1.

Efek Pada Laju Metabolisme

Hormon tiroid meningkatkan laju metabolik basal seluruh tubuh, atau kecepatan langsam.
Hormon Tiroid adalah hormone terpenting laju konsumsi Oksigen dan pengeluaran energi tubuh
pada keaadan istirahat. Peningkatan produksi panas yang terjadi menyebabkan keringat
berlebihan dan intoleransi panas. Selain itu laju metabolisme yang meningkat dapat pula
menyebabkan keringat dan berat tubuh turun karena tubuh menggunakan bahan bakar dengan
kecepatan yang abnormal. Terjadi pula penguraian simpanan lemak, karbohidrat, dan protein
pada peningkatan laju metabolisme tubuh. Berkurangnya protein menyebabkan rasa lemah.
(Sherwood)

Kecepatan metabolisme basal tubuh meningkat 60 sampai 100 persen diatas nilai normal.
(Guyton)

Salah satu fungsi tiroksin yang utama adalah meningkatkan jumlah dan aktivitas mitokondria,
sehingga mempercepat pembentukan Adenosin Trifosfat (ATP) untuk energi fungsi selular.
(Guyton)

Hormon Tiroid Meningkatkan transport aktif ion-ion melalui membran sel dengan cara
meningkatkan aktivitas sintesis enzim, aktivitas Na+/K+ -ATPase dan penggunaan oksigen.
(Stefan)

2. Efek Simpatomimetik
Efek yang serupa dengan yang ditimbulkan oleh sistem saraf simpatis, disebut dengan efek
simpatomimetik. Hormon tiroid meningkatkan responsitivitas sel sasaran terhadap katekolamin
(epinefrin norepinefrin), sehingga terjadi penguatan sekresi hormon pada medulla adrenal. Hal
ini menyebabkan terjadinya proliferasi dari reseptor sel sasaran katekolamin. (Sherwood)

3. Efek pada laju kardiovaskular

Peningkatan kepekaan jantung pada katekolamin meningkatkan kecepatan jantung dan kekuatan
kontraksi sehingga curah jantung meningkat. (Sherwood)

Metabolisme jaringan yang meningkat akan mempercepat pemakaian oksigen dan

memperbanyak jumlah ATP dalam jaringan. Efek ini menyebabkan vasodilatasi di sebagian besar
jaringan tubuh dan tingkatkan aliran darah. Aliran darah yang meningkat juga sebabkan curah
jantung meningkat bahkan hingga 60% diatas normal. Terjadilah takikardi (Guyton)

4. Efek pada pertumbuhan dan sistem saraf

Hormon tiroid merangsang sekresi GH, serta berperan dalam perkembangan sistem saraf pusat.
Hal ini menyebabkan peningkatan berlebihan kewaspadaan mental hingga titik ketika pasien
mudah tersinggung, tegang, cemas, dan sangat emosional. (Sherwood)

Hormon tiroid memiliki pengaruh pada pertumbuhan, terutama pada anak anak. Tingginya kadar
hormone tiroid dapat menyebabkan pertumbuhan tulang yang berlebihan namun tulang juga
mengalami pematangan lebih cepat dan epifisisnya menutup pada usia muda. (Guyton)
5. Efek pada metabolisme lemak
Hormon tiroid meningkatkan seluruh aspek metabolisme lemak, sehingga lipid secara cepat
diangkut dari jaringan lemak dan menurunkan cadangan lemak tubuh secara signifikan. Hormon
ini juga meningkatkan konsentrasi asam lemak bebas di dalam plasma dan sangat mempercetap
oksidasi asam lemak bebas oleh sel. (Guyton)

6. Efek pada kebutuhan vitamin

Hormon tiroid meningkatkan jumlah berbagai enzim tubuh, dan karena beberapa vtamin menjadi
bagian penting dari beberapa enzim maupun koenzim maka kebutuhan akan vitamin pun akan
bertambah. Karenanya di tugas terstruktur pun membahas tentang hal tersebut. (Guyton)

7. Pernafasan
Pemakaian oksigen bertambah, sehingga asupan oksigen harus terus disupplai untuk
keberlanjutan proses metabolisme. (Guyton)

8. Peningkatan motilitas saluran cerna

Tingkatkan kecepatan sekresi getah pencernaan dan pergerakan saluran cerna.

9. Efek pada fungsi otot

Menyebabkan lemah karena berlebihannya katabolisme protein.

10. Tremor otot

Terjadi tremor halus pada otot

11. Fungsi Seksual

Hipertiroid dapat sebabkan impotensi. Pada wanita hipotiroid menyebabkan menoragia (darah
berlebihan) daj polimenore (frekuensi mens lebih sering). Pada beberapa kasus unik, terjadi
menstruasi tidak teratur dan timbul amenore. (Guyton)
PATOFIS

In Graves disease, B and T lymphocyte-mediated autoimmunity are known to be directed at 4 well-known

thyroid antigens: thyroglobulin, thyroid peroxidase, sodium-iodide symporter and the thyrotropin
receptor. However, the thyrotropin receptor itself is the primary autoantigen of Graves disease and is
responsible for the manifestation of hyperthyroidism. In this disease, the antibody and cell-mediated
thyroid antigen-specific immune responses are well defined. Direct proof of an autoimmune disorder that
is mediated by autoantibodies is the development of hyperthyroidism in healthy subjects by transferring
thyrotropin receptor antibodies in serum from patients with Graves disease and the passive transfer of
thyrotropin receptor antibodies to the fetus in pregnant women.

The thyroid gland is under continuous stimulation by circulating autoantibodies against the thyrotropin
receptor, and pituitary thyrotropin secretion is suppressed because of the increased production of thyroid
hormones. The stimulating activity of thyrotropin receptor antibodies is found mostly in the
immunoglobulin G1 subclass. These thyroid-stimulating antibodies cause release of thyroid hormone and
thyroglobulin that is mediated by 3,'5'-cyclic adenosine monophosphate (cyclic AMP), and they also
stimulate iodine uptake, protein synthesis, and thyroid gland growth.

The anti-sodium-iodide symporter, antithyroglobulin, and antithyroid peroxidase antibodies appear to

have little role in the etiology of hyperthyroidism in Graves disease. However, they are markers of
autoimmune disease against the thyroid. Intrathyroidal lymphocytic infiltration is the initial histologic
abnormality in persons with autoimmune thyroid disease and can be correlated with the titer of thyroid
antibodies. Besides being the source of autoantigens, the thyroid cells express molecules that mediate T
cell adhesion and complement regulation (Fas and cytokines) that participate and interact with the
immune system. In these patients, the proportion of CD4 lymphocytes is lower in the thyroid than in the
peripheral blood. The increased Fas expression in intrathyroidal CD4 T lymphocytes may be the cause of
CD4 lymphocyte reduction in these individuals.

Several autoimmune thyroid disease susceptibility genes have been identified: CD40, CTLA-4,
thyroglobulin, TSH receptor, and PTPN22. [3, 4] Some of these susceptibility genes are specific to either
Graves disease or Hashimoto thyroiditis, while others confer susceptibility to both conditions. The genetic
predisposition to thyroid autoimmunity may interact with environmental factors or events to precipitate
the onset of Graves disease.

Two new susceptibility loci were found: the RNASET2-FGFR1OP-CCR6 region at 6q27 and an
intergenic region at 4p14. [5] Moreover, strong associations of thyroid-stimulating hormone receptor and
major histocompatibility complex class II variants with persistently thyroid stimulating hormone receptor
autoantibodies (TRAb)-positive Graves disease were found.

Graves disease patients a have higher rate of peripheral blood mononuclear cell conversion into CD34+
fibrocytes compared with healthy controls. These cells may contribute to the pathophysiology of
ophthalmopathy by accumulating in orbital tissues and producing inflammatory cytokines, including
TNF-alpha and IL-6. [6] In a genome-wide association study of more than 1500 Graves disease patients
and 1500 controls, 6 susceptibility loci were found to be related to Graves disease (major
histocompatibility complex, TSH receptor, CTLA4, FCRL3, RNASET2-FGFR1OP-CCR6 region at
6q27, and an intergenic region at 4p14. [7]

Pathophysiologic mechanisms are shown in the image below.

Pathophysiologic mechanisms of Graves disease relating thyroid-stimulating immunoglobulins to
hyperthyroidism and ophthalmopathy. T4 is levothyroxine. T3 is triiodothyronine.
EPIDEM

International

Among the causes of spontaneous thyrotoxicosis, Graves disease is the most common. Graves disease
represents 60-90% of all causes of thyrotoxicosis in different regions of the world. In the Wickham Study
in the United Kingdom, the incidence was reported to be 100-200 cases per 100,000 population per year.
[9]
The incidence in women in the UK has been reported to be 80 cases 100,000 per year. [10]

Mortality/Morbidity

If left untreated, Graves disease can cause severe thyrotoxicosis. A life-threatening thyrotoxic crisis (ie,
thyroid storm) can occur. Long-standing severe thyrotoxicosis leads to severe weight loss with catabolism
of bone and muscle. [11] Cardiac complications and psychocognitive complications can cause significant
morbidity. Graves disease is also associated with ophthalmopathy, dermopathy, and acropachy.

Thyroid storm is an exaggerated state of thyrotoxicosis. [12] It occurs in patients who have unrecognized or
inadequately treated thyrotoxicosis and a superimposed precipitating event such as thyroid surgery,
nonthyroidal surgery, infection, or trauma. When thyroid storm was first described, the acute mortality
rate was nearly 100%. In current practice, with aggressive therapy and early recognition of the syndrome,
the mortality rate is approximately 20%. [13]

Long-term excess of thyroid hormone can lead to osteoporosis in men and women. The effect can be
particularly devastating in women, in whom the disease may compound the bone loss secondary to
chronic anovulation or menopause. Bone loss is accelerated in patients with hyperthyroidism. The
increase in bone loss can be demonstrated by increased urinary pyridinoline cross-link excretion. Serum
calcium and phosphate, plasma FGF-23 were significantly higher in the patients with Graves disease than
in healthy control subjects, suggesting that FGF-23 is physiologically related to serum phosphate
homeostasis in untreated Graves disease. [14]

Hyperthyroidism increases muscular energy expenditure and muscle protein breakdown. These
abnormalities may explain the sarcopenia and myopathy observed in patients with hyperthyroid Graves
disease.

Cardiac hypertrophy has been reported in thyrotoxicosis of different etiologies. Rhythm disturbances such
as extrasystolic arrhythmia, atrial fibrillation, and flutter are common. Cardiomyopathy and congestive
heart failure can occur. [15]

Psychiatric manifestations such as mood and anxiety disorders are common. [16] Subjective cognitive
dysfunction is often reported by Graves disease patients and may be due to affective and somatic
manifestations of thyrotoxicosis, which remit after treatment of Graves thyrotoxicosis. [17]

Nonpitting edema is the most prevalent form of dermopathy (about 40%) and are primarily in the pretibial
area. The nearly all (>95%) patients with dermopathy had ophthalmopathy. [18] Advanced forms of
dermopathy are elephantiasis or thyroid acropachy. Severe acropachy can be disabling and can lead to
total loss of hand function.

Progression of ophthalmopathy can lead to compromised vision and blindness. Visual loss due to corneal
lesions or optic nerve compression can be seen in severe Graves ophthalmopathy.
Maternal Graves disease can lead to neonatal hyperthyroidism by transplacental transfer of thyroid-
stimulating antibodies. Approximately 1-5% of children of mothers with Graves disease (usually with
high TSI titer) are affected. Usually, the TSI titer falls during pregnancy.

Elderly individuals may develop apathetic hyperthyroidism, and the only presenting features may be
unexplained weight loss or cardiac symptoms such as atrial fibrillation and congestive heart failure.

Boelaert et al investigated the prevalence of and relative risks for coexisting autoimmune diseases in
patients with Graves disease (2791 patients) or Hashimoto thyroiditis (495 patients). The authors found
coexisting disorders in 9.7% of patients with Graves disease and in 14.3% of those with Hashimoto
thyroiditis, with rheumatoid arthritis being the most common of these (prevalence = 3.15% and 4.24% in
Graves disease and Hashimoto thyroiditis, respectively). Relative risks of greater than 10 were found for
pernicious anemia, systemic lupus erythematosus, Addison disease, celiac disease, and vitiligo. The
authors also reported a tendency for parents of patients with Graves disease or Hashimoto thyroiditis to
have a history of hyperthyroidism or hypothyroidism, respectively. [19]

Race

In whites, autoimmune thyroid diseases are, based on linkage analysis, linked with the following loci:
AITD1, CTLA4, GD1, GD2, GD3, HT1, and HT2. Different loci have been reported to be linked with
autoimmune thyroid diseases in persons of other races.

Susceptibility is influenced by genes in the human leukocyte antigen (HLA) region on chromosome 6 and
in CTLA4 on band 2q33. Association with specific HLA haplotypes has been observed and is found to
vary with ethnicity.

Sex

As with most autoimmune diseases, susceptibility is increased in females. Hyperthyroidism due to Graves
disease has a female-to-male ratio of 7-8:1.

The female-to-male ratio for pretibial myxedema is 3.5:1. Only 7% of patients with localized myxedema
have thyroid acropachy.

Unlike the other manifestations of Graves disease, the female-to-male ratio for thyroid acropachy is 1:1.

Age

Typically, Graves disease is a disease of young women, but it may occur in persons of any age.

The typical age range is 20-40 years.

Most affected women are aged 30-60 years.

Prognosis

The natural history of Graves disease is that most patients become hypothyroid and require replacement.
Similarly, the ophthalmopathy generally becomes quiescent. On occasion, hyperthyroidism returns
because of persisting thyroid tissue after ablation and high antibody titers of anti-TSI. Further therapy may
be necessary in the form of surgery or radioactive iodine ablation.

A study by Tun et al indicated that in patients with Graves disease receiving thionamide therapy, high
thyrotropin receptorstimulating antibody (TRab) levels at diagnosis of the disease and/or high TRab
levels at treatment cessation are risk factors for relapse, particularly within the first two years. The study
included 266 patients. [20]

A retrospective study by Rabon et al indicated that in children with Graves disease, antithyroid drugs
usually do not induce remission, although most children who do achieve remission through these agents
do not relapse. Of 268 children who were started on an antithyroid drug, 57 (21%) experienced remission,
with 16 of them (28%) relapsing. [21]

Patient Education

Awareness of the symptoms related to hyperthyroidism and hypothyroidism is important, especially in

the titration of antithyroid agents and in replacement therapy for hypothyroidism.

Patients also should be aware of the potential adverse effects of these medicines. They should watch for
fever, sore throat, and throat ulcers.

Patients also must be instructed to avoid cold medicines that contain alpha-adrenergic agonists such as
ephedrine or pseudoephedrine.