Graves' disease overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1],Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]
Historical Perspective
Graves disease owes its name to the Irish doctor Randy Danny Graves,[1] who described a case of goiter with exophthalmos in 1835. However, the German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. As a result, on the European Continent the term Basedow's disease is more common than Graves' disease.[2][3]
Pathophysiology
Genetic factors, anti thyrotropin receptor antibodies, T cells, B cells and thyroid epithelial cells involvement are the main pathologic features of Graves' disease.
Genetic factors have role as initiating factor include Thyroglobulin, Thyrotropin receptor, HLA-DRβ-Arg74, The protein tyrosine phosphatase nonreceptor type 22 (PTPN22), Cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), CD25, CD40.
Graves' disease is an autoimmune disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSH). These are IgG1 subclass of antibodies.[4]
Causes
Graves' disease may be caused by either genetic factors, autoimmune antibodies against thyrotropin receptors, T cells and B cells auto activation and infectious agents.[5][6][4]
Differential Diagnosis
The table below summarizes the list of differential diagnosis for Graves' disease.[7][8][9][10][11]
| Cause of thyrotoxicosis | TSH receptor Antibodies | Thyroid US | Color flow Doppler | Radioactive iodine uptake/Scan | Other features |
|---|---|---|---|---|---|
| Graves' disease | Present | Hypoechoic pattern | ↑ | ↑ | Ophthalmopathy, dermopathy, acropachy |
| Toxic nodular goiter | Absent | Multiple nodules | - | Hot nodules at thyroid scan | - |
| Toxic adenoma | Absent | Single nodule | - | Hot nodule | - |
| Subacute thyroiditis | Absent | Heterogeneous hypoechoic areas | Reduced/absent flow | ↓ | Neck pain-fever and elevated inflammatory index |
| Painless thyroiditis | Absent | Hypoechoic pattern | Reduced/absent flow | ↓ | - |
| Amiodarone induced thyroiditis-Type 1 | Absent | Diffuse or nodular goiter | ↓/Normal/↑ | ↓ but higher than in Type 2 | High urinary iodine |
| Amiodarone induced thyroiditis-Type 2 | Absent | Normal | Absent | ↓/absent | High urinary iodine |
| Central hyperthyroidism | Absent | Diffuse or nodular goiter | Normal/↑ | ↑ | Inappropriately normal or high TSH |
| Trophoblastic disease | Absent | Diffuse or nodular goiter | Normal/↑ | ↑ | - |
| Factitious thyrotoxicosis | Absent | Variable | Reduced/absent flow | ↓ | ↓ serum thyroglobulin |
| Struma ovarii | Absent | Variable | Reduced/absent flow | ↓ | Abdominal RAIU |
Epidemiology and Demographics
Graves’ disease is the most common cause of hyperthyroidism.
Incidence
- Grave's disease annual incidence is about 20 to 50 cases per 100,000 persons.[12]
Prevalence
The prevalence of Graves’ disease in 1970s estimated to be 0.4% in the United States.[13]
Age
- The incidence peaks between 30 and 50 years of age, but people can be affected at any age.
Race
- Graves' disease is more common in Caucasians than in Asians.[14]
Sex
- Graves' disease is more common among women than men. The lifetime risk is 3% for women and 0.5% for men.[15]
Risk factors
The most potent risk factor in the development of Graves' disease is genetic susceptibility. Other risk factors include infections, stress and smoking.
Natural History, Complications and Prognosis
- If left untreated it may lead to serious complications such as, thyroid storm, life threatening arrhythmias, orbitopathies, weight loss and even osteoporosis.
- Cardiac complications are the most important complications of Graves' disease because they are life threatening. Heart failure and atrial fibrillation are the most common cardiac complications. Thyroid dermopathy, presents as pretibial myxedema and acropachy is another complication.[16]
- When compared with people older than 60 years with a healthy thyroid, those who are hyperthyroid have three times the risk of atrial fibrillation.[17][18]
- Thyroid associated ophtalmopathy must be evaluated in every patient with Graves' disease.[16]
- Thyroid crisis is another life threatening complication of Graves' disease.
- Prognosis is varied depends on severity of the disease and adequate treatment. However, it is concidered good.
Diagnosis
In the presence of relative clinical symptoms and signs for hyperthyroidism, a diagnostic approach must be taken to address accurate diagnosis and start the management.[19][20][21] Presence of at least one of the following findings in a hyperthyroid patient is definitive for Graves' disease.[22]
- Detectable TSH receptor antibodies (TRAbs) in the serum
- Evidence of ophthalmopathy and/or dermopathy
- Diffuse and increased RAIU
Symptoms
Some of the most typical symptoms of Graves' Disease are the following:[23]
Palpitations, tremor (usually fine shaking eg. hands), excessive sweating, heat intolerance, increased appetite, unexplained weight loss despite increased appetite, shortness of breath, muscle weakness (especially in the large muscles of the arms and legs) and degeneration, insomnia, increased energy, fatigue, mental impairment, memory lapses, diminished attention, decreased concentration, nervousness, agitation, irritability, restlessness, erratic behavior, emotional lability, gynecomastia, goiter (enlarged thyroid gland), double vision, eye pain, irritation, or the feeling of grit or sand in the eyes, swelling or redness of eyes or eyelids/eyelid retraction, sensitivity to light, decrease in menstrual periods (oligomenorrhea), amenorrhea, infertility/recurrent miscarriage, hair loss, a non-pitting edema with thickening of the skin, described as peau d'orange or orange peel, usually found on the lower extremities, smooth, velvety skin, increased bowel movements or diarrhea.
Physical Examination
- Signs include tachycardia, stare, eyelid lag, proptosis, goiter, resting tremor, hyperreflexia, and warm, moist, and smooth skin. [24]
Laboratory Findings
The laboratory findings for Graves' disease are:
- Elevated levels of serum thyroxine (T4) and triiodothyronine (T3)
- Undetectable serum TSH.
Hyperthyroidism Therapy
Genreral aspects
- In a small proportion of patients, spontaneous remission occurs.
- Smoking cessation is one of the mainstays of treatment.
- Antithyroid drugs are the first line treatment in Europe.
- Ablation therapy either by thyroidectomy or radioactive iodine is more accepted in North America.
Antithyroid Drugs
- Methimazole, carbimazole and propylthiouracil are the available anti thyroid drugs.
- Methimazole is preferred for initial therapy in both Europe and North America because of its favorable side-effect profile.[25][26]
- Durable remission occurs in 40 to 50% of patients which is defined as euthroidism for at least 12 months following 1-2 years of treatment.
- Patients may be switched from one drug to another when necessitated by minor side effects.
- Monitoring by means of liver function tests and white-cell counts before and during antithyroid drug therapy is advocated by some experts but is not currently supported by consensus opinion.
Radioactive Iodine
- Radioactive iodine therapy offers relief from symptoms of hyperthyroidism within weeks.
- Radioiodine is not associated with an increased risk of cancer.[27]
- It can provoke or worsen ophthalmopathy.[28]
Ophtalmopathy
Treatment for ophthalmopathy depends on the phase and severity of the disease. It is ranged from enhancement of tear-film quality and maintenance of ocular surface moisture for mild disease to intravenously administered pulse glucocorticoid therapy for severe and sight threatening disease.
Surgery
- The patients' thyroid hormone must be normalized before surgery to minimize the risk of surgery.
- Surgery is recommended for some patients including,[29]
- Patients with large goiters
- Women wishing to become pregnant shortly after treatment
- Patients who want to avoid exposure to antithyroid drugs or radioiodine.
References
- ↑ Template:WhoNamedIt
- ↑ Template:WhoNamedIt - the history and naming of the disease
- ↑ Goiter, Diffuse Toxic at eMedicine
- ↑ 4.0 4.1 Weetman AP, Yateman ME, Ealey PA, Black CM, Reimer CB, Williams RC, Shine B, Marshall NJ (1990). "Thyroid-stimulating antibody activity between different immunoglobulin G subclasses". J. Clin. Invest. 86 (3): 723–7. doi:10.1172/JCI114768. PMC 296786. PMID 2168443.
- ↑ Tomer Y (2014). "Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics". Annu Rev Pathol. 9: 147–56. doi:10.1146/annurev-pathol-012513-104713. PMC 4128637. PMID 24460189.
- ↑ Limbach M, Saare M, Tserel L, Kisand K, Eglit T, Sauer S, Axelsson T, Syvänen AC, Metspalu A, Milani L, Peterson P (2016). "Epigenetic profiling in CD4+ and CD8+ T cells from Graves' disease patients reveals changes in genes associated with T cell receptor signaling". J. Autoimmun. 67: 46–56. doi:10.1016/j.jaut.2015.09.006. PMID 26459776.
- ↑ Lambert M, Unger J, De Nayer P, Brohet C, Gangji D (1990). "Amiodarone-induced thyrotoxicosis suggestive of thyroid damage". J. Endocrinol. Invest. 13 (6): 527–30. PMID 2258582.
- ↑ Ahmadieh H, Salti I (2013). "Tyrosine kinase inhibitors induced thyroid dysfunction: a review of its incidence, pathophysiology, clinical relevance, and treatment". Biomed Res Int. 2013: 725410. doi:10.1155/2013/725410. PMC 3824811. PMID 24282820.
- ↑ Vialettes B, Guillerand MA, Viens P, Stoppa AM, Baume D, Sauvan R, Pasquier J, San Marco M, Olive D, Maraninchi D (1993). "Incidence rate and risk factors for thyroid dysfunction during recombinant interleukin-2 therapy in advanced malignancies". Acta Endocrinol. 129 (1): 31–8. PMID 8351956.
- ↑ Jha S, Waghdhare S, Reddi R, Bhattacharya P (2012). "Thyroid storm due to inappropriate administration of a compounded thyroid hormone preparation successfully treated with plasmapheresis". Thyroid. 22 (12): 1283–6. doi:10.1089/thy.2011.0353. PMID 23067331.
- ↑ Cohen JH, Ingbar SH, Braverman LE (1989). "Thyrotoxicosis due to ingestion of excess thyroid hormone". Endocr. Rev. 10 (2): 113–24. doi:10.1210/edrv-10-2-113. PMID 2666114.
- ↑ Zimmermann MB, Boelaert K (2015). "Iodine deficiency and thyroid disorders". Lancet Diabetes Endocrinol. 3 (4): 286–95. doi:10.1016/S2213-8587(14)70225-6. PMID 25591468.
- ↑ Furszyfer J, Kurland LT, McConahey WM, Woolner LB, Elveback LR (1972). "Epidemiologic aspects of Hashimoto's thyroiditis and Graves' disease in Rochester, Minnesota (1935-1967), with special reference to temporal trends". Metab. Clin. Exp. 21 (3): 197–204. PMID 5066850.
- ↑ Tellez M, Cooper J, Edmonds C (1992). "Graves' ophthalmopathy in relation to cigarette smoking and ethnic origin". Clin. Endocrinol. (Oxf). 36 (3): 291–4. PMID 1563082.
- ↑ Smith TJ, Hegedüs L (2016). "Graves' Disease". N. Engl. J. Med. 375 (16): 1552–1565. doi:10.1056/NEJMra1510030. PMID 27797318.
- ↑ 16.0 16.1 Devereaux D, Tewelde SZ (2014). "Hyperthyroidism and thyrotoxicosis". Emerg. Med. Clin. North Am. 32 (2): 277–92. doi:10.1016/j.emc.2013.12.001. PMID 24766932.
- ↑ Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PW, Benjamin EJ, D'Agostino RB (1994). "Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons". N. Engl. J. Med. 331 (19): 1249–52. doi:10.1056/NEJM199411103311901. PMID 7935681.
- ↑ Jabbar A, Pingitore A, Pearce SH, Zaman A, Iervasi G, Razvi S (2017). "Thyroid hormones and cardiovascular disease". Nat Rev Cardiol. 14 (1): 39–55. doi:10.1038/nrcardio.2016.174. PMID 27811932.
- ↑ Tozzoli R, Bagnasco M, Giavarina D, Bizzaro N (2012). "TSH receptor autoantibody immunoassay in patients with Graves' disease: improvement of diagnostic accuracy over different generations of methods. Systematic review and meta-analysis". Autoimmun Rev. 12 (2): 107–13. doi:10.1016/j.autrev.2012.07.003. PMID 22776786.
- ↑ Pedersen IB, Knudsen N, Perrild H, Ovesen L, Laurberg P (2001). "TSH-receptor antibody measurement for differentiation of hyperthyroidism into Graves' disease and multinodular toxic goitre: a comparison of two competitive binding assays". Clin. Endocrinol. (Oxf). 55 (3): 381–90.
- ↑ Terry J. Smith & Laszlo Hegedus (2016). "Graves' Disease". The New England journal of medicine. 375 (16): 1552–1565. doi:10.1056/NEJMra1510030. PMID 27797318. Unknown parameter
|month=ignored (help) - ↑ Shoenfeld, Yehuda (2014). Diagnostic criteria in autoimmune diseases. Place of publication not identified: Humana. ISBN 978-1627038584.
- ↑ Terry J. Smith & Laszlo Hegedus (2016). "Graves' Disease". The New England journal of medicine. 375 (16): 1552–1565. doi:10.1056/NEJMra1510030. PMID 27797318. Unknown parameter
|month=ignored (help) - ↑ Terry J. Smith & Laszlo Hegedus (2016). "Graves' Disease". The New England journal of medicine. 375 (16): 1552–1565. doi:10.1056/NEJMra1510030. PMID 27797318. Unknown parameter
|month=ignored (help) - ↑ Burch HB, Burman KD, Cooper DS (2012). "A 2011 survey of clinical practice patterns in the management of Graves' disease". J. Clin. Endocrinol. Metab. 97 (12): 4549–58. doi:10.1210/jc.2012-2802. PMID 23043191.
- ↑ Bartalena L, Burch HB, Burman KD, Kahaly GJ (2016). "A 2013 European survey of clinical practice patterns in the management of Graves' disease". Clin. Endocrinol. (Oxf). 84 (1): 115–20. doi:10.1111/cen.12688. PMID 25581877.
- ↑ Ron E, Doody MM, Becker DV, Brill AB, Curtis RE, Goldman MB, Harris BS, Hoffman DA, McConahey WM, Maxon HR, Preston-Martin S, Warshauer ME, Wong FL, Boice JD (1998). "Cancer mortality following treatment for adult hyperthyroidism. Cooperative Thyrotoxicosis Therapy Follow-up Study Group". JAMA. 280 (4): 347–55. PMID 9686552.
- ↑ Bartalena L, Tanda ML (2009). "Clinical practice. Graves' ophthalmopathy". N. Engl. J. Med. 360 (10): 994–1001. doi:10.1056/NEJMcp0806317. PMID 19264688.
- ↑ Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN (2011). "Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists". Endocr Pract. 17 (3): 456–520. PMID 21700562.