94284109-Thyroid

Ronald Chrisbianto Gani405090223

Faculty of Medicine 2009Tarumanagara University

ENDOCRINE SYSTEM BLOCK

CASE 4

HISTOLOGY OF THYROID

Junqueira’s Basic Histology 12th Ed

HISTOLOGY OF THYROID• composed of millions of rounded epithelial

structures called thyroid follicles• Follicles epithelium + gelatinous substance

(coloid) contains Thyroglobulin

C : CapsuleS : Septa

L : Lumen C : C cells


HISTOLOGY

C : C cellF : Folicullar Cell


HISTOLOGY

F : Follicular CellL : LumenBM : Basal MembraneC : Parafollicular Cell / C Cell

G : Golgi Apparatus


THYROID SYNTHESIS


PHYSIOLOGY OF THYROID

HORMON TIROID

• Bentuk kelenjar tiroid nya seperti pita• Letaknya tepat di tempat kita biasa memasang

dasi kupu• Sel sekretorik utama tiroid tersusun menjadi

gelembung berongga yang disebut folikel• Folikel berisi lumen yang disebut koloid• Konstituen utama koloid adalah tiroglobulin• Sel folikel akan menghasilkan hormon tiroid, yaitu

T3 dan T4

Sherwood’s Human Physiology From Cell’s to System 2nd Ed

FOLLICULAR CELL

Sherwood’s Human Physiology From Cell’s to System 7th Ed

HORMON TIROID

• Proses pembentukan hormon tiroid– TGB dihasilkan di RE sel folikel tiroid, lalu

dimasukkan ke koloid– Tiroid menangkap iodium dari darah lalu

dimasukkan ke dalam koloid melalui iodine-trapping mechanism.

– Dalam koloid, Iodium melekat pada tirosin. 1 iodium + tirosin MIT (Monoiodotirosin) 2 iodium + tirosin DIT (Diiodotirosin)

– MIT + DIT T3 dan DIT + DIT T4, tidak ada reaksi MIT + MIT


HORMON TIROID

• Sel folikel memfagositosiskan koloid berisi TGB untuk melakukan sekresi hormon tiroid

• Di luar tiroid, sebagian besar T4 dirubah menjadi T3 karena T3 adalah bentuk hormon tiroid yang secara biologis aktif di tingkat sel, namun tiroid lebih banyak mengeluarkan T4

• Di dalam darah, hormon tiroid diikat di :– T3 : thyroxine-binding globulin 65%, albumin 35%– T4 : thyroxine-binding globulin 55%, albumin 10%,

thyroxine-binding prealbumin 35%


HORMON TIROID

• Efek dari hormon tiroid– Meningkatkan laju metabolik basal tubuh keseluruhan– Efek kalorigenik– Tiroid sedikit, glukosa glikogen, dan sebaliknya– Diperlukan dalam sintesis protein pertumbuhan, tapi jika

berlebih katabolisme protein– Efek simpatomimetik– Meningkatkan denyut jantung, merangsang vasodilatasi perifer– Merangsang GH, mendorong efek GH, jika kurang kelainan,

jika berlebih tidak ada pertumbuhan berlebih.– Penting dalam pembentukan dan segala aktivitas SSP


KONTROL HORMON TIROID


HORMON TIROID• Kelainan fungsi tiroid :

– Hipotiroidisme• terjadi krn :

– Kegagalan primer kelenjar tiroid– Kegagalan sekunder defisiensi TRH, TSH, atau keduanya– Defisiensi iodium

• Gejala :– Penurunan laju metabolik dasar– Tidak ada efek kalorigenik– Terjadi penambahan berat– Mudah lelah– Denyut nadi lambat dan lemah– Perlambatan refleks dan gangguan mental– Berkurangnya kewaspadaan, bicara melambat, gangguan

ingatanSherwood’s Human Physiology From Cell’s to System 2nd Ed

HORMON TIROID• Pembengkakan pada tangan, kaki, dan wajah disebut miksedema• Jika hipotiroidisme sejak lahir kretinisme• Kerusakan SSP dapat dicegah dengan terapi

– Hipertiroidisme• Paling sering disebabkan oleh penyakit grave• Gejala :

– Keringat berlebih– Penurunan toleransi thdp panas– Nafsu makan meningkat, tapi berat badan menurun– Degradasi netto simpanan karbo, lemak, protein– Penurunan massa otot rangka– Jantung berdebar– Emosional, mudah tersinggung, tegang, dan cemas


HORMON TIROID• Pada penyakit grave, terjadi eksoftalmos• Pengobatan :

– Pengangkatan sebagian kelenjar tiroid yg hipersekresif– Pemberian iodium radioaktif– Penggunaan obat anti-tiroid

– Gondok (goiter) dapat menyertai pada hipotiroid dan hipertiroid


HYPOTYROIDISM

HYPOTYROIDISM• Lebih dominan pada wanita• Secara klinis, dibagi menjadi

– Hipotiroidisme sentral• kerusakan hipotalamus / hipofisis

– Hipotiroidisme primer (paling banyak)• Kerusakan kelenjar tiroid

– Hipotiroidisme krn sebab lain• Farmakologis, kekurangan / kelebihan yodium, resistensi perifer

• Klasifikasi perjalanan penyakit– Hipotiroidisme klinis (TSH ↑, fT4 ↓)– Hipotiroidisme subklinis (TSH ↑, fT4 Normal)

• Hipotiroid intrauterin dan neonatal retardasi mental & fisik yg ireversibel jika tdk diberi terapi

• Hipotiroid pada usia remaja –dewasa reversibel• Hipotiroid pd usia lanjut gejala klinis tdk spesifik

Buku Ajar Ilmu Penyakit Dalam Ed V

ETIOLOGI• Hiportiroidisme Sentral

– Kegagalan hipofisis hipotiroidisme sekunder– Kegagalan hipotalamus hipotitoidisme tertier– 50% kasus tumor hipofisis

• Hipotiroidisme Primer– Pasca operasi : stromektomi subtotal M.grave, dalam 10 th, 40%

hipotiroidisme– Pascaradiasi : RAI pd hipertiroidisme, 40-50% menjadi hipotiroidisme dalam

10th. RAI pada nodul toksik 5% menjadi hipotiroidisme– Tiroiditis Autoimun– Tiroiditis pascapartum : silih berganti hipo & hipertiroid, Marker : antibodi anti

TPO dan anti Tg, prevalensi 5,5%– Tiroiditis subakut (De Quervain) : nyeri di kelenjar, demam, menggigil. Etio : virus

nekrosis jaringan hormon masuk ke sirkulasi– Dishormogenesis : defek pd enzim hormogenesis– Karsinoma – Hipotiroidisme sepintas / transien : pasca pengobatan RAI, pascatiroidektomi

subtotalBuku Ajar Ilmu Penyakit Dalam Ed V

Harrison’s Principle of Medicine 18th Ed

PENGARUH FARMAKOLOGIS

• OAT berlebih hipotiroidism• Menghambat sintesis tiroid : tionamid,

peklorat, sulfonamid, iodida.• Meningkatkan katabolisme tiroid : fenitoin,

fenobarbital• Menghambat jalur enterohepatik hormon

tiroid di usus ↑ : kolestipol, kolestiramin


SIGN & SYMPTOMS


MYXEDEMA

Pathophysiology of Disease : Introduction to Clinical Medicine 6th Ed

ALGORITHM


DIFFERENTIAL DIAGNOSIS

• Hashimoto’s thyroiditis• Multinodular Goiter• Thyroid Carcinoma


TREATMENT• No residual thyroid function levothyroxine 1,6 μg/kg

body weight (100-150 μg/d)• Adult patient <60yo start with 50-100 μg/d levothyroxine,

adjusted on the basis of TSH level• TSH level measured per 2 months• Levothyroxine + Liothyronine effect has not been

confirmed yet• Once normal TSH achieved, interval of follow up of TSH

level may be extended to 2-3 years if the results are stable• Problems : self-discontinuation after symptoms reliefs• Elevated TSH after 200μg/d or fluctuating TSH poor

adherence to treatment Harrison’s Principle of Medicine 18th Ed

THYROTOXICOSIS

THYROTOXICOSIS

• Thyrotoxicosis : state of thyroid hormone excess

• Hyperthyroidism : result of excessive thyroid function

• Major etiologies of thyrotoxicosis are hyperthyroidism caused by Grave’s disease (60-80%) , toxic MNG, and toxic adenoma


EPIDEMIOLOGY

• Varies among populations• High iodine intake higher prevalence of

Grave’s disease• Grave disease 2% of women• Onset occurs between age 20-50, or elder


ETIOLOGY


SIGNS & SYMPTOMS


Signs & SymptomsA . Grave’s Opthalmopathy (Periorbital edema, lid retraction, conjunctival injection, proptosis)B . Thyroid DermopathyC . Thyroid Acropachy


PATHOGENESIS


GRAVE’S OPTHALMOPATHY


DIFFERENTIAL DIAGNOSIS

n engl j med 348;26

ALGORITHM


TATA LAKSANA

• Tirostatika• Tiroidektomi• Iodium Radioaktif


Kelompok Obat Efek Indikasi

Obat Anti Tiroid Menghambat sintesis hormon tiroid dan berefek imun non supresif (PTU menghambat konversi T4 T3)

Pengobatan lini pertama pada Graves.Obat jangka pendek prabedah /pra-RAI

Propiltiourasil (PTU) Metimazol (MMI) Karbimazol (CTZ MMI) Antagonis Adrenergik β

β-blocker Mengurangi dampak hormon tiroid pd jaringan

Obat tambahan, kadang sebagai obat tunggal pd tiroiditis

Propanolol Metoprolol Atenolol Nadolol

Bahan mengandung iodine Menghambat keluarnya T4 dan T3Menghambat T4 dan T3 serta menghambat produksi T3 ektratiroidal

Persiapan tiroidektomi. Pada krisis tiroid.Bukan untuk penggunaan rutin Kalium Iodida

Solusi Lugol Natrium Ipodat Asam Lopanoat

Obat Lain Menghambat traspor iodium, sintesis dan keluarnya hormonMemperbaiki efek hormon di jaringan dan sifat imunologis

Bukan indikasi rutinPada subakut tiroiditis berat dan krisis tiroid Kalium Perklorat

Litium Karbonat Glukokortikoid


TIROIDEKTOMI

• Dikerjakan saat pasien dalam keadaan eutiroid baik scr biokimia maupun klinis

• Operasi menyisakan jaringan sebesar ibu jari, atau lobektomi total termasuk ismus, dan tiroidektomi subtotal lobus lain


IODIUM RADIOAKTIF• Belum ada petunjuk baku untuk dosis, ada 2 cara

– Pemberian dosis bertahap hingga pasien mencapai eutiroid– Langsung dosis besar, hipotiroid dikoreksi dengan substitusi

• Pemberian dosis (185mBq / 5mCi – 555 mBq / mCi) mempertimbangkan– Tingkat keparahan penyakit (↑)– Ukuran goiter (↑)– Level of radioiodine uptake (↓)

• Hiportiroidisme terjadi 10-20% dalam 1 tahun, 5% dalam 1 tahun

• Pasien disarankan untuk tidak hamil selama 6 bulan pascaradiasi


THYROIDITIS

ETIOLOGY & CLASSIFICATION


THYROIDITIS SYNDROMES

n engl j med 348;26

ACUTE THYROIDITIS• Most common cause : presence of piriform sinus• Sign & Symptoms :

– thyroid pain, referred to throat or ears– small, tender, asymetric goiter– Fever, dysphagia, erythema

• Differential Diagnosis : Subacute or Chronic Thyroiditis, Hemmorhage into a cyst, malignancy, amiodarone-induced thyroiditis or amyloidosis

• Lab : ESR & WBC ↑, Thyroid function N, FNA Infiltration of PMN, Culture to identify organism

• Treatment : Antibiotic treatment (guided by gram stain or culture from FNA biopsy), surgery (draining abscess)

• Complication : Tracheal obstruction, septicemia, retropharingeal abscess, mediastinitis, jugular venous thrombosis


SUBACUTE THYROIDITIS• De Quervain’s thyroiditis, granulomatous thyroiditis, viral thyroiditis (mumps,

coxsackie, influenza, adenovirus, echovirus)• Peak incidence age 30-50, F : M = 3 : 1• Clinical Manifestations : painful & enlarged thyroid, fever (sometimes), features of

thyrotoxicosis or hypothyroidism, malaise, Upper respiratory tract infections, sore throat, small & tender goiter, pain referred jaw or ear

• Lab : Thyrotoxic phase :– T4 & T3 ↑, TSH ↓, ESR ↑, Radioiodine uptake ↓. – Thyroid antibodies (-), – FNA biopsy to distunguish unilateral involvement from bleeding into a cyst or

neoplasm• Treatment :

– Large dose of Aspirin (600mg/4-6h) or NSAID relief symptoms, if not successful glucocorticoid (prednisone 40-60mg) tappered in 6-8 weeks.

– Monitor thyroid function every 2-4 weeks (TSH & fT4)– Low dose Levothyroxine (50-100 μg) if hypothyroid prolonged


PATHOPHYSIOLOGY


SILENT THYROIDITIS• Painless post-partum thyroiditis.• Occurs in patient with underlying autoimmune thyroid disease• Clinical course similiar to subacute, except there’s little or no

thyroid tenderness.• Occurs in 5% of post-partum women• Phases : Throtoxicosis (2-4 weeks), hypothyroidism (4-12

weeks), resolution• 3 times more common in women with T1DM.• Normal ESR & presence of TPO antibodies• Treatment : Glucocorticoid not recommended, thyrotoxicosis

propanolol 20-40mg,3-4x/d, hypothyroid levothyroxine. Annual follow up, may develop permanent hypothyroidism


CHRONIC THYROIDITIS

• Hashimoto’s Thyroiditis• Supurative Thyroiditis• Riedel’s Thyroiditis


HASHIMOTO’S THYROIDITIS

• Most common type of thyroiditis

• High-serum thyroid antibodies & goiter

• Most frequent cause of hypothyroidism & goiter in iodine sufficient areas

• 2 types : goitrous (90%), athropic (10%) thyroid failure

G : Germinal CenterP : Small Lymphocytes & Plasma CellsH : Hurthe Cell MetaplasiaC : Minimal Coloid Materials

n engl j med 348;26

PATHOGENESIS OF HASHIMOTO

Robbins Basic Pathology 8th Ed

HASHIMOTO’S THYROIDITIS

• F : M = 7 : 1• Firm, bumpy, symmetric, painless goiter• Natural History : Hyperthyroidism (inflammation)

hypothyroidism (permanent)• 4 antigents : TGB, Thyroid peroxidase, TSH receptor,

sodium iodine symporter• Thyroid appears hypoechogenic in USG• Treatment : Levothyroxine euthyroid, after 6

months goiter size decreased by 30%. FNA to distunguish limphoma or carcinoma

n engl j med 348;26

SUPPURATIVE THYROIDITIS• Rarely happens, because thyroid has encapsulation, high

iodide content, rich blood supply, and extensive lymphatic drainage

• Occurs in patients with preexisting thyroid disease (cancer, hashimoto, MNG), pyriform sinus fistula, AIDS, elderly

• Signs : fever, dysphagia, dysphonia, anterior neck pain and erythema, and a tender thyroid mass. Predeced by acute respirary tract infection

• Lab : Thyroid function : N (but hypo/hyper is possible), WBC & ESR ↑, Cold in radioactive-iodine scan, FNA to identify organism

• Treatment : antibiotics and surgery to drain abscessn engl j med 348;26

DRUG-INDUCED THYROIDITIS

• Amiodarone • Lithium• Interferon α and Interleukin 2

n engl j med 348;26

AMIODARONE-INDUCED THYROIDITIS

n engl j med 348;26

MONITORING OF THYROID FUNCTION IN PATIENT WITH AMIODARONE THERAPY

n engl j med 348;26

RIEDEL’S THYROIDITIS

• Fibrosis of tyroid gland that may extend to surrounding tissue, unknown cause, requiring surgery

• High serum thyroid antibodies in 67% patient.• Signs & Symptoms : rock-hard, fixed, painless

goiter tracheal or esophageal compression, extended fibrosis hypoparathyroidism

• Lab : euthyroid progress to hypothyroid. • Treatment : Surgery, glucocorticoid useful in

early stagesn engl j med 348;26

GOITER AND THYROID NODULES

GOITER & THYROID NODULES

• Diffuse Nontoxic Goiter• Nontoxic Multinodular Goiter• Toxic Multinodular Goiter• Hyperfunctioning Solitary Nodule


DIFFUSE NONTOXIC GOITER

• Diffuse enlargement of thyroid occurs in the absence of nodules and hyperthyroidism

• Also called simple goiter or colloid goiter• Most common cause : iodine deficiency, called endemic

goiter if affects >5% population• More common in women• Iodine deficiency compensatory to trap more iodine to

produce more hormones• TSH level : N or slightly ↑, indicate increased sensitivity to

TSH or other pathways that lead to thyroid growth• Goitrogens : cassava roots, cruciferae family, milk from

areas where goitrogen present in grassHarrison’s Principle of Medicine 18th Ed

DIFFUSE NONTOXIC GOITER

• Sign & Symptoms : asymptomatic. Hemmorhage to cyst or nodule pain & swelling. symmetrically enlarged thyroid, nontender without any palpable nodules. Tracheal / esophageal compression. Pemberton’s sign

• Lab : Thyroid function: fT4 ↓, fT3 & TSH (N), Urinary iodine level ↓ (<10 μg/dL).Thyroid scan increased iodine uptake, USG indicated only if there’s any palpable mass in PE

• Treatment : – Levothyroxine goiter size regression within 3-6month, dose :

young start at 100 μg, elder start at 50 μg– Surgery : Rare, only when compression is documented– Radioiodine


NONTOXIC MULTINODULAR GOITER

• Occurs in up to 12% in population• More common in women, higher age, iodine-

deficiency areas• Hypercellular regions to cystic area filled with

colloid, extensive fibrosis, hemmorhage, lymphocyte infiltration

• Clinical Manifestation : asymptomatic, euthyroid, large goiter compression (rare). Sudden pain hemmorhage or malignancy. Hoarseness laryngeal nerve involvement or malignancy


NONTOXIC MULTINODULAR GOITER

• Diagnosis : – thyroid architecture

distorted, multiple nodules, Thyroid function N,

– Tracheal deviation – Pulmonary function testing

assess compression or tracheomalacia.

– CT & MRI anatomy of goiter.

– Barium meal asses esophageal compression.

– Biopsy malignancy screening

• Treatment : – Avoid contrast agent or

other iodine containing substance

– Radioiodine with increasing frequency goiter size regression 40-50%

– Acute compression glucocorticoid or surgery

– Surgery : Effective ↑, risk ↑, especially in elder with cardiopulmonary underlying disease


TOXIC MULTINODULAR GOITER• Similiar to Nontoxic MNG, difference is presence of functional

autonomy in toxic MNG• Many nodules are polyclonal• Genetic abnormalities, TSH-R and Gsα mutation• Clinical presentation : goiter, subclinical hyperthyroidism or mild

thyrotoxicosis, patient usually elderly with atrial fibrilation,• Lab : TSH ↓, T3 ↑ ↑ & T4 ↑, 24h uptake of radioiodine not

increased• Thyroid scan : heterogenous uptake with increased and decreased

uptake• Treatment :

– Antithyroid drugs & beta blockers normalize thyroid function– Radioiodine decrease the mass of goiter– Surgery effective to goiter, last choice after drugsHarrison’s Principle of Medicine 18th Ed

MULTINODULAR GOITER


HYPERFUNCTIONING SOLITARY NODULE

• A solitary, autonomously functionung thyroid nodule• acquired somatic activating mutation in TSH-R or Gsα in 90%

patient• Clinical Sign : mild thyrotoxicosis, presence of palpable nodule,

absence of clinical features to Grave.• Thyroid scan : focal uptake in hyperfunctioning nodule,

diminished uptake in remainder gland• Treatment :

– Radioiodine ablation. Large dose correct 75% of patient in 3 month. <10% develop hypothyroidism in 5 years.

– Surgery resection– Antithyroid drugs & beta blockers not suggested for long term therapy


BENIGN NEOPLASM

CLASSIFICATION OF THYROID NEOPLASM


THYROID CANCER

THYROID CARCINOMA

• Most common malignancy in the endocrine system

• Incidence ~9/100.000 per year, incrases with age, plateuing in age ~50

• Bad prognosis in age <20 or >45• F : M = 2 : 1, but male has worse prognosis


AGE OF INCIDENCE


RISK FACTOR


PATHOGENESIS• Radiation

– External radiation predispose to chromosomal breaks genetic rearrangement loss of tumor supressor genes

– Radiation risk of benign and malign nodules ↑– Radiation from iodine therapy contribute minimal increased

risk of thyroid cancer• TSH & Growth factor

– Residual expression of TSH-R allows TSH stimulated uptake of iodine

• Oncogenes & Tumor supressor genes– Increased rate of proliferation– Exhibit impaired apoptosis and features that enchances

invasion, angiongenesis, and metastasisHarrison’s Principle of Medicine 18th Ed

CLASSIFICATION


WELL DIFFERENTIATED THYROID CANCER

• Papillary Thyroid Cancer• Follicular Thyroid Cancer


PAPILLARY THYROID CARCINOMA

• Most common type of thyroid cancer (70-90%)• Present in 25% of autopsy• Small lesion, not clinically significant• Diagnosis by FNA or surgical resection• Multifocal, invade locally to the gland and adjacent tissue• Spread via lymphatic system, metastasize to bone and

lung• Mostly identified in early stages (80%) excelent

prognosis• Identified in stage IV (~1%) poor prognosis


PAPILLARY CARCINOMA


FOLLICULAR THYROID CARCINOMA

• More common in iodine deficient regions• Difficult to diagnosed by FNA• Spread hematogenous to bone, lung and CNV• Mortality risk is higher than PTC• Mostly identified in later stage• Poor prognostic factor : distant metastases, age

>50, tumor size >4cm, Hurthe Cell histology, presence of marked vascular invasion


FOLLICULAR CARCINOMA


TREATMENT OF WELL DIFFERENTIATED THYROID CANCER

• Surgery– Surgery to remove the cancer and involed tissue

or lymph node• TSH supression Therapy– Levothyroxine

• Radioiodine Treatment


FOLLOW UP


ANAPLASTIC AND OTHER THYROID CARCINOMA

• Anaplastic Thyroid Cancer– Poorly differentiated, agressive cancer– Patient died in 6 month after diagnosis– Chemotherapy or External beam radiation

• Thyroid Lymphoma– Arises in the background of Hashimoto’s disease– Highly sensitivie to external radiation– Surgical resection is avoided, treatment follow guideline from other

lymphoma• Meduallry Thyroid Carcinoma

– 5-10% of all Thyroid carcinioma– 3 types : MEN 2A, MEN 2B, Familial MTC– MEN 2B more aggresive than MEN 2A, Familial MTC is more aggresive

than sporadic– Management : surgical, it doesn’t uptake radioiodine


MEDULLARY CARCINOMA


REFERENCES

• Harrison’s Principle of Medicine 18th Ed• Buku Ajar Ilmu Penyakit Dalam Edisi V• Junqueira Basic Histology 12th Ed• Robbin’s Basic Pathology 8th Ed• McPhee SJ, Hammer GD, Pathophysiology of

Disease : Introduction to Clinical Medicine 6th Ed• Sherwood’s Physiology from cells to system 7th Ed• New England Journal of Medicine

94284109-Thyroid

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