ENDOCRINE SYSTEM BLOCK

CASE 4

Ronald Chrisbianto Gani 405090223 Faculty of Medicine 2009 Tarumanagara University

HISTOLOGY OF THYROID

Junqueiras 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 : Capsule S : Septa

L : Lumen

C : C cells
Junqueiras Basic Histology 12th Ed

HISTOLOGY
C : C cell F : Folicullar Cell

Junqueiras Basic Histology 12th Ed

HISTOLOGY

F : Follicular Cell L : Lumen BM : Basal Membrane C : Parafollicular Cell / C Cell

G : Golgi Apparatus

Junqueiras Basic Histology 12th Ed

THYROID SYNTHESIS

Junqueiras Basic Histology 12th Ed

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
Sherwoods Human Physiology From Cells to System 2nd Ed

FOLLICULAR CELL

Sherwoods Human Physiology From Cells 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 iodinetrapping 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
Sherwoods Human Physiology From Cells to System 2nd Ed

Sherwoods Human Physiology From Cells to System 7th Ed

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%
Sherwoods Human Physiology From Cells to System 2nd Ed

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

Sherwoods Human Physiology From Cells to System 2nd Ed

KONTROL HORMON TIROID

Sherwoods Human Physiology From Cells to System 7th Ed

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 ingatan
Sherwoods Human Physiology From Cells 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
Sherwoods Human Physiology From Cells to System 2nd Ed

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

Sherwoods Human Physiology From Cells to System 2nd Ed

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 subtotal
Buku Ajar Ilmu Penyakit Dalam Ed V

Harrisons 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

Buku Ajar Ilmu Penyakit Dalam Ed V

SIGN & SYMPTOMS

Harrisons Principle of Medicine 18th Ed

MYXEDEMA

Pathophysiology of Disease : Introduction to Clinical Medicine 6th Ed

ALGORITHM

Harrisons Principle of Medicine 18th Ed

DIFFERENTIAL DIAGNOSIS
Hashimotos thyroiditis Multinodular Goiter Thyroid Carcinoma

Harrisons Principle of Medicine 18th Ed

TREATMENT
No residual thyroid function levothyroxine 1,6 g/kg body weight (100-150 g/d) Adult patient <60yo start with 50-100 g/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 200g/d or fluctuating TSH poor adherence to treatment
Harrisons 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 Graves disease (60-80%) , toxic MNG, and toxic adenoma

Harrisons Principle of Medicine 18th Ed

EPIDEMIOLOGY
Varies among populations High iodine intake higher prevalence of Graves disease Grave disease 2% of women Onset occurs between age 20-50, or elder

Harrisons Principle of Medicine 18th Ed

E T I O L O G Y
Harrisons Principle of Medicine 18th Ed

SIGNS & SYMPTOMS

Harrisons Principle of Medicine 18th Ed

Signs & Symptoms

A . Graves Opthalmopathy (Periorbital edema, lid retraction, conjunctival injection, proptosis) B . Thyroid Dermopathy C . Thyroid Acropachy

Harrisons Principle of Medicine 18th Ed

PATHOGENESIS

Pathophysiology of Disease : Introduction to Clinical Medicine 6th Ed

GRAVES OPTHALMOPATHY

Harrisons Principle of Medicine 18th Ed

DIFFERENTIAL DIAGNOSIS

n engl j med 348;26

A L G O R I T H M
Harrisons Principle of Medicine 18th Ed

TATA LAKSANA
Tirostatika Tiroidektomi Iodium Radioaktif

Buku Ajar Ilmu Penyakit Dalam Ed V

Kelompok Obat Obat Anti Tiroid

Propiltiourasil (PTU) Metimazol (MMI) Karbimazol (CTZ MMI) Antagonis Adrenergik -blocker Propanolol Metoprolol Atenolol Nadolol Bahan mengandung iodine Kalium Iodida Solusi Lugol Natrium Ipodat Asam Lopanoat Obat Lain Kalium Perklorat Litium Karbonat Glukokortikoid

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

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

Mengurangi dampak hormon tiroid pd jaringan

Obat tambahan, kadang sebagai obat tunggal pd tiroiditis

Menghambat keluarnya T4 dan T3 Menghambat T4 dan T3 serta menghambat produksi T3 ektratiroidal

Persiapan tiroidektomi. Pada krisis tiroid. Bukan untuk penggunaan rutin

Menghambat traspor iodium, sintesis dan keluarnya hormon Memperbaiki efek hormon di jaringan dan sifat imunologis

Bukan indikasi rutin Pada subakut tiroiditis berat dan krisis tiroid

Buku Ajar Ilmu Penyakit Dalam Ed V

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

Buku Ajar Ilmu Penyakit Dalam Ed V

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
Buku Ajar Ilmu Penyakit Dalam Ed V

THYROIDITIS

ETIOLOGY & CLASSIFICATION

Harrisons Principle of Medicine 18th Ed

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
Harrisons Principle of Medicine 18th Ed

SUBACUTE THYROIDITIS
De Quervains 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 g) if hypothyroid prolonged
Harrisons Principle of Medicine 18th Ed

PATHOPHYSIOLOGY

Harrisons Principle of Medicine 18th Ed

SILENT THYROIDITIS
Painless post-partum thyroiditis. Occurs in patient with underlying autoimmune thyroid disease Clinical course similiar to subacute, except theres 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
Harrisons Principle of Medicine 18th Ed

CHRONIC THYROIDITIS
Hashimotos Thyroiditis Supurative Thyroiditis Riedels Thyroiditis

Harrisons Principle of Medicine 18th Ed

HASHIMOTOS 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 Center P : Small Lymphocytes & Plasma Cells H : Hurthe Cell Metaplasia C : Minimal Coloid Materials
n engl j med 348;26

PATHOGENESIS OF HASHIMOTO

Robbins Basic Pathology 8th Ed

HASHIMOTOS 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 abscess
n engl j med 348;26

DRUG-INDUCED THYROIDITIS
Amiodarone Lithium Interferon 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

RIEDELS 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 stages
n engl j med 348;26

GOITER AND THYROID NODULES

GOITER & THYROID NODULES

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

Harrisons Principle of Medicine 18th Ed

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 grass
Harrisons 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. Pembertons sign Lab : Thyroid function: fT4 , fT3 & TSH (N), Urinary iodine level (<10 g/dL).Thyroid scan increased iodine uptake, USG indicated only if theres any palpable mass in PE Treatment :
Levothyroxine goiter size regression within 3-6month, dose : young start at 100 g, elder start at 50 g Surgery : Rare, only when compression is documented Radioiodine
Harrisons Principle of Medicine 18th Ed

NONTOXIC MULTINODULAR GOITER

Occurs in up to 12% in population More common in women, higher age, iodinedeficiency 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
Harrisons Principle of Medicine 18th Ed

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

Harrisons Principle of Medicine 18th Ed

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 Gs 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 drugs
Harrisons Principle of Medicine 18th Ed

MULTINODULAR GOITER

Pathophysiology of Disease : Introduction to Clinical Medicine 6th Ed

MULTINODULAR GOITER

Robbins Basic Pathology 8th Ed

HYPERFUNCTIONING SOLITARY NODULE

A solitary, autonomously functionung thyroid nodule acquired somatic activating mutation in TSH-R or Gs 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
Harrisons Principle of Medicine 18th Ed

Harrisons Principle of Medicine 18th Ed

BENIGN NEOPLASM

CLASSIFICATION OF THYROID NEOPLASM

Harrisons Principle of Medicine 18th Ed

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

Harrisons Principle of Medicine 18th Ed

AGE OF INCIDENCE

Harrisons Principle of Medicine 18th Ed

RISK FACTOR

Harrisons Principle of Medicine 18th Ed

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 metastasis
Harrisons Principle of Medicine 18th Ed

CLASSIFICATION

Harrisons Principle of Medicine 18th Ed

WELL DIFFERENTIATED THYROID CANCER

Papillary Thyroid Cancer Follicular Thyroid Cancer

Harrisons Principle of Medicine 18th Ed

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
Harrisons Principle of Medicine 18th Ed

PAPILLARY CARCINOMA

Robbins Basic Pathology 8th Ed

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
Harrisons Principle of Medicine 18th Ed

FOLLICULAR CARCINOMA

Robbins Basic Pathology 8th Ed

TREATMENT OF WELL DIFFERENTIATED THYROID CANCER

Surgery
Surgery to remove the cancer and involed tissue or lymph node

TSH supression Therapy

Levothyroxine

Radioiodine Treatment

Harrisons Principle of Medicine 18th Ed

FOLLOW UP

Harrisons Principle of Medicine 18th Ed

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 Hashimotos 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 doesnt uptake radioiodine

Harrisons Principle of Medicine 18th Ed

MEDULLARY CARCINOMA

Robbins Basic Pathology 8th Ed

Harrisons Principle of Medicine 18th Ed

REFERENCES
Harrisons Principle of Medicine 18th Ed Buku Ajar Ilmu Penyakit Dalam Edisi V Junqueira Basic Histology 12th Ed Robbins Basic Pathology 8th Ed McPhee SJ, Hammer GD, Pathophysiology of Disease : Introduction to Clinical Medicine 6th Ed Sherwoods Physiology from cells to system 7th Ed New England Journal of Medicine