Sumber: Mayo Clinic

Causes:

Graves' disease is caused by a dysfunction in the body's disease-fighting immune system. One normal immune system response is the production of antibodies designed to target a specific virus, bacterium or other foreign substance. In Graves' disease for reasons that aren't well understood the body produces an antibody to a particular protein on the surface of cells in the thyroid, a hormone-producing gland in the neck. Normally, thyroid function is regulated by a hormone released by a tiny gland at the base of the brain (pituitary gland). The antibody associated with Graves' disease thyrotropin receptor antibody (TRAb) can essentially mimic the action of the regulatory pituitary hormone. Therefore, TRAb overrides normal regulation of the thyroid and results in overproduction of thyroid hormones (hyperthyroidism).

Result of hyperthyroidism
Thyroid hormones affect a number of body functions, including:

Metabolism, the processing of nutrients to create energy for cells Heart and nervous system function Body temperature Muscle strength Menstrual cycle

Consequently, the impact of Graves' disease may be widespread and result in a decline in the overall quality of life.

Cause of Graves' ophthalmopathy

The exact cause of Graves' ophthalmopathy is also not well understood. However, it appears that the same antibody that can cause thyroid dysfunction may also have an "attraction" to tissues surrounding the eyes. The antibody activity triggers inflammation and other immune system events that result in the signs and symptoms of Graves' ophthalmopathy. Graves' ophthalmopathy often appears at the same time as hyperthyroidism or several months later. But signs and symptoms of ophthalmopathy may appear years before or after the onset of hyperthyroidism. Graves' ophthalmopathy may also appear in the absence of hyperthyroidism.

Risk Factors Although anyone can develop Graves' disease, a number of factors can increase the risk of disease. These risk factors include the following:
Family history. Because a family history of Graves' disease is a known risk factor, there is likely a gene or genes that can make a person more susceptible to the disorder. Gender. Women are much more likely to develop Graves' disease than are men. Age. Graves' disease usually develops in people younger than 40. Other autoimmune disorders. People with other disorders of the immune system, such as type 1 diabetes or rheumatoid arthritis, have an increased risk. Emotional or physical stress. Stressful life events or illness may act as a trigger for the onset of Graves' disease among people who are genetically susceptible. Pregnancy. Pregnancy or recent childbirth may increase the risk of the disorder, particularly among women who are genetically susceptible. Smoking. Cigarette smoking, which can affect the immune system, increases the risk of Graves' disease. The degree of risk is linked to the number of cigarettes smoked daily the larger the number, the greater the risk. Smokers who have Graves' disease are also at increased risk of developing Graves' ophthalmopathy

Test and Diagnosis A diagnosis of Graves' disease is based primarily on your answers to the doctor's questions and findings from a physical exam. He or she may also order laboratory tests to confirm a diagnosis or gather more evidence if a diagnosis isn't clear. Diagnostic procedures may include:
Physical exam. Your doctor examines your eyes to see if they're irritated or protruding and looks to see if your thyroid gland is enlarged. Because Graves' disease increases your metabolism, your doctor will check your pulse and blood pressure and look for signs of tremor. Blood sample. Your doctor may order blood tests to determine your levels of thyroid-stimulating hormone (TSH), the pituitary hormone that normally stimulates the thyroid gland, as well as levels of thyroid hormones. People with Graves' disease usually have lower than normal levels of TSH and higher levels of thyroid hormones. Another laboratory test measures the levels of the antibody known to cause Graves' disease. This test usually isn't necessary to make a diagnosis, but a negative result might indicate another cause for hyperthyroidism. Radioactive iodine uptake. Your body needs iodine to make thyroid hormones. By giving you a small amount of radioactive iodine and later measuring the amount of it in your thyroid gland with a specialized scanning camera, your doctor can determine the rate at which your thyroid gland takes up iodine. A high uptake of radioactive iodine indicates your thyroid gland is overproducing hormones. Imaging tests. If the diagnosis of Graves' ophthalmopathy isn't clear from a clinical assessment, your doctor may order an imaging test, such as computerized tomography (CT), a specialized Xray technology that produces thin cross-sectional images. Magnetic resonance imaging (MRI), which uses magnetic fields and radio waves to create either cross-sectional or 3-D images, may also be used.

Sumber: MedicineNet.com

How do I find out if I have Graves' disease?

Most people with Graves' disease have symptoms that are bothersome. If you have symptoms of Graves' disease, your doctor will do an exam and order one or more tests. Tests used to help find out if you have Graves' disease include: Thyroid function tests. A blood sample is sent to a lab to see if your body has the right amount of thyroid hormone (T4) and TSH. A high level of thyroid hormone in the blood plus a low level of TSH is a sign of overactive thyroid. Sometimes, routine screening of thyroid function reveals mild overactive thyroid in a person without symptoms. In such cases, doctors might suggest treatment or watchful waiting to see if levels return to normal. Radioactive iodine uptake (RAIU).An RAIU tells how much iodine the thyroid takes up. The thyroid takes up iodine and uses it to make thyroid hormone. A high uptake suggests Graves' disease. This test can be helpful in ruling out other possible causes of overactive thyroid. Antibody tests. A blood sample is sent to a lab to look for antibodies that suggest Graves' disease. Graves' disease can be hard to diagnose during pregnancy because it has many of the same symptoms as normal pregnancy, like fatigue and heat intolerance. Also, some lab tests can be harder to interpret. Plus, doctors cannot use RAIU during pregnancy to rule out other causes.

Sumber: Patologi Robbins

Causes Thyroid-stimulating immunoglobulin An IgG antibody that binds to the TSH receptor and mimics the action of TSH, stimulating adenylcyclase, with resultant increased release of thyroid hormones. Almost all persons with Gravesdisease have detectable amounts of this autoantibody to the TSH receptor. This antibody isrelatively specific for Graves disease, in contrast to thyroglobulin and thyroid peroxidase antibodies. Thyroid growth-stimulating immunoglobulins (TGIs) Directed against the TSH receptor, TGIs have been implicated in the proliferation of thyroid follicularepithelium. TSH-binding inhibitor immunoglobulins (TBII) These anti-TSH receptor antibodies prevent TSH from binding normally to its receptor on thyroidepithelial cells. In so doing, some forms of TBIIs mimic the action of TSH, resulting in the stimulationof thyroid epithelial cell activity, whereas other forms may actually inhibit thyroid cell function

Sumber: Medscape Causes

Graves disease is autoimmune in etiology, and the immune mechanisms involved may be one of the following:

Expression of a viral antigen (self-antigen) or a previously hidden antigen The specificity crossover between different cell antigens with an infectious agent or a superantigen Alteration of the T cell repertoire, idiotypic antibodies becoming pathogenic antibodies New expression of HLA class II antigens on thyroid epithelial cells (eg, HLA-DR antigen) The autoimmune process in Graves disease is influenced by a combination of environmental and genetic factors. Several autoimmune thyroid disease susceptibility genes have been identified: CD40, CTLA4, thyroglobulin, TSH receptor, and PTPN22.[4] Some of these susceptibility genes are specific to either Graves disease or Hashimoto thyroiditis, while others confer susceptibility to both conditions. HLA-DRB1 andHLA-DQB1 also appear to be associated with Graves disease susceptibility. Genetic factors contribute approximately 20-30% of overall disease susceptibility. Cytotoxic T lymphocyte-associated molecule-4 (CTLA4) is a major thyroid autoantibody susceptibility gene,[27, 28] and it is a negative regulator of T-cell activation and may play an important role in the pathogenesis of Graves disease. The G allele of exon1 +49 A/G single nucleotide polymorphism (SNP) of the CTLA4 gene influences higher TPOAb and TgAb production in patients who are newly diagnosed with Graves disease. [27] This SNP of theCTLA4 gene can also predict recurrence of Graves disease after cessation of thionamide treatment.[29] There is an association of a C/T SNP in the Kozak sequence of CD40 with Graves disease.[4, 30] The association of SNPs in PTPN22 varies among autoimmune diseases individually or as part of a haplotype, and the mechanisms by which PTPN22 confers susceptibility to Graves disease may differ from other autoimmune diseases.[31] Alleles of intron 7 of the thyrotropin receptor gene (TSHR) have also been shown to contribute to susceptibility to Graves disease. Inhibitory antibodies directed against insulinlike growth factor receptor-1 (IGFR-1) were seen in 14% of patients with Graves orbitopathy, but there was no activation of IGFR-1 in association with these antibodies.[32] Environmental factors associated with susceptibility are largely unproven. Other factors include infection, iodide intake, stress, female sex, steroids, and toxins. Smoking has been implicated in the worsening of Graves ophthalmopathy. Graves disease has been associated with a variety of infectious agents such as Yersinia enterocolitica and Borrelia burgdorferi. Homologies have been shown between proteins of these organisms and thyroid autoantigens.[33, 34] Stress can be a factor for thyroid autoimmunity. Acute stress-induced immunosuppression may be followed by immune system hyperactivity, which could precipitate autoimmune thyroid disease. This may occur during the postpartum period, in which Graves disease may occur 3-9 months after delivery. Estrogen may influence the immune system, particularly the B-cell repertoire. Both T- and B-cell function are diminished during pregnancy, and the rebound from this immunosuppression is thought to contribute to the development of postpartum thyroid syndrome. Interferon beta-1b and interleukin-4, when used therapeutically, may cause Graves disease. Trauma to the thyroid has also been reported to be associated with Graves disease. This may include surgery of the thyroid gland, percutaneous injection of ethanol, and infarction of a thyroid adenoma.

Laboratories Findings
Ultrasensitive (third-generation) thyrotropin assays remain the best screening test for thyroid disorders.

With the exception of thyrotropin-induced hyperthyroidism, subnormal or suppressed thyrotropin levels are seen in most patients with thyrotoxicosis. Free T4 levels or the free T4 index is usually elevated, as is the free T3 level or free T3 index. Subclinical hyperthyroidism, defined as a free T4 or free T3

level within the reference range with suppressed thyrotropin, also can be seen. On occasion, only the free T3 level is elevated, a syndrome known as T3 toxicosis. This may be associated with toxic nodular goiter or the ingestion of T3. Assays for thyrotropin-receptor antibodies (particularly TSIs) almost always are positive. Detection of TSIs is diagnostic for Graves disease. The presence of TSIs is particularly useful in reaching the diagnosis in pregnant women, in whom the use of radioisotopes is contraindicated. Other markers of thyroid autoimmunity, such as antithyroglobulin antibodies or antithyroidal peroxidase antibodies, are usually present. Other autoantibodies that may be present include thyrotropin receptor blocking antibodies and antisodium-iodide symporter antibody. The presence of these antibodies supports the diagnosis of an autoimmune thyroid disease.
Liver function test results should be obtained to monitor for liver toxicity caused by thioamides (antithyroid medications). A CBC count with differential should be obtained at baseline and with the development of fever or symptoms of infection. Graves disease may be associated with normocytic anemia, low-normal to slightly depressed total WBC count with relative lymphocytosis and monocytosis, low-normal to slightly depressed platelet count. Thionamides may rarely cause severe hematologic side effects, but routine screening for these rare events is not costeffective. Investigation of gynecomastia associated with Graves disease may reveal increased sex hormonebinding globulin levels and decreased free testosterone levels. Graves disease may worsen diabetes control and may be reflected by an increase in hemoglobin A1C in diabetic patients. A fasting lipid profile may show decreased total cholesterol levels and decreased triglyceride levels. Thyrotropin-releasing hormone testing has largely been replaced by third-generation thyrotropin assays. A high titer of serum antibodies to collagen XIII is associated with active Graves ophthalmopathy.[36]

Imaging Studies
Radioactive iodine scanning and measurements of iodine uptake are useful in differentiating the causes of hyperthyroidism. In Graves disease, the radioactive iodine uptake is increased and the uptake is diffusely distributed over the entire gland.[35] Ultrasounds with color-Doppler evaluation have been found to be cost-effective in hyperthyroid patients.[24, 37] A prospective trial showed that thyroid ultrasound findings are predictive of radioiodine treatment outcome, and, in patients with Graves disease, normoechogenic and large glands are associated with increased radioresistance. [38] Computed tomography scanning or magnetic resonance imaging (of the orbits) may be necessary in the evaluation of proptosis. If routinely performed, most patients have evidence of orbitopathy, such as an increased volume of extraocular muscles and/or retrobulbar connective tissue. These techniques are useful to monitor changes over time or to ascertain the effects of treatment. Careful monitoring is required after using iodinated contrast agents as they may affect ongoing treatment plans.

Histologic Findings
In select cases in which thyroidectomy was performed for the treatment of severe hyperthyroidism, the thyroid glands from patients with Graves disease show lymphocytic infiltrates and follicular hypertrophy, with little colloid present.

GRAVES DISEASE Latar belakang Graves disease berasal dari nama Robert J. Graves, MD, circa tahun1830, adalah penyakit autoimun yang ditandai dengan hipertiroidisem (produksi berlebihan dari kelenjar tiroid) yang ditemukan dalam sirkulasi darah. Graves disease lazim juga disebut penyakit Basedow. Struma adalah istilah lain untuk pembesaran kelenjar gondok. Gondok atau goites adalah suatu pembengkakan atau pembesaran kelanjar tiroid yang abnormal yang penyebabnya bisa bermacammacam. Penyakit ini lebih sering ditemukan pada orang muda usia 20 40 tahun terutama wanita, tetapi penyakit ini dapat terjadi pada segala umur . Kelenjar tiroid dalam keadaan normal tidak tampak, merupakan suatu kelanjar yang terletak di leher bagian depan, di bawah jakun. Kelenjar tiroid ini berfungsi untuk memproduksi hormon tiroid yang berfungsi untuk mengontrol metabolisme tubuh sehingga tercapai pertumbuhan dan perkembangan yang normal. Penyebab Penyebabnya tidak diketahui. Karenai ini merupakan penyakit autoimun yaitu saat tubuh menghasilkan antibodi yang menyerang komponen spesifik dari jaringan itu sendiri, maka penyakit ini dapat timbul tiba-tiba. Tidak diketahui mekanismenya secara pasti, kebanyakan dijumpai pada wanita. Reaksi silang

tubuh terhadap penyakit virus mungkin merupakan salah satu penyebabnya ( mekanisme ini sama seperti postulat terjadinya diabetes mellitus tipe I).Obatobatan tertentu yang digunakan untuk menekan produksi hormon kelenjar tiroid dan Kurang yodium dalam diet dan air minum yang berlangsung dalam kurun waktu yang cukup lama mungkin dapat menyebabkan penyakit ini. Walaupun etiologi penyakit Graves tidak diketahui, tampaknya terdapat peran antibody terhadap reseptor TSH, yang menyebabkan peningkatan produksi tiroid. Penyakit ini ditandai dengan peninggian penyerapan yodium radioaktif oleh kelenjar tiroid. Patofisiologi Graves disease merupakan salah satu contoh dari gangguan autoimun hipersensitif tipe II. Sebagian besar gambaran klinisnya disebabkan karena produksi autoantibodi yang berikatan dengan reseptor TSH, dimana tampak pada sel folikuler tiroid ( sel yang memproduksi tiroid). Antibodi mengaktifasi sel tiroid sama seperti TSH yang menyebabkan peningkatan produksi dari hormon tiroid. Opthalmopathy infiltrat ( gangguan mata karena tiroid) sering terjadi yang tampak pada ekspresi reseptor TSH pada jaringan retroorbital. Penyebab peningkatan produksi dari antibodi tidak diketahui. Infeksi virus mungkin merangsang antibodi, dimana bereaksi silang dengan reseptor TSH manusia. Ini tampak sebagai faktor predisposisi genetik dari Graves disease, sebagian besar orang lebih banyak terkena Graves disease dengan aktivitas antibodi dari reseptor TSH yang bersifat genetik.Yang berperan adalah HLA DR (terutama DR3). Gambaran Klinis Gejala dan tanda peningkatan metabolisme di segala sistem tubuh, mungkin terlihat jelas. Peningkatan metabolisme menyebabkan peningkatan kalori, karena itu masukkan kalori umumnya tidak mencukupi kebutuhan sehingga berat badan menurun. Peningkatan metabolisme pada sistem kardiovaskuler terlihat dalam bentuk peningkatan sirkulasi darah dengan penambahan curah jantung sampai 23 kali normal, juga dalam istirahat. Irama nadi naik dan tekanan denyut bertambah sehingga menjadi pulses seler dan penderita mengalami takikardi dan palpitasi. Beban miokard, dan rangsangan persarafannya dapat meningkatkan kekacauan irama jantung berupa fibrilasi atrium Pada saluran cerna sekresi maupun peristalsis meningkat sehingga sering timbul diare. Hipermetabolisme susunan saraf biasanya menyebabkan tremor, penderita bangun di waktu malam dan sering terganggu mimpi yang tidak karuan. Selain

itu, penderita mengalami ketidakstabilan emosi, kegelisahan, kekacauan pikiran dan ketakutan yang tidak beralasan yang sangat mengganggu. Pada saluran nafas hipermetabolisme berupa dispnea dan takipnea yang tidak terlalu mengganggu. Kelemahan otot biasanya cukup mengganggu, demikian juga menoragia. Kelainan mata disebabkan oleh reaksi autoimun pada jaringan ikat di dalam rongga mata. Jaringan ikat dengan jaringan lemaknya menjadi hiperplasik sehingga bola mata terdorong keluar dan otot mata terjepit. Akibat terjadi eksoftalmus yang dapat menyebabkan rusaknya bola mata akibat keratitis. Gangguan faal otot mata yang menyebabkan strabismus. Diagnosis Diagnosis dapat dibuat berdasarkan dari tanda dan gejala yang ada, dan dari hasil laboratorium berupa kadar dari hormon tiroid (tiroksin/ T4, triyodotironin/ T3) dan kadar dari tiroid stimulating hormone (TSH). Free T4 dan free T3 yang tinggi merupakan suatu petanda, sambil TSH memberikan negative feedback. Peningkatan ikatan protein iodium mungkin dapat terdeteksi. Struma yang besar kadang terlihat pada foto rontgen. Tiroid stimulating antibodi mungkin dapat terlihat pada pemeriksaan serologi. Penatalaksanaan Pengobatan terhadap Graves disease termasuk penggunaan obat-obat anti tiroid (OAT), yodium radioaktif dan tiroidektomi (eksisi pembedahan dari kelenjar tiroid). Pengobatan hipertiroid pada graves disease adalah dengan obat-obatan seperti methimazole atau propylthiouracil (PTU), yang akan menghambat produksi dari hormon tiroid, atau juga dengan yodium radioaktif . Pembedahan merupakan salah satu pilihan pengobatan, sebelum pembedahan pasien diobati dengan methimazole atau propylthiouracil (PTU). Beberapa ahli memberikan terapi kombinasi tiroksin dengan OAT dosis tinggi untuk menghambat produksi hormon tiroid namun pasien tetap dipertahankan eutiroid dengan pemberian tiroksin. Penambahan tiroksin selama terapi dengan OAT juga akan menurunkan produksi antibodi terhadap reseptor TSH dan frekuensi kambuhnya hipertiroid. Pengobatan dengan iodium radioaktif diindikasikan pada : pasien umur 35 tahun atau lebih, hipertiroid yang kambuh setelah dioperasi, gagal mencapai remisi sesudah pemberian OAT, tidak mampu atau tidak mau pengobatan dengan OAT dan pada adenoma toksik, goiter multinodular toksik. Digunakan I131 dengan dosis 5-12mCi per oral.

Tiroidektomi subtotal sangat efektif untuk menanggulangi hipertiroid. Indikasi operasi adalah : 1. Pasien umur muda dengan struma yang besar serta tidak mempan dengan OAT 2. Pada wanita hamil (trimester kedua) yang memerlukan OAT dosis tinggi. 3. Alergi terhadap OAT, pasien tidak bisa menerima iodium radioaktif. 4. Adenoma toksik atau struma multinodular toksik. 5. Pada penyakit grave yang berhubungan dengan satu atau lebih nodul. DAFTAR PUSTAKA 1. Sjamsuhidajat R, Jong WD. Buku Ajar Ilmu Bedah. EGC, Jakarta, 1996. Hal 932 4. 2. Noer S, dkk. Buku Ajar Ilmu Penyakit Dalam Jilid 1. FKUI, Jakarta, 1996. Hal 766 72 3. Leksana, Mirzanie H. Chirurgica. Tosca Enterprise. Yogyakarta, 2005. Hal VIII.1 5 4. http://www.eMedicine.com 5. http://www.wikepedia.com 6. http://www.konsultasigizi.com 7. http://www.GraveDisease.com