Tujuan Pembelajaran:

Pada akhir diskusi, mahasiswa diharapkan mampu:

1. Mereview singkat mengenai organ/jaringan yang terlibat dalam kasus (tiroid:
struktur dan sel sel penyusunnya).
2. Menjelaskan hormon yang mempengaruhi gejala pada pasien (TSH, T3 dan T4:
struktur, biosintesis dan pelepasannya di dalam sirkulasi darah).
3. Menjelaskan aktifitas TSH, T3 dan T4 di dalam sirkulasi dan mekanisme umpan
baliknya.
4. Menjelaskan faktor-faktor yang mempengaruhi sintesis T3 dan T4.
5. Menjelaskan peran nutrisi dalam sintesis T3 dan T4.
6. Menjelaskan mengenai mekanisme kerja T3 dan T4 dalam sel.
7. Menjelaskan mengenai peran T3 dan T4 dalam regulasi metabolisme tubuh.
8. Menjelaskan macam-macam etiologi yang mendasari hipertiroid.
9. Menjelaskan mengenai patogenesis penyakit yang mendasari pada kasus
10. Menjelaskan mekanisme hubungan antara hipertiroid dengan gejala-gejala
kardiovaskular (berdebar-debar)
11. Menjelaskan mekanisme hubungan antara hipertiroid dengan gejala-gejala
metabolisme (mudah berkeringat, mudah lelah, dan penurunan berat badan).
12. Menjelaskan mekanisme terjadinya eksoftalmus pada kasus
13. Menjelaskan mekanisme hubungan antara hipertiroid dengan gejala-gejala saraf
(gelisah, mudah marah, dan tremor)
14. Menjelaskan farmakokinetik dan farmakodinamik obat pada kasus

Skenario kasus:
Pasien seorang laki-laki, berusia 34 tahun datang ke RS dengan keluhan jantung
berdebar yang dialaminya sejak 3 minggu sebelum masuk rumah sakit yang dirasakan
terus menerus sepanjang hari. Keluhan tersebut tidak disertai dengan sakit dada,
namun pasien mengeluh tangan sering gemetaran, mudah berkeringat, sulit tidur dan
menjadi lebih mudah marah. Selain itu, pasien juga mengeluhkan adanya lemas, mual
dan muntah. Lemas dirasakan sepanjang hari, terutama setelah melakukan pekerjaan.
Setiap habis makan, pasien mengeluh mual dan muntah. Dimana muntahannya berisi
makanan yang dimakan pasien. Disamping itu, nafsu makan pasien meningkat, tetapi
berat badannya dirasakan terus menurun. Pasien juga mengeluh cepat haus sehingga
sering minum yang berakibat pasien sering buang air kecil. Adanya diare atau
konstipasi disangkal.
Pasien tidak memiliki riwayat DM, hipertensi, asma, penyakit ginjal, penyakit liver,
maupun penyakit jantung. Pasien sudah pernah berobat ke poli jantung, namun
dinyatakan tidak memiliki penyakit jantung dan dikonsulkan ke poli dalam.
Tidak ada keluarga pasien yang mengalami keluhan yang sama. Tetapi ayah pasien
memiliki riwayat penyakit jantung.
Saat muda sering mengkonsumsi alcohol dan merokok kira-kira sebungkus per hari.
Namun, pasien mengaku sudah berhenti sejak merasa dada nya sering berdebar.

Dokter kemudian memberikan obat Propiltiourasil dan Propanolol kepada pasien

setelah selesai pemeriksaan.

Keadaan umum : Tampak sakit sedang, tampak lemah

Kesadaran : Compos mentis
Kesan gizi : Gizi kurang
Tanda vital :
TD : 130/80 mmHg
Nadi : 120x/menit
Nafas : 26x/menit
Suhu : 36,3
Kepala : normosefali, rambut hitam kecoklatan, mudah dicabut, distribusi merata.
Mata : SI -/- CA -/-, eksoftalmus +
Leher : KGB tidak membesar, Tampak benjolan bilateral, simetris kanan-kiri,
permukaan rata, nyeri tekan negatif, konsistensi kenyal, ukuran sekitar 7 cm.
Thorax
Jantung
Inspeksi : ictus cordis tidak terlihat
Palpasi : ictus cordis teraba pada ICS 5 linea midklavikularis kiri
Perkusi : batas kanan jantung : ICS III-V linea sternalis kanan
batas kiri jantung : ICS IV linea midklavikularis kiri
batas atas jatntung : ICS III linea parasternalis kiri.
Auskultasi : BJ I & II reguler, gallop (-), murmur (-)
Paru
Inspeksi : pergerakan napas simetris
Palpasi : vocal fremitus teraba sama kuat
Perkusi : sonor pada kedua hemithorax
Auskultasi : suara napas vesikular, Rh -/-, Wh -/-
Abdomen
Inspeksi : bentuk cekung, kulit sawo matang, venektasi (-), smiling umbilikus (-),
efloresensi (-)
Auskultasi : bising usus (+), venous hum (-), arterial bruit (-)
Palpasi : supel, nyeri tekan (-), turgor kulit baik, hepar dan lien tidak teraba,
undulasi (-)
Perkusi : timpani pada seluruh abdomen, shifting dullness (-)
Ekstremitas
Inspeksi : warna kulit sawo matang, ikterik (-), flapping tremor (-), palmar
eritema (-), deformitas (-), efloresensi (-), dan kuku normal
Akral hangat +|+
+|+
Edema: - | -
-|-
Pemeriksaan lab darah
Hb : 15
Leukosit : 12.930 (leukositosis)
Trombosit : 191.000
Ht : 42
Diff.count : 0/2/0/71/21/6
GDS : 127
Ureum : 27,1
Kreatinin : 0.53
Natrium : 127
Kalium : 5,6
Chlorida : 95
TSH : 0,006 µIU/ml,
T3 : 5,56 ng/dl
FT4 : 18,2 ng/dl.

PANDUAN UNTUK TUTOR

1. Kelenjar Tiroid: struktur dan sel sel penyusunnya

The thyroid (Greek thyreos, shield, plus eidos, form) consists of two lobes that
are connected by an isthmus. It is located anterior to the trachea between the
cricoid cartilage and the suprasternal notch. The normal thyroid is 12–20 g in size,
highly vascular, and soft in consistency. Four parathyroid glands, which produce
parathyroid hormone, are located posterior to each pole of the thyroid. The
recurrent laryngeal nerves traverse the lateral borders of the thyroid gland and
must be identified during thyroid surgery to avoid vocal cord paralysis.
The thyroid gland develops from the floor of the primitive pharynx during the
third week of gestation. The developing gland migrates along the thyroglossal
duct to reach its final location in the neck. This feature accounts for the rare
ectopic location of thyroid tissue at the base of the tongue (lingual thyroid) as well
as the occurrence of thyroglossal duct cysts along this developmental tract.
Thyroid hormone synthesis normally begins at about 11 weeks' gestation.
The thyroid gland consists of numerous spherical follicles composed of thyroid
follicular cells that surround secreted colloid, a proteinaceous fluid containing
large amounts of thyroglobulin, the protein precursor of thyroid hormones (Fig.
335-2). The thyroid follicular cells are polarized—the basolateral surface is
apposed to the bloodstream and an apical surface faces the follicular lumen.
Increased demand for thyroid hormone is regulated by thyroid-stimulating
hormone (TSH), which binds to its receptor on the basolateral surface of the
follicular cells, leading to Tg reabsorption from the follicular lumen and
proteolysis within the cell to yield thyroid hormones for secretion into the
bloodstream.
 Reference:
Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., & Loscalzo, J. (2018).
Harrison's principles of internal medicine. McGraw-Hill Professional Publishing.

2. TSH, T3 dan T4: struktur, biosintesis dan pelepasannya di dalam sirkulasi

darah
The thyroid gland produces two related hormones, thyroxine (T 4) and triiodothyronine
(T3) (Fig. 335-1). Acting through nuclear receptors, these hormones play a critical role in
cell differentiation during development and help maintain thermogenic and metabolic
homeostasis in the adult.

Thyroid hormones are derived from Tg, a large iodinated glycoprotein. After
secretion into the thyroid follicle, Tg is iodinated on tyrosine residues that are
subsequently coupled via an ether linkage. Reuptake of Tg into the thyroid
follicular cell allows proteolysis and the release of newly synthesized T4 and T3.
Iodide uptake is a critical first step in thyroid hormone synthesis. Ingested iodine is
bound to serum proteins, particularly albumin. Unbound iodine is excreted in the urine.
The thyroid gland extracts iodine from the circulation in a highly efficient manner. For
example, 10–25% of radioactive tracer (e.g., 123I) is taken up by the normal thyroid
gland over 24 h; this value can rise to 70–90% in Graves' disease. Iodide uptake is
mediated by the Na+/I– symporter (NIS), which is expressed at the basolateral
membrane of thyroid follicular cells. NIS is most highly expressed in the thyroid gland,
but low levels are present in the salivary glands, lactating breast, and placenta. The
iodide transport mechanism is highly regulated, allowing adaptation to variations in
dietary supply.
After iodide enters the thyroid, it is trapped and transported to the apical membrane of
thyroid follicular cells, where it is oxidized in an organification reaction that involves TPO
and hydrogen peroxide. The reactive iodine atom is added to selected tyrosyl residues
within Tg, a large (660 kDa) dimeric protein that consists of 2769 amino acids. The
iodotyrosines in Tg are then coupled via an ether linkage in a reaction that is also
catalyzed by TPO. Either T4 or T3 can be produced by this reaction, depending on the
number of iodine atoms present in the iodotyrosines. After coupling, Tg is taken back
into the thyroid cell, where it is processed in lysosomes to release T4 and T3. Uncoupled
mono- and diiodotyrosines (MIT, DIT) are deiodinated by the enzyme dehalogenase,
thereby recycling any iodide that is not converted into thyroid hormones.
Although TSH is the dominant hormonal regulator of thyroid gland growth and function,
a variety of growth factors, most produced locally in the thyroid gland, also influence
thyroid hormone synthesis. These include insulin-like growth factor I (IGF-I), epidermal
growth factor, transforming growth factor (TGF-), endothelins, and various cytokines.
The quantitative roles of these factors are not well understood, but they are important
in selected disease states. In acromegaly, for example, increased levels of growth
hormone and IGF-I are associated with goiter and predisposition to multinodular goiter
(MNG).
Reference:
Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., & Loscalzo, J. (2018).
Harrison's principles of internal medicine. McGraw-Hill Professional Publishing.
3. Aktifitas TSH, T3 dan T4 di dalam sirkulasi dan mekanisme umpan baliknya

TSH, secreted by the thyrotrope cells of the anterior pituitary, plays a pivotal role
in control of the thyroid axis and serves as the most useful physiologic marker of
thyroid hormone action. TSH is a 31-kDa hormone composed of and subunits;
the subunit is common to the other glycoprotein hormones [luteinizing hormone,
follicle-stimulating hormone, human chorionic gonadotropin (hCG)], whereas the
TSH subunit is unique to TSH. The extent and nature of carbohydrate
modification are modulated by thyrotropin-releasing hormone (TRH) stimulation
and influence the biologic activity of the hormone.
The thyroid axis is a classic example of an endocrine feedback loop.
Hypothalamic TRH stimulates pituitary production of TSH, which, in turn,
stimulates thyroid hormone synthesis and secretion. Thyroid hormones feed back
to inhibit TRH and TSH production (Fig. 335-2). The "set-point" in this axis is
established by TSH. TRH is the major positive regulator of TSH synthesis and
secretion. Peak TSH secretion occurs ~15 min after administration of exogenous
TRH. Dopamine, glucocorticoids, and somatostatin suppress TSH but are not of
 major physiologic importance except when these agents are administered in
pharmacologic doses. Reduced levels of thyroid hormone increase basal TSH
production and enhance TRH-mediated stimulation of TSH. High thyroid
hormone levels rapidly and directly suppress TSH gene expression secretion and
inhibit TRH stimulation of TSH, indicating that thyroid hormones are the
dominant regulator of TSH production. Like other pituitary hormones, TSH is
released in a pulsatile manner and exhibits a diurnal rhythm; its highest levels
occur at night. However, these TSH excursions are modest in comparison to those
of other pituitary hormones, in part because TSH has a relatively long plasma
half-life (50 min). Consequently, single measurements of TSH are adequate for
assessing its circulating level. TSH is measured using immunoradiometric assays
that are highly sensitive and specific. These assays readily distinguish between
normal and suppressed TSH values; thus, TSH can be used for the diagnosis of
hyperthyroidism (low TSH) as well as hypothyroidism (high TSH).
T4 is secreted from the thyroid gland in about twentyfold excess over T3 (Table
335-2). Both hormones are bound to plasma proteins, including thyroxine-binding
globulin (TBG); transthyretin (TTR, formerly known as thyroxine-binding
prealbumin, or TBPA); and albumin. The plasma-binding proteins increase the
pool of circulating hormone, delay hormone clearance, and may modulate
hormone delivery to selected tissue sites. The concentration of TBG is relatively
low (1–2 mg/dL), but because of its high affinity for thyroid hormones (T4 > T3),
it carries about 80% of the bound hormones. Albumin has relatively low affinity
for thyroid hormones but has a high plasma concentration (~3.5 g/dL), and it
binds up to 10% of T4 and 30% of T3. TTR carries about 10% of T4 but little T3.
Reference:
Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., & Loscalzo, J. (2018).
Harrison's principles of internal medicine. McGraw-Hill Professional Publishing.
4. Faktor-faktor yang mempengaruhi sintesis T3 dan T4
Iodide uptake is a critical first step in thyroid hormone synthesis. Although TSH is
the dominant hormonal regulator of thyroid gland growth and function, a variety
of growth factors, most produced locally in the thyroid gland, also influence
thyroid hormone synthesis. These include insulin-like growth factor I (IGF-I),
epidermal growth factor, transforming growth factor (TGF-), endothelins, and
various cytokines.
 Reference:
Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., & Loscalzo, J. (2018).
Harrison's principles of internal medicine. McGraw-Hill Professional Publishing.

5. Peran nutrisi dalam sintesis T3 dan T4

Iodide uptake is a critical first step in thyroid hormone synthesis. In areas of
relative iodine deficiency, there is an increased prevalence of goiter and, when
deficiency is severe, hypothyroidism and cretinism. Cretinism is characterized by
mental and growth retardation and occurs when children who live in iodine-
deficient regions are not treated with iodine or thyroid hormone to restore normal
thyroid hormone levels during early life. These children are often born to mothers
with iodine deficiency, and it is likely that maternal thyroid hormone deficiency
worsens the condition. Concomitant selenium deficiency may also contribute to
the neurologic manifestations of cretinism. Iodine supplementation of salt, bread,
and other food substances has markedly reduced the prevalence of cretinism.
Unfortunately, however, iodine deficiency remains the most common cause of
preventable mental deficiency, often because of societal resistance to food
additives or the cost of supplementation. In addition to overt cretinism, mild
iodine deficiency can lead to subtle reduction of IQ. Oversupply of iodine,
through supplements or foods enriched in iodine (e.g., shellfish, kelp), is
associated with an increased incidence of autoimmune thyroid disease. The
recommended average daily intake of iodine is 150 g/d for adults, 90–120 g/d for
children, and 200 g/d for pregnant women. Urinary iodine is >10 g/dL in iodine-
sufficient populations.
Reference:
Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., & Loscalzo, J. (2018).
Harrison's principles of internal medicine. McGraw-Hill Professional Publishing.

6. Mekanisme kerja T3 dan T4 dalam sel

Metabolisme sel
Circulating thyroid hormones enter cells by passive diffusion and via the
monocarboxylate 8 (MCT8) transporter that was identified in patients with
multiple neurologic deficits and thyroid function abnormalities (low T4, high T3,
and high TSH). After entering cells, thyroid hormones act primarily through
nuclear receptors, although they also stimulate plasma membrane and
mitochondrial enzymatic responses.

Mechanism of thyroid hormone receptor action. The thyroid hormone receptor

(TR) and retinoid X receptor (RXR) form heterodimers that bind specifically to
thyroid hormone response elements (TRE) in the promoter regions of target
genes. In the absence of hormone, TR binds co-repressor (CoR) proteins that
silence gene expression. The numbers refer to a series of ordered reactions that
occur in response to thyroid hormone: (1) T4 or T3 enters the nucleus; (2) T3
binding dissociates CoR from TR; (3) Coactivators (CoA) are recruited to the T3-
bound receptor; (4) gene expression is altered.

Thyroid hormones bind with high affinity to nuclear thyroid hormone receptors
(TRs). TR are expressed in most tissues, but their relative expression levels vary
among organs; TR is particularly abundant in brain, kidney, gonads, muscle, and
heart, whereas TR expression is relatively high in the pituitary and liver. Both
receptors are variably spliced to form unique isoforms. The TR2 isoform, which
has a unique amino terminus, is selectively expressed in the hypothalamus and
pituitary, where it plays a role in feedback control of the thyroid axis. The TR2
isoform contains a unique carboxy terminus that precludes thyroid hormone
binding; it may function to block the action of other TR isoforms.
The TRs contain a central DNA-binding domain and a C-terminal ligand-binding
domain. They bind to specific DNA sequences, termed thyroid response elements
(TREs), in the promoter regions of target genes (Fig. 335-4). The receptors bind as
homodimers or, more commonly, as heterodimers with retinoic acid X receptors
(RXRs) (Chap. 332). The activated receptor can either stimulate gene transcription
(e.g., myosin heavy chain ) or inhibit transcription (e.g., TSH -subunit gene),
depending on the nature of the regulatory elements in the target gene.
Thyroid hormones (T3 and T4) bind with similar affinities to TR. However,
structural differences in the ligand binding domains provide the potential for
developing receptor-selective agonists or antagonists. T3 is bound with 10–15
times greater affinity than T4, which explains its increased hormonal potency.
Though T4 is produced in excess of T3, receptors are occupied mainly by T3,
reflecting T4 T3 conversion by peripheral tissues, greater T3 bioavailability in the
plasma, and receptors' greater affinity for T3. After binding to TRs, thyroid
hormone induces conformational changes in the receptors that modify its
interactions with accessory transcription factors. In the absence of thyroid
hormone binding, the aporeceptors bind to co-repressor proteins that inhibit gene
transcription. Hormone binding dissociates the co-repressors and allows the
recruitment of coactivators that enhance transcription. The discovery of TR
interactions with co-repressors explains the fact that TR silences gene expression
in the absence of hormone binding. Consequently, hormone deficiency has a
profound effect on gene expression because it causes gene repression as well as
loss of hormone-induced stimulation. This concept has been corroborated by the
finding that targeted deletion of the TR genes in mice has a less-pronounced
phenotypic effect than hormone deficiency.
Reference:
Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., & Loscalzo, J. (2018).
Harrison's principles of internal medicine. McGraw-Hill Professional Publishing.
7. Peran T3 dan T4 dalam regulasi metabolisme tubuh

Overview of sites of thyroid hormone regulation of metabolism. Hypothalamic-

Pituitary-Thyroid axis: thyrotropin releasing hormone (TRH) and thyroid
stimulating hormone (TSH) respond primarily to circulating serum T4, converted
in the hypothalamus and pituitary to T3 by the 5′-deiodinase type 2 (D2). The
monocarboxylate transporter 8 (MCT8) is required for T3 transport into the
pituitary and hypothalamus. A, parvalbuminergic neurons (PBN): PBN are a
population of newly discovered neurons in the anterior hypothalamus that are
directly linked to the regulation of cardiovascular function, including heart rate,
blood pressure, and body temperature. Thyroid hormone receptor signaling is
required for the normal development of PBN neurons linking thyroid hormone to
cardiac and temperature regulation. B, paraventricular nucleus of the hypothlamus
(VPN): leptin, produced in peripheral fat tissue, provides feedback at the VPN,
stimulates signal transducer and activator of transcription (STAT)3
phosphorylation (STAT3-P*), which directly stimulates TRH expression. Leptin
also stimulates TRH indirectly in the arcuate nucleus by inhibiting neuropeptide Y
and agouti-related protein, stimulating proopiomelanocortin (POMC), and the
POMC product α-melanocyte stimulating hormone (α-MSH) stimulates CREB in
the TRH neuron (indirect pathway is not shown in Figure 1). C, ventromedial
nucleus of the hypothalamus (VMH): hyperthyroidism or T3 treatment stimulates
de novo fatty acid synthesis in the VMH, which inhibits AMPK phosphorylation
and increases fatty acid synthase (FAS) activity. Increased hypothalamic lipid
synthesis is associated with activation of the sympathetic nervous system (SNS)
which stimulates brown adipose tissue (BAT). D, BAT: adrenergic signaling
through the β3-adrenergic receptor (AR) stimulates UCP1 gene expression,
stimulates D2 activity by deubiquitination, and promotes thermogenesis and
weight loss. The metabolic signal from bile acid via the G protein-coupled
membrane bile acid receptor (TGR5) has been shown in one model to stimulate
D2 activity and local T3 production, which further stimulates BAT lipolysis,
UCP1 expression, and thermogenesis. E, white adipose tissue (WAT): SNS
signals via β1- and β2-AR stimulate WAT lipolysis. T3 stimulates local
production of norepinephrine (NE), increasing lipolysis and reducing body fat. F,
liver: T3 is involved in both cholesterol and fatty acid metabolism (see details in
Figure 3). HOMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; ACC1, acetyl-
CoA carboxylase 1; CYP7a1, cytochrome P-450 7A1; CPT-1α, carnitine
palmitoyltransferase 1α; LDL-R, low-density lipoprotein receptor. G, muscle:
Forkhead box O3 (FoxO3) induces D2 expression, increases local T3 in skeletal
muscle, and promotes T3-target gene expression; myoD, myosin heavy chain
(MHC) and sarcoplasmic reticulum Ca2+-ATPase (SERCA). Local T3 also
determines the relative expression level of MHC and SERCA isoforms.
Expression level of these isoforms determines muscle fiber types and initiation of
repair. SERCA2a is primarily expressed in slow-twitch fibers and SERCA1 in
fast-twitch fibers. T3 stimulates SERCA, which hydrolyzes ATP and increases
energy expenditure. H, pancreas: T3 and TR are required for normal pancreatic
development and function. In rat pancreatic β cells, expression of TR and D2 are
activated during normal development. T3 treatment enhances Mafa (v-maf
musculoaponeurotic fibrosarcoma oncogene homolog A) transcription factor gene
expression and increases MAFA protein content, the key factor for maturation of
β cells to secrete insulin in response to glucose. T3 stimulates cyclin D1 (CD1)
gene expression and protein level and promotes proliferation. Increasing cyclin
 D1 activates the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F
pathway.

Reference:
Mullur, R., Liu, Y. Y., & Brent, G. A. (2014). Thyroid hormone regulation of
metabolism. Physiological reviews, 94(2), 355–382.
doi:10.1152/physrev.00030.2013

8. Peran T3 dan T4 dalam pertumbuhan dan perkembangan anak

Thyroid hormones are essential for brain maturation, and for brain function
throughout life. In adults, thyroid diseases can lead to various clinical
manifestations (1,2). For example, hypothyroidism causes lethargy, hyporeflexia
and poor motor coordination. Subclinical hypothyroidism is often associated with
memory impairment. Hypothyroidism is also associated to bipolar affective
disorders, depression, or loss of cognitive functions, especially in the elderly (3).
Hyperthyroidism causes anxiety, irritability, and hyperreflexia. Both,
hypothyroidism or hyperthyroidism can lead to mood disorders, dementia,
confusion, and personality changes. Most of these disorders are usually reversible
with proper treatment, indicating that thyroid hormone alterations of adult onset
do not leave permanent structural defects.
The actions of thyroid hormone during development are different, in the sense that
they are required to perform certain actions during specific time windows.
Thyroid hormone deficiency, even of short duration may lead to irreversible brain
damage, the consequences of which depend not only on the severity, but also on
the specific timing of onset and duration of the deficiency (4-8).
Reference:
Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., & Loscalzo, J. (2018).
Harrison's principles of internal medicine. McGraw-Hill Professional Publishing.

9. Macam-macam etiologi yang mendasari hipertiroid

Primary hyperthyroidism
1) Graves' disease
2) Toxic multinodular goiter
3) Toxic adenoma
 4) Functioning thyroid carcinoma metastases
5) Activating mutation of the TSH receptor
6) Activating mutation of Gsa (McCune-Albright syndrome)
7) Struma ovarii
8) Drugs: iodine excess (Jod-Basedow phenomenon)
9) Subacute thyroiditis
10) Other causes of thyroid destruction: amiodarone, radiation, infarction of
adenoma

Secondary hyperthyroidism
1) TSH-secreting pituitary adenoma
2) Thyroid hormone resistance syndrome: occasional patients may have
features of thyrotoxicosis
3) Chorionic gonadotropin-secreting tumors
4) Gestational thyrotoxicosis
Reference:
Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., & Loscalzo, J. (2018).
Harrison's principles of internal medicine. McGraw-Hill Professional Publishing.

10. Menjelaskan mengenai patogenesis penyakit yang mendasari pada kasus

Pathogenesis Grave’s Disease
As in autoimmune hypothyroidism, a combination of environmental and genetic
factors, including polymorphisms in HLA-DR, CTLA-4, and PTPN22 (a T cell
regulatory gene), contribute to Graves' disease susceptibility. The concordance for
Graves' disease in monozygotic twins is 20–30%, compared to <5% in dizygotic
twins. Indirect evidence suggests that stress is an important environmental factor,
presumably operating through neuroendocrine effects on the immune system.
Smoking is a minor risk factor for Graves' disease and a major risk factor for the
development of ophthalmopathy. Sudden increases in iodine intake may
precipitate Graves' disease, and there is a threefold increase in the occurrence of
Graves' disease in the postpartum period.
The hyperthyroidism of Graves' disease is caused by TSI that are synthesized in
the thyroid gland as well as in bone marrow and lymph nodes. Such antibodies
can be detected by bioassays or by using the more widely available TBII assays.
 The presence of TBII in a patient with thyrotoxicosis implies the existence of TSI,
and these assays are useful in monitoring pregnant Graves' patients in whom high
levels of TSI can cross the placenta and cause neonatal thyrotoxicosis. Other
thyroid autoimmune responses, similar to those in autoimmune hypothyroidism
(see above), occur concurrently in patients with Graves' disease. In particular,
TPO antibodies occur in up to 80% of cases and serve as a readily measurable
marker of autoimmunity. Because the coexisting thyroiditis can also affect thyroid
function, there is no direct correlation between the level of TSI and thyroid
hormone levels in Graves' disease. In the long term, spontaneous autoimmune
hypothyroidism may develop in up to 15% of Graves' patients.
Cytokines appear to play a major role in thyroid-associated ophthalmopathy.
There is infiltration of the extraocular muscles by activated T cells; the release of
cytokines such as IFN-, TNF, and IL-1 results in fibroblast activation and
increased synthesis of glycosaminoglycans that trap water, thereby leading to
characteristic muscle swelling. Late in the disease, there is irreversible fibrosis of
the muscles. Orbital fibroblasts may be particularly sensitive to cytokines, perhaps
explaining the anatomic localization of the immune response. Though the
pathogenesis of thyroid-associated ophthalmopathy remains unclear, there is
mounting evidence that the TSH-R may be a shared autoantigen that is expressed
in the orbit and this would explain the close association with autoimmune thyroid
disease. Increased fat is an additional cause of retrobulbar tissue expansion. The
increase in intraorbital pressure can lead to proptosis, diplopia, and optic
neuropathy.

Reference:
Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., & Loscalzo, J. (2018).
Harrison's principles of internal medicine. McGraw-Hill Professional Publishing.

11. Pengaruh faktor keturunan/genetik dengan hipertiroid

As in autoimmune hypothyroidism, a combination of environmental and genetic
factors, including polymorphisms in HLA-DR, CTLA-4, and PTPN22 (a T cell
regulatory gene), contribute to Graves' disease susceptibility. The concordance for
Graves' disease in monozygotic twins is 20–30%, compared to <5% in dizygotic
twins.
 Genetics Conditions Associated with Hyperthyroid
Familial dysalbuminemic hyperthyroxinemia (FDH)
Albumin mutations, usually R218H  Autosomal Dominant
TBG Familial excess
Increased TBG production  X-Linked
Thyroxine-binding prealbumin (TBPA) Mutations
Increased affinity for T4 or T3 Autosomal Dominant
Resistance to thyroid hormone (RTH)
Thyroid hormone receptor mutations  Autosomal Dominant

Reference:
Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J., & Loscalzo, J. (2018).
Harrison's principles of internal medicine. McGraw-Hill Professional Publishing.

12. Hubungan antara hipertiroid dengan gejala-gejala kardiovaskular

(berdebar-debar)
The thyroid secretes two active hormones: thyroxine (T4) which is a prohormone
and tri-iodothyronine (T3) which acts as the final mediator. In hyperthyroidism
there is excessive production of T3, owing to hypersecretion by the thyroid gland,
and an increase in the peripheral monodeiodination of T4, which leads to
profound changes in the cardiovascular system through both nuclear and non-
nuclear actions at the cellular level.
The interrelation between the direct and indirect actions of T3 on the peripheral
circulation and the heart is shown in fig 1.2Myocardial contractility is increased as
a result of a change in the synthesis of myosin heavy chain protein from the β to
the α form, increased transcription of the calcium ATPase gene, and enhanced
calcium and glucose uptake. These changes make contraction less efficient and
increase heat production. Afterload is reduced, with a reduction of as much as 50–
70% in systemic vascular resistance, caused by the direct effects of T3 and the
indirect effects of excess lactate production (increased tissue thermogenesis) on
vascular smooth muscle. Blood flow, particularly to skin, muscle, and heart, is
therefore greatly increased. The preload of the heart rises because blood volume is
expanded owing to increases in the serum concentrations of angiotensin
converting enzyme and erythropoietin, with resultant increases in renal sodium
absorption and red cell mass.
Hyperthyroidism is characterised by a high left ventricular ejection fraction
(LVEF) at rest but, paradoxically, by a significant fall during exercise. Restoration
of euthyroidism is accompanied by the anticipated rise in LVEF on exercise at the
same workload and heart rate.3 This reversible “cardiomyopathy” could explain
the reduced exercise tolerance of patients with hyperthyroidism. Rather than being
an intermediate state between normal left ventricular function and left ventricular
dysfunction at rest, the failure of LVEF to increase on exercise is perhaps better
 viewed as a consequence of the additional burden of exercise induced increase in
afterload on a heart performing near its maximum capacity.
The characteristic tachycardia is caused by a combination of more rapid diastolic
depolarisation and shortening of the action potential of the sinoatrial cells. The
refractory period of the atrial cells is also shortened which may explain the well
known propensity to atrial fibrillation.
There is a complex interaction between thyroid hormones and the adrenergic
system, and many of the clinical features of hyperthyroidism such as tachycardia,
increased pulse pressure, and tremor resemble the heightened β adrenergic state of
phaeochromocytoma. However, serum and urinary catecholamine concentrations
are normal or even low in hyperthyroidism, and there is no good evidence of
greater sensitivity to catecholamines despite an increased density of
β1adrenoceptors in cardiac muscle. It may well be that thyroid hormones and
catecholamines act independently at the cellular level but share a signalling
pathway. This would explain why non-selective β adrenoceptor antagonists, such
as propranolol or nadolol, improve but do not abolish many of the symptoms of
hyperthyroidism.
Reference:
Toft AD, Boon NA. Thyroid disease and the heart. Heart 2000;84:455-460.

13. Hubungan antara hipertiroid dengan gejala-gejala metabolisme (mudah

berkeringat, mudah lelah, dan penurunan berat badan).
Tingginya kadar hormon tiroid menyebabkan terjadinya peningkatan metabolisme
pada tubuh. Peningkatan metabolisme yang terjadi karena banyaknya hormon
tiroid membuat tbuh menggunakan senyawa-senyawa glukagonik yang ada di
dalam otot untuk membentuk glukosa melalui proses glukoneogenesis. Karena
diambil dari otot, maka pemakaian senyawa glukogenik secara terus-menerus
dapat mengurangi massa otot sehingga berat badan pun bisa mengalami
penurunan.
 Reference:
Hall, J. E. (2015). Guyton and Hall textbook of medical physiology e-Book.
Elsevier Health Sciences.

14. Hubungan antara hipertiroid dengan gejala-gejala saraf (gelisah, mudah

marah, dan tremor)
Berbeda dengan tremor yang biasa tejadi pada penyakit Parkinson, tremor pada
penyakit Graves merupakan tremor lembut, bukan tremor kasar. Tremor halus
terjadi dengan frekuensi 10-15 x/detik, dan dianggap sebagai efek dari
bertambahnya kepekaan sinaps saraf pengatur tonus otot di daerah medulla.
 Reference:
Hall, J. E. (2015). Guyton and Hall textbook of medical physiology e-Book.
Elsevier Health Sciences.

15. Menjelaskan farmakokinetik dan farmakodinamik PTU dan Propanolol

PTU

Pharmacokinetics

Well absorbed following oral administration. Propylthiouracil is readily absorbed

and is extensively metabolized. Approximately 35% of the drug is excreted in the
urine, in intact and conjugated forms, within 24 hours. Half life 2 hours.
Pharmacodynamics

Propylthiouracil is a thiourea antithyroid agent. Grave's disease is the most

common cause of hyperthyroidism. It is an autoimmune disease where an
individual's own antibodies attach to thyroid stimulating hormone receptors within
cells of the thyroid gland and then trigger overproduction of thyroid hormone. The
two thyroid hormones manufactured by the thyroid gland, thyroxine (T4) and
triiodothyronine (T3), are formed by combining iodine and a protein called
thyroglobulin with the assistance of an enzyme called peroxidase. PTU inhibits
iodine and peroxidase from their normal interactions with thyroglobulin to form
T4 and T3. This action decreases thyroid hormone production. PTU also interferes
with the conversion of T4 to T3, and, since T3 is more potent than T4, this also
reduces the activity of thyroid hormones. The actions and use of propylthiouracil
are similar to those of methimazole.

Propanolol

Pharmacokinetics

Approximately 90% of propranolol is protein bound in plasma.91% of an oral

dose of propranolol is recovered as 12 metabolites in the urineThe elimination half
life of propranolol is approximately 8 hours.9 The plasma half life of propranolol
is 3 to 6 hours.

Pharmacodynamics

Propranolol is the most widely studied non-selective, beta-1 and beta-2-blocker

that can treat the increased heart rate and tremor. Additionally, it may reverse
some of the reduced systemic vascular resistance and inhibit the peripheral
conversion of T4 to the more biologically active hormone, T3. Propranolol
decreases plasma T3 and increases plasma rT3 in a dose-dependent manner due to
a decreased production rate of T3 and a decreased metabolic clearance rate of rT3,
respectively, caused by inhibition of the conversion of T4 into T3 and of rT3 into
3,3'-T2.

Reference:
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson
D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N,
Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank
5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017
Nov 8. doi: 10.1093/nar/gkx1037. www.drugbank.ca