ENDOKRIN dr. Jimmy H.W. , Sp.PA

ENDOKRIN Kelenjar mengeluarkan hormon

Figure 24-1 Hormones released by the anterior pituitary Figure 24-1 Hormones released by the anterior pituitary. The adenohypophysis (anterior pituitary) releases five hormones that are in turn under the control of various stimulatory and inhibitory hypothalamic releasing factors. TSH, thyroid-stimulating hormone (thyrotropin); PRL, prolactin; ACTH, adrenocorticotrophic hormone (corticotropin); GH, growth hormone (somatotropin); FSH, follicle-stimulating hormone; LH, luteinizing hormone. The stimulatory releasing factors are TRH (thyrotropin-releasing factor), CRH (corticotropin-releasing factor), GHRH (growth hormone-releasing factor), GnRH (gonadotropin-releasing factor). The inhibitory hypothalamic influences are comprised of PIF (prolactin inhibitory factor or dopamine) and growth hormone inhibitory factor (GIH or somatostatin). Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 03:46 AM) © 2005 Elsevier

Kelenjar Hipofise ( Pituitary ) 1 cm, 0,5 gr, pada sella tursica Jenis hormon : Adenohipofise - GH - ACTH - FSH - PRL - TSH - LH Neurohipofise - Oksitosin - Vasopresin - ADH

Figure 24-7 Homeostasis in the hypothalamus-pituitary-thyroid axis and mechanism of action of thyroid hormones. Secretion of thyroid hormones (T3 and T4) is controlled by trophic factors secreted by both the hypothalamus and the anterior pituitary. Decreased levels of T3 and T4 stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-stimulating hormone (TSH) from the anterior pituitary, causing T3 and T4 levels to rise. Elevated T3 and T4 levels, in turn, suppress the secretion of both TRH and TSH. This relationship is termed a negative-feedback loop. TSH binds to the TSH receptor on the thyroid follicular epithelium, which causes activation of G proteins, and cyclic AMP (cAMP)-mediated synthesis and release of thyroid hormones (T3 and T4). In the periphery, T3 and T4 interact with the thyroid hormone receptor (TR) to form a hormone-receptor complex that translocates to the nucleus and binds to so-called thyroid response elements (TREs) on target genes initiating transcription. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 03:46 AM) © 2005 Elsevier

Hiperpituitarism Oleh karena : Adenoma Hiperplasia Carcinoma Kelainan Hipotalamus

ADENOMA HIPOFISE : 10 % tumor otak Usia 30 – 50 tahun Satu jenis tumor  1 jenis hormon Makroskopis : Batas jelas, lunak Kecil (mm) – besar (cm) Lesi besar  invasive adenoma Perdarahan  apoplexi

Mikroskopis : Sel uniform, poligonal, jalur-jalur/lembaran Jaringan ikat penyangga Inti uniform – pleomorfik

Klinik : Rö  bayangan pada sella tursica  ekspansi sellar  erosi tulang  kerusakan diafragma Gangguan produksi  hipopituitarisme Penekanan tumor  gangguan chiasmo opticum (bitemporal hemianopsi) Tekanan intracranial naik Pusing Mual/muntah

Figure 24-4 Pituitary adenoma Figure 24-4 Pituitary adenoma. This massive, nonfunctional adenoma has grown far beyond the confines of the sella turcica and has distorted the overlying brain. Nonfunctional adenomas tend to be larger at the time of diagnosis than those that secrete a hormone. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 03:46 AM) © 2005 Elsevier

Figure 24-4 Pituitary adenoma Figure 24-4 Pituitary adenoma. This massive, nonfunctional adenoma has grown far beyond the confines of the sella turcica and has distorted the overlying brain. Nonfunctional adenomas tend to be larger at the time of diagnosis than those that secrete a hormone. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 03:46 AM) © 2005 Elsevier

PROLAKTINOMA Tumor hipofise terbanyak ( 30 % ) Usia 20 – 40 th, pria > wanita Mikro atau makro Efek dari tumor  PRL naik - amenorrhea - galactorrhea - libido kurang - infertil

PROLAKTINOMA Prolaktin tinggi juga karena : Hamil Stress Hiperplasi sel laktotrof

PROLAKTINOMA Hiperplasi sel laktotrof karena : Hipotalamus rusak  neuron dopaminergik rusak Obat yang menekan reseptor dopamin pada hipofise - phenotiazin - reserpin - haloperidol

PROLAKTINOMA Terapi : Bromocriptin  sebagai antagonist receptor dopamin

Hipopituitarisme, karena : Faktor Hipofise : Tumor non fungsionil / kista Operasi / radiasi Ischemic necrosis/post partum necrosis (Sheehan syndrome) Empty sella syndrome Genetik

Tumor primer / sekunder Infeksi / degenerasi Klinik hipopituitarisme : Faktor Hipotalamus : Tumor primer / sekunder Infeksi / degenerasi Klinik hipopituitarisme : Fungsi kelenjar perifer turun Adrenal Thyroid Gonad Wajah pucat  MSH rendah Atrofi genitalia

Hipofise posterior Hormon produksi Diabetes insipidus ADH Oksitosin ADH rendah Etiologi : trauma, infeksi, tumor Klinik : - haus - urine banyak - Na serum tinggi, osmositas 

Syndrome of Inappropriate ADH secretion : ADH tinggi Etiologi : Ca small cell paru-paru Klinik : - urine sedikit - Na serum rendah

Tumor Hipotalamus Glioma Craniopharyngioma

Craniopharyngioma Dari : Vestigical Remnants Rathke Pouch Usia : anak – dewasa muda Morfologi : Umumnya jinak Soliter, kistik, multiloculated Mirip adamantinoma

Thyroid Asal : evaginasi epitel pharyngeal Normal : 15-20 gr Hormon aktif : - T3,T4 bebas - ikatan dengan TBG

Thyroid fungsi : - lemak Katabolisme : - karbohidrat Sintesa : - protein

Hipertiroidisme lab : T3,T4 tinggi Gejala : - nervous - lemah otot - keringatan - palpitasi - kurus - emosionil - tremor - diare - capek - kulit panas - tiroid besar - gangguan siklus M

Hipertiroidisme Tirotoxicosis dapat karena : Diffuse hiperplasi (85% Graves)  hipertiroidisme Tx hormon tiroid berlebihan Multinodular goiter Neoplasma tiroid Tiroiditis

Hipertiroidisme Terjadi : Hipermetabolik Overaktif simpatetik

Hipertiroidisme Gejala Hipertiroid : Cardiac : aritmi/palpitasi/cardiomegali Otot : atrofi / fatty changes Tulang : osteoporose, fraktur Limfoid : hiperplasi

Hipertiroidisme Ocular : Staring gaze, lid lag Neuromuscular : tremor, cemas, insomnia, emosional Kulit : berkeringat, rasa panas, kemerahan GI : rasa haus, lapar

Hipertiroidisme Dx : Tx : -  blocker  fungsi adrenergic  Tanda klinik Lab : - T4 bebas >> - T S H << Tx : -  blocker  fungsi adrenergic  - propil tiouracil  sintesa T3T4  - jodium  pelepasan T3T4  - radioactive jodium

Hipotiroidi Sebab : Primer  gangguan tiroid Sekunder

Hipotiroidi Hipotiroidi karena parenchim tiroid  : Embrional Radiasi Operatif Hashimoto

Hipotiroidi Hipotiroidi karena sintesa  : Idiopatik Cacat sintesa turunan Jodium intake kurang Bahan-bahan goitrogen

Hipotiroidi Hipotiroidi karena supratiroidal : Lesi hipofise Lesi hipotalamus

Hashimoto Thyroiditis Penyakit autoimmune  hipotiroidi Umur 45-65, ♀ : ♂ = 10-20 : 1 Ada unsur familiar  twin monozigote = 30-60% Sering disertai Rh, arthritis, SLE

Morfologi Diffuse, berbatas jelas Pucat, abu-abu, kenyal, noduler Kapsul intak

Klinik Struma tidak nyeri, simetrik diffuse Kadang-kadang noduler Hipotiroidisme, kadang-kadang hipertiroidisme transien Risk factor timbul limfoma

Figure 24-9 Pathogenesis of Hashimoto thyroiditis Figure 24-9 Pathogenesis of Hashimoto thyroiditis. Three proposed models for mechanism of thyrocyte destruction in Hashimoto disease. Sensitization of autoreactive CD4+ T cells to thyroid antigens appears to be the initiating event for all three mechanisms of thyroid cell death. See the text for details. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 03:46 AM) © 2005 Elsevier

De Quervain Tiroiditis : Jarang terjadi Usia 30 – 50 tahun Wanita : Pria = 3 – 5 : 1

Morfologi : Unilateral / bilateral Kenyal, kapsul intak Kadang-kadang perlekatan jaringan sekitar Warna kuning pucat, kecoklatan

Klinik : Terjadi mendadak / bertahap Nyeri leher, panas, capek, malas, anorexi, myalgin Terdapat struma Dapat sembuh spontan T3 T4  , TSH 

Figure 24-11 Subacute thyroiditis Figure 24-11 Subacute thyroiditis. The thyroid parenchyma contains a chronic inflammatory infiltrate with a multinucleate giant cell (above left) and a colloid follicle (bottom right). Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 03:46 AM) © 2005 Elsevier

Graves Disease Triad yang harus ada : Hipertiroidi, dengan goiter aktif Ophthalmopathy  exophthalmos Dermatopathy  pretibial myxedema

Klinik : Usia 20-40 tahun, wanita : pria = 7 : 1 Ada faktor genetik

Figure 24-8 A patient with hyperthyroidism Figure 24-8 A patient with hyperthyroidism. A wide-eyed, staring gaze, caused by overactivity of the sympathetic nervous system, is one of the features of this disorder. In Graves disease, one of the most important causes of hyperthyroidism, accumulation of loose connective tissue behind the eyeballs also adds to the protuberant appearance of the eyes. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 03:46 AM) © 2005 Elsevier

Figure 24-12 Diffusely hyperplastic thyroid in a case of Graves disease. The follicles are lined by tall, columnar epithelium. The crowded, enlarged epithelial cells project into the lumens of the follicles. These cells actively resorb the colloid in the centers of the follicles, resulting in the scalloped appearance of the edges of the colloid. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 09:36 AM) © 2005 Elsevier

Ophthalmopathy graves Jaringan ikat orbita Otot extra ocular  Ab  B cell  T cell, CD4+ / CD8+  Mirip TSH receptor

Morfologi : Struma, Sp 80 gr, simetri berkapsul Konsistensi lunak, halus, merah seperti daging Sel-sel silindris, papil-papil kecil Colloid sedikit, dengan ‘scalloped’ margin Infiltrasi limfosit ( B cell )

Terapi : Jodium  involusi epitel  sekresi tiroglobulin turun Propilthiouracil  sintesa kurang Radioaktif jodium pembedahan

Neoplasma Tiroid Bentukan soliter, palpable Wanita : pria = 4 : 1 Sebagian besar nodul soliter jinak Nodul neoplastik  90% adenoma

Beberapa kriteria penyokong Dx Nodul soliter  neoplasma Usia muda  neoplasma Jenis kelamin laki-laki  neoplasma Pernah diterapi Rö  Ca Hot nodule  jinak

Adenoma tiroid Soliter Folikel  follicular adenoma Beberapa jenis, tersering : simple colloid adenoma Adenoma sangat jarang menjadi Carcinoma

Figure 24-14 Follicular adenoma of the thyroid Figure 24-14 Follicular adenoma of the thyroid. A solitary, well-circumscribed nodule is seen. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 09:36 AM) © 2005 Elsevier

Figure 24-14 Follicular adenoma of the thyroid Figure 24-14 Follicular adenoma of the thyroid. A solitary, well-circumscribed nodule is seen. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 09:36 AM) © 2005 Elsevier

Figure 24-14 Follicular adenoma of the thyroid Figure 24-14 Follicular adenoma of the thyroid. A solitary, well-circumscribed nodule is seen. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 09:36 AM) © 2005 Elsevier

Morfologi adenoma Tumor soliter Bentuk speris Berkapsul, tekanan jaringan sekitar Ukuran sekitar 3 cm Warna abu-abu putih, merah kecoklatan Kadang2 perdarahan, fibrosis, kalsifikasi, kistik

mikroskopis Folikel ukuran sama, isi folikel Jenis : - Simple colloid (macrofolicular) - Fetal (microfolicular) - Embryonal (trabecular) - Hurthle cell (oxiphyl, oncocyte) - Atypical - Adenoma with papillae (=Papillae adenoma) (=Encapsuled Papillary Ca)

Tumor Tiroid Jinak yang lain Kista tiroid : - deri adenoma folicular - dari multinodular goiter Kista dermoid Lipoma Hemangioma Terratoma

Carcinoma Thyroid Umumnya usia dewasa Wanita > pria, khususnya usia muda Terdapat reseptor estrogen pada sel-sel tumor

Jenis Carcinoma Papillary Ca 75-85 % Follicular Ca 10-30 % Medullary Ca 5 % Anaplastic Ca 5 %

Papillary Carcinoma Semua usia, terutama 20-40 tahun Erat hubungannya dengan fakta radiasi

Figure 24-17 Papillary carcinoma of the thyroid Figure 24-17 Papillary carcinoma of the thyroid. A, The macroscopic appearance of a papillary carcinoma with grossly discernible papillary structures. This particular example contains well-formed papillae (B), lined by cells with characteristic empty-appearing nuclei, sometimes termed "Orphan Annie eye" nuclei (C). D, Cells obtained by fine-needle aspiration of a papillary carcinoma. Characteristic intranuclear inclusions are visible in some of the aspirated cells. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 09:36 AM) © 2005 Elsevier

Figure 24-17 Papillary carcinoma of the thyroid Figure 24-17 Papillary carcinoma of the thyroid. A, The macroscopic appearance of a papillary carcinoma with grossly discernible papillary structures. This particular example contains well-formed papillae (B), lined by cells with characteristic empty-appearing nuclei, sometimes termed "Orphan Annie eye" nuclei (C). D, Cells obtained by fine-needle aspiration of a papillary carcinoma. Characteristic intranuclear inclusions are visible in some of the aspirated cells. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 09:36 AM) © 2005 Elsevier

Morfologi Soliter atau multipel Berbatas jelas / berkapsul / menyebar diluarnya Kadang2 fibrosis, kalsifikasi, kistik Pada irisan  granula / papil-papil kecil

Mikroskopis : Papil dengan fibrovasculer, dilapisi epitel Inti dengan ground glass / orphan annie Intra nuclear inclusion / groves Psammoma bodies

Klinik Sering a symptomatic Sering dengan metastasis kelenjar leher Radioactive jodium  cold nodule FNA, cara Diagnosa yang tepat

Follicular Carcinoma Wanita > Pria Usia 40 – 50 tahun Sering sudah didapatkan colloid goiter

Morfologi : Single nodule Batas jelas / infiltratif Tumor besar  infiltrasi ke jaringan sekitar Warna abu-abu – coklat – merah muda Kadang2 fibrosis, kalsifikasi

Figure 24-18 Follicular carcinoma Figure 24-18 Follicular carcinoma. Cut surface of a follicular carcinoma with substantial replacement of the lobe of the thyroid. The tumor has a light-tan appearance and contains small foci of hemorrhage. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 09:36 AM) © 2005 Elsevier

Figure 24-19 Follicular carcinoma of the thyroid Figure 24-19 Follicular carcinoma of the thyroid. A few of the glandular lumens contain recognizable colloid. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 02:32 PM) © 2005 Elsevier

mikroskopis : Folikel2 seperti normal, atau dengan diferensiasi yang rendah Kadang2 dengan sel Hurthle Invasi sel pada kapsul atau vascular

Klinik : Nodul kecil, lambat laun membesar Rö  cold nodule Metastasis hematogen  ke organ-organ jauh

Medullary Carcinoma Dari para follicular cell Hormon yang dikeluarkan - Calcitonin - Serotonin - CEA - Somatostatin - VIP (Vasoactive Intestinal Peptide)

Figure 24-21 Medullary carcinoma of thyroid Figure 24-21 Medullary carcinoma of thyroid. These tumors typically show a solid pattern of growth and do not have connective tissue capsules. (Courtesy of Dr. Joseph Corson, Brigham and Women's Hospital, Boston, MA.) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 02:32 PM) © 2005 Elsevier

Figure 24-21 Medullary carcinoma of thyroid Figure 24-21 Medullary carcinoma of thyroid. These tumors typically show a solid pattern of growth and do not have connective tissue capsules. (Courtesy of Dr. Joseph Corson, Brigham and Women's Hospital, Boston, MA.) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 02:32 PM) © 2005 Elsevier

Morfologi Soliter  type sporadic Multipel  type familial Jaringan tumor halus, warna abu2-coklat Kadang2 nekrosis, perdarahan

Klinis Nodul di thyroid Kadang2 disertai diare karena VIP Type sporadic / MEN  tumbuh agresif Type familial  low grade

Mikroskopis Sel poligonal, spindle, dalam sarang/trabekula/folikel Deposit amiloid ( dari molekul calcitonin)

Anaplastic Carcinoma : Sangat agresif Usia tua, 65 tahun Sering didahului multinodular goiter

Morfologi : Large, pleomorfik giant cell Spindle cell Small anaplastic cell

Congenital anomali Tiroid Ductus/cyst thyroglossus Sisa2 vestigial remnant Lesi kecil 2-3 cm Letak antara Glossus - Thyroid

Parathyroid Dari kantung pharyngeal, ada 4 kelenjar Berat 35-40 mg Terdiri dari - chief cell  germal parathormon - oxyphil cell Kerja parathyroid dikendalikan oleh Ca ion darah

Figure 24-24 Parathyroid adenomas are almost always solitary lesions Figure 24-24 Parathyroid adenomas are almost always solitary lesions. Technetium-99m-sestamibi radionuclide scan demonstrates an area of increased uptake corresponding to the left inferior parathyroid gland (arrow). This patient had a parathyroid adenoma. Preoperative scintigraphy is useful in localizing and distinguishing adenomas from parathyroid hyperplasia, where more than one gland would demonstrate increased uptake. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 02:32 PM) © 2005 Elsevier

Figure 24-25 Parathyroid adenoma Figure 24-25 Parathyroid adenoma. A, Solitary chief cell parathyroid adenoma (low-power photomicrograph) revealing clear delineation from the residual gland below. B, High-power detail of a chief cell parathyroid adenoma. There is some slight variation in nuclear size but no anaplasia and some slight tendency to follicular formation. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 02:32 PM) © 2005 Elsevier

Hormon PTH bekerja : Pada tulang menambah aktivitas osteoclast Pada ginjal meningkatkan - resorbsi calcium - konversi vit D aktif - ekskresi phosphat Pada usus menambah absorbsi kalsium

Tumor2 ganas yang lain  calcium darah tinggi Metastasis tulang  osteolisis PTH related protein ( PTH rP )

Hiperparatiroidisme primer Sebabnya : Adenoma 75-80 % Hiperplasia 10-15 % Carcinoma 5 % Usia tersering pada dewasa 50 th lebih Wanita lebih sering dp laki-laki Ada faktor radiasi sebelumnya

Figure 24-26 Cardinal features of hyperparathyroidism Figure 24-26 Cardinal features of hyperparathyroidism. With routine evaluation of calcium levels in most patients, primary hyperparathyroidism is often detected at a clinically silent stage. Hypercalcemia from any other cause can also give rise to the same symptoms. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 6 April 2005 02:32 PM) © 2005 Elsevier

Morfologi Tumor soliter, kecil 0,5 – 5 gr Lunak, batas jelas, kecoklatan Mikroskopis : Sel2 poligonal, uniform Inti kecil, central Klinik, dapat berupa : A symptomatic hyperparathyroidism Symptomatic hyperparathyroidism

Pada symptomatic timbul : Tulang  osteoporosis Ginjal  nephrolithiasis Gastrointestinal  constipasi, ulcus dll CNS  depresi Neuromuscular  lemah Cardiac  kalsifikasi katup