hereditary factors are the major risk factor for the development of Graves disease, with "79% of the liability to the development of GD ... attributable to genetic factors".[1] Smoking and exposure to second-hand smoke is associated with the eye manifestations but not the thyroid manifestations.

Diagnosis is usually made on the basis of symptoms, although thyroid hormone tests may be useful, particularly to monitor treatment.[2]

Medical eponyms are often styled nonpossessively; thus Graves' disease and Graves disease are variant stylings for the same term.

Signs and symptoms[edit]

Graves' disease symptoms

The signs and symptoms of Graves' disease virtually all result from the direct and indirect effects of hyperthyroidism, with main exceptions being Graves' ophthalmopathy, goitre, and pretibial myxedema (which are caused by the autoimmune processes of the disease). Symptoms of the resultant hyperthyroidism are mainly insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, shaking hands, itching, heat intolerance, weight loss despite increased appetite, diarrhea, frequent defecation, palpitations, muscle weakness, and skin warmth and moistness.[3] Further signs that may be seen on physical examination are most commonly a diffusely enlarged (usually symmetric), nontender thyroid, lid lag, excessive lacrimation due to Graves' ophthalmopathy, arrhythmias of the heart, such as sinus tachycardia, atrial fibrillation and premature ventricular contractions, and hypertension.[3] People with hyperthyroidism may experience behavioral and personality changes including: psychosis, mania, anxiety, agitation, and depression.[4]

Cause[edit]

The Immunoglobulin G antibody recognizes and binds to the thyrotropin receptor (TSH receptor). It mimics the TSH to that receptor and activates the secretion of thyroxine (T4) and triiodothyronine (T3), and the actual TSH level will decrease in the blood plasma. The TSH levels fall because the hypothalamus-pituitary-thyroid negative feedback loop is working. The result is very high levels of circulating thyroid hormones and the negative feedback regulation will not work for the thyroid gland.[citation needed]

The trigger for auto-antibody production is not known. There appears to be a genetic predisposition for Graves' disease, suggesting that some people are more prone than others to develop TSH receptor activating antibodies due to a genetic cause. HLA DR (especially DR3) appears to play a significant role.[5]

Since Graves' disease is an autoimmune disease which appears suddenly, often quite late in life, it is thought that a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor (a phenomenon known as antigenic mimicry, also seen in some cases of type I diabetes).[citation needed]

One possible culprit is the bacterium Yersinia enterocolitica (a cousin of Yersinia pestis, the agent of bubonic plague). However, although there is indirect evidence for the structural similarity between the bacteria and the human thyrotropin receptor, direct causative evidence is limited.[5] Yersinia seems not to be a major cause of this disease, although it may contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.[6] It has also been suggested that Y. enterocolitica infection is not the cause of auto-immune thyroid disease, but rather is only an associated condition; with both having a shared inherited susceptibility.[7] More recently the role for Y. enterocolitica has been disputed.[8]

Emotional stress has been posited as a possible cause of Graves' disease as well, based largely on anecdotal evidence. While there are theoretical mechanisms by which stress could cause an aggravation of the autoimmune response that leads to Graves' disease, more robust clinical data are needed for a firm conclusion.[9]

Diagnosis[edit]

Graves' disease may present clinically with one of the following characteristic signs:

The two signs that are truly 'diagnostic' of Graves' disease (i.e., not seen in other hyperthyroid conditions) are exophthalmos and non-pitting edema (pretibial myxedema). Goitre is an enlarged thyroid gland and is of the diffuse type (i.e., spread throughout the gland). Diffuse goitre may be seen with other causes of hyperthyroidism, although Graves' disease is the most common cause of diffuse goitre. A large goitre will be visible to the naked eye, but a small goitre (mild enlargement of the gland) may be detectable only by physical exam. Occasionally, goitre is not clinically detectable but may be seen only with CT or ultrasound examination of the thyroid.

Another sign of Graves' disease is hyperthyroidism, i.e., overproduction of the thyroid hormones T3 and T4. Normothyroidism is also seen, and occasionally also hypothyroidism, which may assist in causing goitre (though it is not the cause of the Graves' disease). Hyperthyroidism in Graves' disease is confirmed, as with any other cause of hyperthyroidism, by measuring elevated blood levels of free (unbound) T3 and T4.

Other useful laboratory measurements in Graves' disease include thyroid-stimulating hormone (TSH, usually low in Graves' disease due to negative feedback from the elevated T3 and T4), and protein-bound iodine (elevated). Thyroid-stimulating antibodies may also be detected serologically.

Biopsy to obtain histiological testing is not normally required but may be obtained if thyroidectomy is performed.

Differentiating two common forms of hyperthyroidism such as Graves' disease and Toxic multinodular goiter is important to determine proper treatment. Measuring TSH-receptor antibodies with the h-TBII assay has been proven efficient and was the most practical approach found in one study.[10]

Eye disease[edit]

Thyroid-associated ophthalmopathy is one of the most typical symptoms of Graves' disease. It is known by a variety of terms, the most common being Graves' ophthalmopathy. Thyroid eye disease is an inflammatory condition, which affects the orbital contents including the extraocular muscles and orbital fat. It is almost always associated with Graves' disease but may rarely be seen in Hashimoto's thyroiditis, primary hypothyroidism, or thyroid cancer.

The ocular manifestations that are relatively specific to Graves' disease include soft tissue inflammation, proptosis (protrusion of one or both globes of the eyes), corneal exposure, and optic nerve compression. Also seen, if the patient is hyperthyroid, (i.e., has too much thryoid hormone) are more general manifestations, which are due to hyperthyroidism itself and which may be seen in any conditions that cause hyperthyroidism (such as toxic multinodular goitre or even thyroid poisoning). These more general symptoms include lid retraction, lid lag, and a delay in the downward excursion of the upper eyelid, during downward gaze.

It is believed that fibroblasts in the orbital tissues may express the Thyroid Stimulating Hormone receptor (TSHr). This may explain why one autoantibody to the TSHr can cause disease in both the thyroid and the eyes.[11]

Classification[edit]

Mnemonic: "NO SPECS":[12]

Pathophysiology[edit]

Histopathological image of diffuse hyperplasia of the thyroid gland (clinically presenting as hyperthyroidism)

Graves' disease is an autoimmune disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSH). (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.)

These antibodies cause hyperthyroidism because they bind to the TSH receptor and chronically stimulate it. The TSH receptor is expressed on the follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This in turn causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter.

The infiltrative exophthalmos that is frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball.

The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.

There are 3 types of autoantibodies to the TSH receptor currently recognized:

Another effect of hyperthyroidism is bone loss from osteoporosis, caused by an increased excretion of calcium and phosphorus in the urine and stool. The effects can be minimized if the hyperthyroidism is treated early. Thyrotoxicosis can also augment calcium levels in the blood by as much as 25%. This can cause stomach upset, excessive urination, and impaired kidney function.[13]

Management[edit]

Treatment of Graves' disease includes antithyroid drugs which reduce the production of thyroid hormone; radioiodine (radioactive iodine I-131); and thyroidectomy (surgical excision of the gland). As operating on a frankly hyperthyroid patient is dangerous, prior to thyroidectomy preoperative treatment with antithyroid drugs is given to render the patient "euthyroid" (i.e. normothyroid).

Treatment with antithyroid medications must be given for six months to two years to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells. Therapy with radioiodine is the most common treatment in the United States, while antithyroid drugs and/or thyroidectomy are used more often in Europe, Japan, and most of the rest of the world.

β-blockers (such as propranolol) may be used to inhibit the sympathetic nervous system symptoms of tachycardia and nausea until such time as antithyroid treatments start to take effect. Pure beta blockers do not inhibit lid-retraction in the eyes, which is mediated by alpha adrenergic receptors.

Antithyroid drugs[edit]

The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and propylthiouracil/PTU. These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side-effect is agranulocytosis (1/250, more in PTU). Others include granulocytopenia (dose dependent, which improves on cessation of the drug) and aplastic anemia. Patients on these medications should see a doctor if they develop sore throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are secreted in breast milk. Lygole is used to block hormone synthesis before surgery.

A randomized control trial testing single dose treatment for Graves' found methimazole achieved euthyroid state more effectively after 12 weeks than did propylthyouracil (77.1% on methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups).[14]

A study has shown no difference in outcome for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However two markers were found that can help predict the risk of recurrence. These two markers are a positive Thyroid Stimulating Hormone receptor antibody (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to have an impact independent to a positive TSHR-Ab.[15]

Radioiodine[edit]

Scan of affected thyroid before and after radioiodine therapy.

Radioiodine (radioactive iodine-131) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center. This modality is suitable for most patients, although some prefer to use it mainly for older patients. Indications for radioiodine are: failed medical therapy or surgery and where medical or surgical therapy are contraindicated. Hypothyroidism may be a complication of this therapy, but may be treated with thyroid hormones if it appears. The rationale for radioactive iodine is that it accumulates in the thyroid and irradiates the gland with its beta and gamma radiations, about 90% of the total radiation being emitted by the beta (electron) particles. The most common method of iodine-131 treatment is to administer a specified amount in microcuries per gram of thyroid gland based on palpation or radiodiagnostic imaging of the gland over 24 hours.[16] Patients who receive the therapy must be monitored regularly with thyroid blood tests to ensure that they are treated with thyroid hormone before they become symptomatically hypothyroid. For some patients, finding the correct thyroid replacement hormone and the correct dosage may take many years and may be in itself a much more difficult task than is commonly understood.[citation needed]

Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), solitary nodules.

Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring eventual thyroid hormone supplementation in the form of a daily pill(s). The radio-iodine treatment acts slowly (over months to years) to destroy the thyroid gland, and Graves' disease-associated hyperthyroidism is not cured in all persons by radioiodine, but has a relapse rate that depends on the dose of radioiodine which is administered.

Surgery[edit]

This modality is suitable for young patients and pregnant patients. Indications are: a large goitre (especially when compressing the trachea), suspicious nodules or suspected cancer (to pathologically examine the thyroid) and patients with ophthalmopathy.

Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on one side and partial lobectomy on other side) are possible.

Advantages are immediate cure and potential removal of carcinoma. Its risks are injury of the recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands), hematoma (which can be life-threatening if it compresses the trachea) and scarring. Removal of the gland enables complete biopsy to be performed to have definite evidence of cancer anywhere in the thyroid. (Needle biopsies are not so accurate at predicting a benign state of the thyroid). No further treatment of the thyroid is required, unless cancer is detected. Radioiodine uptake study may be done after surgery, to ensure that all remaining (potentially cancerous) thyroid cells (i.e., near the nerves to the vocal chords) are destroyed. Besides this, the only remaining treatment will be Synthroid, or thyroid replacement pills to be taken for the rest of the patient's life.

Disadvantages are as follows. A scar is created across the neck just above the collar bone line. However, the scar is very thin, and can eventually recede and appear as nothing more than a crease in the neck. The patient may spend a night in hospital after the surgery, and endure the effects of total anesthesia (i.e., vomiting), as well as sore throat, raspy voice, cough from having a breathing tube stuck down the windpipe during surgery.[citation needed]

Eye disease[edit]

Mild cases are treated with lubricant eye drops or non steroidal antiinflammatory drops. Severe cases threatening vision (Corneal exposure or Optic Nerve compression) are treated with steroids or orbital decompression. In all cases cessation of smoking is essential. Double vision can be corrected with prism glasses and surgery (the latter only when the process has been stable for a while).

Difficulty closing eyes can be treated with lubricant gel at night, or with tape on the eyes to enable full, deep sleep.

Orbital decompression can be performed to enable bulging eyes to retreat back into the head. Bone is removed from the skull behind the eyes, and space is made for the muscles and fatty tissue to fall back into the skull.

Eyelid surgery can be performed on upper and/or lower eyelids to reverse the effects of Graves' on the eyelids. Eyelid muscles can become tight with Graves, making it impossible to close eyes all the way. Eyelid surgery involves an incision along the natural crease of the eyelid, and a scraping away of the muscle that holds the eyelid open. This makes the muscle weaker, which allows the eyelid to extend over the eyeball more effectively. Eyelid surgery helps reduce or eliminate dry eye symptoms.

Prognosis[edit]

If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, and in extreme cases, death. Graves disease is often accompanied by an increase in heart rate, which may lead to further heart complications including loss of the normal heart rhythm (atrial fibrillation), which may lead to stroke. If the eyes are proptotic (bulging) enough that the lids do not close completely at night, dryness will occur with a risk of a secondary corneal infection which could lead to blindness. Pressure on the optic nerve behind the globe can lead to visual field defects and vision loss as well.

Epidemiology[edit]

The disease occurs most frequently in women (7:1 compared to men). It occurs most often in middle age (most commonly in the third to fifth decades of life), but is not uncommon in adolescents, during pregnancy, during menopause, or in people over age 50. There is a marked family preponderance, which has led to speculation that there may be a genetic component. To date, no clear genetic defect has been found that would point at a monogenic cause.

History[edit]

Graves' disease owes its name to the Irish doctor Robert James Graves,[17] who described a case of goitre with exophthalmos in 1835.[18] The German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840.[19][20] As a result, on the European Continent, the terms Basedow's syndrome,[21] Basedow's disease, or Morbus Basedow[22] are more common than Graves' disease.[21][23]

Graves' disease[21][22] has also been called exophthalmic goitre.[22]

Less commonly, it has been known as Parry's disease,[21][22] Begbie's disease, Flajani's disease, Flajani-Basedow syndrome, and Marsh's disease.[21] These names for the disease were derived from Caleb Hillier Parry, James Begbie, Giuseppe Flajani, and Henry Marsh.[21] Early reports, not widely circulated, of cases of goitre with exophthalmos were published by the Italians Giuseppe Flajina[24] and Antonio Giuseppe Testa,[25] in 1802 and 1810, respectively.[26] Prior to these, Caleb Hillier Parry,[27] a notable provincial physician in England of the late 18th century (and a friend of Edward Miller-Gallus),[28] described a case in 1786. This case was not published until 1825, but still 10 years ahead of Graves.[29]

However, fair credit for the first description of Graves' disease goes to the 12th century Persian physician Sayyid Ismail al-Jurjani,[30] who noted the association of goitre and exophthalmos in his "Thesaurus of the Shah of Khwarazm", the major medical dictionary of its time.[21][31][32]

Notable cases[edit]

Marty Feldman used his bulging eyes, caused by Graves' disease, to good effect in his work as a comedian.

Notes[edit]

  1. ^ Brix, TH; Kyvik, KO; Christensen, K; Hegedüs, L (2001 Feb). "Evidence for a major role of heredity in Graves' disease: a population-based study of two Danish twin cohorts.". The Journal of Clinical Endocrinology and Metabolism 86 (2): 930–4. PMID 11158069. 
  2. ^ "Brent GA. Clinical practice. Graves' disease. N Engl J Med. 2008 Jun 12;358(24):2594-605". Content.nejm.org. Retrieved 2013-02-27. 
  3. ^ a b page 157 in:Elizabeth D Agabegi; Agabegi, Steven S. (2008). Step-Up to Medicine (Step-Up Series). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-7153-6. 
  4. ^ Bunevicius, R; Prange AJ, Jr (2006). "Psychiatric manifestations of Graves' hyperthyroidism: pathophysiology and treatment options.". CNS Drugs 20 (11): 897–909. doi:10.2165/00023210-200620110-00003. PMID 17044727. 
  5. ^ a b Tomer Y, Davies T (1993). "Infection, thyroid disease, and autoimmunity" (PDF). Endocr Rev 14 (1): 107–20. doi:10.1210/er.14.1.107. PMID 8491150. 
  6. ^ Toivanen P, Toivanen A (1994). "Does Yersinia induce autoimmunity?". Int Arch Allergy Immunol 104 (2): 107–11. doi:10.1159/000236717. PMID 8199453. 
  7. ^ Strieder T, Wenzel B, Prummel M, Tijssen J, Wiersinga W (2003). "Increased prevalence of antibodies to enteropathogenic Yersinia enterocolitica virulence proteins in relatives of patients with autoimmune thyroid disease". Clin Exp Immunol 132 (2): 278–82. doi:10.1046/j.1365-2249.2003.02139.x. PMC 1808711. PMID 12699417. 
  8. ^ Hansen P, Wenzel B, Brix T, Hegedüs L (2006). "Yersinia enterocolitica infection does not confer an increased risk of thyroid antibodies: evidence from a Danish twin study". Clin Exp Immunol 146 (1): 32–8. doi:10.1111/j.1365-2249.2006.03183.x. PMC 1809723. PMID 16968395. 
  9. ^ Falgarone G, Heshmati HM, Cohen R, Reach G (2013). "Mechanisms in endocrinology. Role of emotional stress in the pathophysiology of Graves' disease". Eur. J. Endocrinol. 168 (1): R13–8. doi:10.1530/EJE-12-0539. PMID 23027804. 
  10. ^ Wallaschofski H, Kuwert T, Lohmann T (2004). "TSH-receptor autoantibodies - differentiation of hyperthyroidism between Graves' disease and toxic multinodular goiter". Exp. Clin. Endocrinol. Diabetes 112 (4): 171–4. doi:10.1055/s-2004-817930. PMID 15127319. 
  11. ^ "Mary Ann Liebert, Inc. - Thyroid - 17(10):1013". Liebertonline.com. doi:10.1089/thy.2007.0185. Retrieved 2009-06-03. 
  12. ^ Cawood T, Moriarty P, O'Shea D (August 2004). "Recent developments in thyroid eye disease". BMJ 329 (7462): 385–90. doi:10.1136/bmj.329.7462.385. PMC 509348. PMID 15310608. 
  13. ^ "Thyroid Disease, Osteoporosis and Calcium - Womens Health and Medical Information on". Medicinenet.com. 2006-12-07. Retrieved 2013-02-27. 
  14. ^ Homsanit M, Sriussadaporn S, Vannasaeng S, Peerapatdit T, Nitiyanant W, Vichayanrat A (2001). "Efficacy of single daily dosage of methimazole vs. propylthiouracil in the induction of euthyroidism". Clin. Endocrinol. (Oxf) 54 (3): 385–90. doi:10.1046/j.1365-2265.2001.01239.x. PMID 11298092. 
  15. ^ Glinoer D, de Nayer P, Bex M (2001). "Effects of l-thyroxine administration, TSH-receptor antibodies and smoking on the risk of recurrence in Graves' hyperthyroidism treated with antithyroid drugs: a double-blind prospective randomized study". Eur. J. Endocrinol. 144 (5): 475–83. doi:10.1530/eje.0.1440475. PMID 11331213. 
  16. ^ Saha, Gopal B. (2009). Fundamentals of Nuclear Pharmacy (5 ed.). Springer-Verlag New York, LLC. p. 342. ISBN 0387403604. 
  17. ^ Mathew Graves at Who Named It?
  18. ^ Graves, RJ. New observed affection of the thyroid gland in females. (Clinical lectures.) London Medical and Surgical Journal (Renshaw), 1835; 7: 516-517. Reprinted in Medical Classics, 1940;5:33-36.
  19. ^ Von Basedow, KA. Exophthalmus durch Hypertrophie des Zellgewebes in der Augenhöhle. [Casper's] Wochenschrift für die gesammte Heilkunde, Berlin, 1840, 6: 197-204; 220-228. Partial English translation in: Ralph Hermon Major (1884–1970): Classic Descriptions of Disease. Springfield, C. C. Thomas, 1932. 2nd edition, 1939; 3rd edition, 1945.
  20. ^ Von Basedow, KA. Die Glotzaugen. [Casper's] Wochenschrift für die gesammte Heilkunde, Berlin, 1848: 769-777.
  21. ^ a b c d e f g Basedow's syndrome or disease at Who Named It? - the history and naming of the disease
  22. ^ a b c d Robinson, Victor, Ph.C., M.D. (editor) (1939). "Exophthalmic goiter, Basedow's disease, Grave's disesase". The Modern Home Physician, A New Encyclopedia of Medical Knowledge. WM. H. Wise & Company (New York). , pages 82, 294, and 295.
  23. ^ Goiter, Diffuse Toxic at eMedicine
  24. ^ Flajani, G. Sopra un tumor freddo nell'anterior parte del collo broncocele. (Osservazione LXVII). In Collezione d'osservazioni e reflessioni di chirurgia. Rome, Michele A Ripa Presso Lino Contedini, 1802;3:270-273.
  25. ^ Testa, AG. Delle malattie del cuore, loro cagioni, specie, segni e cura. Bologna, 1810. 2nd edition in 3 volumes, Florence, 1823; Milano 1831; German translation, Halle, 1813.
  26. ^ Giuseppe Flajani at Who Named It?
  27. ^ Parry, CH. Enlargement of the thyroid gland in connection with enlargement or palpitations of the heart. Posthumous, in: Collections from the unpublished medical writings of C. H. Parry. London, 1825, pp. 111–129. According to Garrison, Parry first noted the condition in 1786. He briefly reported it in his Elements of Pathology and Therapeutics, 1815. Reprinted in Medical Classics, 1940, 5: 8-30.
  28. ^ Hull G (1998). "Caleb Hillier Parry 1755–1822: a notable provincial physician". Journal of the Royal Society of Medicine 91 (6): 335–8. PMC 1296785. PMID 9771526. 
  29. ^ Caleb Hillier Parry at Who Named It?
  30. ^ Sayyid Ismail Al-Jurjani.Thesaurus of the Shah of Khwarazm.
  31. ^ Ljunggren JG (August 1983). "[Who was the man behind the syndrome: Ismail al-Jurjani, Testa, Flajina, Parry, Graves or Basedow? Use the term hyperthyreosis instead]". Lakartidningen 80 (32–33): 2902. PMID 6355710. 
  32. ^ Nabipour, I. (2003). "Clinical Endocrinology in the Islamic Civilization in Iran". International Journal of Endocrinology and Metabolism 1: 43–45 [45]. 
  33. ^ LAWRENCE K. ALTMAN, M.D (1991-05-28). "THE DOCTOR'S WORLD; A White House Puzzle: Immunity Ailments-Science Section". Nytimes.com. Retrieved 2013-02-27. 
  34. ^ Ganz, Caryn (Fri, Jun 24, 2011). "Missy Elliott Has Been M.I.A. for a Very Good Reason". Yahoo Music. Retrieved 6 July 2013. 
  35. ^ Kugler, R.N., Mary (December 9, 2003). "Graves' Disease and Research: Multiple Areas of Study". About.com. Retrieved 2009-06-03. 
  36. ^ "Barbara Leigh". Home.rmci.net. Retrieved 2013-02-27. 
  37. ^ A Dame in a Hot Room Apr. 12th, 2012 at 8:47 AM (2012-04-12). "Dame Maggie Daily - A Dame in a Hot Room". Damemaggiedaily.livejournal.com. Retrieved 2013-08-07. 

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