PENYAKIT KELENJAR PENYAKIT KELENJAR ADRENAL ADRENAL

- Cushing’s Syndrome -- Cushing’s Syndrome -

OLEH :OLEH :

Woro HarjaningsihWoro Harjaningsih

DefinisiDefinisi

adalah kondisi klinik sebagai akibat dari paparan adalah kondisi klinik sebagai akibat dari paparan kronik glukokortikoid menyebabkan kadar kronik glukokortikoid menyebabkan kadar glukokortikoid dlm sirkulasi berlebihan.glukokortikoid dlm sirkulasi berlebihan.

disebut juga sebagai disebut juga sebagai hiperadrenokortikalisme hiperadrenokortikalisme HiperadrenalkortikalismeHiperadrenalkortikalismeHiperkortisolismeHiperkortisolismePenyebab paling umum : sekresi berlebih ACTH Penyebab paling umum : sekresi berlebih ACTH dari kelenjar hipofisis anterior (Cushing’s dari kelenjar hipofisis anterior (Cushing’s disease)disease)

ETIOLOGIETIOLOGI

A.A. Cushing’s disease :Cushing’s disease :Dapat tjd :Dapat tjd :

secara spontan secara spontan cushing’s syndrome cushing’s syndrome spontaneous atau , merupakan penyebab spontaneous atau , merupakan penyebab terbesar, kejadian kiraterbesar, kejadian kira22 2 – 4 kasus / juta 2 – 4 kasus / juta populasi dan pd wanita 9 X lebih banyak drpd populasi dan pd wanita 9 X lebih banyak drpd laki-lakilaki-lakisebagai hasil pemberian kronik (jangka sebagai hasil pemberian kronik (jangka panjang) kortikosteroid panjang) kortikosteroid Cushing’s syndrome Cushing’s syndrome iatrogeniciatrogenic

Spontaneous cushing’s syndrome / Cushing’s Spontaneous cushing’s syndrome / Cushing’s disease bisa tjd akibat :disease bisa tjd akibat :

Adenoma hipofisis Adenoma hipofisis sekresi berlebih ACTH (> sekresi berlebih ACTH (> 90%)90%)

Hiperplasia difuse / pituitary corticotroph cells yg Hiperplasia difuse / pituitary corticotroph cells yg bertanggung jawab thdp hipersekresi ACTHbertanggung jawab thdp hipersekresi ACTH

Hiperplasia kmk krn hipersekresi CRH oleh Hiperplasia kmk krn hipersekresi CRH oleh hipotalamus atau tumor pensekresi CRH (CRH-hipotalamus atau tumor pensekresi CRH (CRH-secreting tumors)secreting tumors)

Hipersekresi kronik CRH tidak menyebabkan Hipersekresi kronik CRH tidak menyebabkan adenoma hipofisisadenoma hipofisis

B. Ectopic ACTH SyndromeB. Ectopic ACTH Syndrome

Tumor non hipofisis mensintesis & Tumor non hipofisis mensintesis & mensekresikan secara berlebih mensekresikan secara berlebih (hipersekresi) ACTH yg aktif secara biologi (hipersekresi) ACTH yg aktif secara biologi atau peptida menyerupai ACTH (ACTH-atau peptida menyerupai ACTH (ACTH-like peptide)like peptide)

Biasanya karsinoma sel kecil dari paru Biasanya karsinoma sel kecil dari paru atau tumor karsinoid dari bronkhialatau tumor karsinoid dari bronkhial

Lebih banyak menyerang laki-lakiLebih banyak menyerang laki-laki

C. ECTOPIC CRH SyndromeC. ECTOPIC CRH Syndrome

Sangat jarang menyebabkan Cushing’s Sangat jarang menyebabkan Cushing’s SyndromeSyndrome

Sebagian besar kasus berhub dg tumor Sebagian besar kasus berhub dg tumor karsinoid bronkhialkarsinoid bronkhial

D. D. Functioning Adrenocortical TumorsFunctioning Adrenocortical Tumors

Baik adrenocortical adenoma dan Baik adrenocortical adenoma dan carcinoma menyebabkan Cushing’s carcinoma menyebabkan Cushing’s syndrome melalui pengeluaran kortisol syndrome melalui pengeluaran kortisol secara autonomsecara autonom

Adenoma memp vaskuler yang tinggi, Adenoma memp vaskuler yang tinggi, dengan area nekrosis, perdarahan, dengan area nekrosis, perdarahan, degenerasi kista dan kalsifikasi degenerasi kista dan kalsifikasi bisa bisa metastase ke ginjal, retroperitoneum, liver metastase ke ginjal, retroperitoneum, liver dan parudan paru

E. Adrenal Micronodular HyperplasiaE. Adrenal Micronodular Hyperplasia

Jarang menyebabkan Cushing’s Jarang menyebabkan Cushing’s SyndromeSyndrome

Sekitar separuh kasus timbul secara Sekitar separuh kasus timbul secara mendadak pada anak2 dan dewasa muda mendadak pada anak2 dan dewasa muda

F. Adrenal Macronodular HyperplasiaF. Adrenal Macronodular Hyperplasia

Jarang menyebabkan Cushing’s Jarang menyebabkan Cushing’s SyndromeSyndrome

Beberapa pasien dg macronodular Beberapa pasien dg macronodular hyperplasia tidak menunjukkan gambaran hyperplasia tidak menunjukkan gambaran cushingoid tipikalcushingoid tipikal

PatofisiologiPatofisiologi

PatofisiologiPatofisiologi

Penyebab dapat dibagi 2 kategori :Penyebab dapat dibagi 2 kategori :ACTH-dependent ACTH-dependent peningkatan kadar peningkatan kadar kortisol tergantung pada ACTH dan tidak kortisol tergantung pada ACTH dan tidak dapat menekan sekresi ACTH dari dapat menekan sekresi ACTH dari hipofisishipofisisACTH-independent ACTH-independent peningkatan kadar peningkatan kadar kortisol tidak tergantung ACTH (autonom) kortisol tidak tergantung ACTH (autonom) dan dapat menekan sekresi ACTH dari dan dapat menekan sekresi ACTH dari hipofisis hipofisis

Klasifikasi Klasifikasi

ACTH dependentACTH dependentCushing’s diseaseCushing’s diseaseEctopic ACTH syndromeEctopic ACTH syndromeEctopic corticotropin-releasing hormone syndrome*Ectopic corticotropin-releasing hormone syndrome* ACTH independentACTH independentIatrogenicIatrogenicAdrenal adenomaAdrenal adenomaMicronodular hyperplasia*Micronodular hyperplasia*Macronodular hyperplasia*Macronodular hyperplasia*

Ket : ACTH : Adrenocorticotropin hormoneKet : ACTH : Adrenocorticotropin hormone * : accounts per 1 percent or less of cases* : accounts per 1 percent or less of cases(Adapted with permission from Orth DN Cushing’s Syndrome. (Adapted with permission from Orth DN Cushing’s Syndrome.

N Engl. J. N Engl. J. Med, 1995 ; 332 : 791 – 803)Med, 1995 ; 332 : 791 – 803)

ACTH-dependent Cushing’s syndrome :ACTH-dependent Cushing’s syndrome :

~ ~ Cushing’s disease Cushing’s disease 80% kasus ACTH-80% kasus ACTH-dependentdependent

~ ~ Ectopic ACTH hypersecretion Ectopic ACTH hypersecretion 20%20%

~ ~ Ectopic CRH secretion Ectopic CRH secretion jarangjarang

Dimana kesemuanya ditandai dg Dimana kesemuanya ditandai dg hipersekresi ACTH kronik dan hipersekresi ACTH kronik dan peningkatan sekresi kortisolpeningkatan sekresi kortisol

ACTH-independent Cushing’s syndrome :ACTH-independent Cushing’s syndrome :

~ ~ Glucocorticoid-secreting adrenocortical Glucocorticoid-secreting adrenocortical adenoma dan carcinomaadenoma dan carcinoma

~ ~ Adrenal micronodular dan macronodular Adrenal micronodular dan macronodular hyperplasiahyperplasia

Kesemuanya ditandai dg sekresi secara Kesemuanya ditandai dg sekresi secara autonom kortisol dan penekanan ACTH autonom kortisol dan penekanan ACTH hipofisishipofisis

Adrenal tumorAdrenal tumor

Carcinoma dan adrenal Carcinoma dan adrenal adenoma primer tidak di adenoma primer tidak di bawah kendali bawah kendali hipotalamus-hipofisis dan hipotalamus-hipofisis dan kmd secara autonom kmd secara autonom mensekresikan lebih mensekresikan lebih kortisolkortisol

Hiperkortisol menekan Hiperkortisol menekan produksi ACTH hipofisis produksi ACTH hipofisis menyebabkan atrofi menyebabkan atrofi korteks adrenal korteks adrenal

Manifestasi KlinikManifestasi Klinik

FUNGSI KORTISOLFUNGSI KORTISOL

Memelihara tekanan darah dan fungsi Memelihara tekanan darah dan fungsi kardiovaskuler.kardiovaskuler.

Menurunkan respon inflamasi sistem imun.Menurunkan respon inflamasi sistem imun. Menyeimbangkan efek insulin dalam memecah Menyeimbangkan efek insulin dalam memecah

glukosa untuk energi.glukosa untuk energi. Mengatur metabolisme protein, karbohidrat, dan Mengatur metabolisme protein, karbohidrat, dan

lemak.lemak. Fungsi terpenting : membantu tubuh terhadap Fungsi terpenting : membantu tubuh terhadap

respon stress.respon stress. (kadar kortisol wanita pada kehamilan 3 bln (kadar kortisol wanita pada kehamilan 3 bln

terakhir dan atlit secara normal tinggi).terakhir dan atlit secara normal tinggi). dmk juga pada orang2 dg depresi, alkoholisme, dmk juga pada orang2 dg depresi, alkoholisme,

malnutrisi dan gangguan panik.malnutrisi dan gangguan panik.

GEJALAGEJALA

Obesitas tubuh bagian atas, muka bulat, peningkatan Obesitas tubuh bagian atas, muka bulat, peningkatan lemak sekitar leher, lengan dan kaki kurus, pada anak-anak lemak sekitar leher, lengan dan kaki kurus, pada anak-anak pertumbuhan lambat.pertumbuhan lambat.

Gejala lain : kulit fragile, kurus, memar dan tidak sehat, Gejala lain : kulit fragile, kurus, memar dan tidak sehat, kulit warna ungu pink pada perut, paha, lengan dan kulit warna ungu pink pada perut, paha, lengan dan payudara.(striae)payudara.(striae)

Tulang rapuh dan bengkok, patah tulang (fraktur) pada Tulang rapuh dan bengkok, patah tulang (fraktur) pada tulang rusuk (iga) dan tulang belakang.tulang rusuk (iga) dan tulang belakang.

Sangat lelah, otot lemah, tek. darah dan kadar gula darah Sangat lelah, otot lemah, tek. darah dan kadar gula darah tinggi, irritabilitas, ansietas, depresi.tinggi, irritabilitas, ansietas, depresi.

Pertumbuhan rambut pada muka, leher, dada, perut dan Pertumbuhan rambut pada muka, leher, dada, perut dan paha (pada wanita)paha (pada wanita)

Periode menstruasi tidak teratur/ terhenti.Periode menstruasi tidak teratur/ terhenti. Penurunan libido sex pada laki-lakiPenurunan libido sex pada laki-laki

Penderita Cushing’s SyndromePenderita Cushing’s Syndrome

Penderita Cushing’s Syndrome anakPenderita Cushing’s Syndrome anak

Gejala Cushing’s SyndromeGejala Cushing’s SyndromeStriae pada abdomen dan payudaraStriae pada abdomen dan payudara

Moonface Moonface

MoonfaceMoonface

Striae pada stomachStriae pada stomach

Striae Striae

Pertumbuhan rambut pada dada Pertumbuhan rambut pada dada

Striae pada lengan Striae pada lengan

Striae pada siku Striae pada siku

Buffalohump (punggung menebal)Buffalohump (punggung menebal)

Buffalohump (punggung menebal)Buffalohump (punggung menebal)

Exogenous Cushing SyndrommeExogenous Cushing Syndromme

DIAGNOSISDIAGNOSIS

Berdasarkan tinjauan riwayat medis pasien, pemeriksaan Berdasarkan tinjauan riwayat medis pasien, pemeriksaan fisik, dan test lab.fisik, dan test lab.

X ray : utk menentukan lokasi tumor.X ray : utk menentukan lokasi tumor. 24 urin 24 jam bebas kortisol24 urin 24 jam bebas kortisol

paling spesifik, kadar > 50 – 100 µg / hari utk dewasa paling spesifik, kadar > 50 – 100 µg / hari utk dewasa cushing’s syndromecushing’s syndrome

Test Supresi DexametasonTest Supresi Dexametason

utk membedakan peningkatan ACTH karena adenoma utk membedakan peningkatan ACTH karena adenoma hipofisis dan tumor ektopik.hipofisis dan tumor ektopik.

Test Stimulasi CRHTest Stimulasi CRH

utk membedakan antara adenoma hipofisis dengan utk membedakan antara adenoma hipofisis dengan sindroma ACTH ektopik atau tumor adrenal penghasil sindroma ACTH ektopik atau tumor adrenal penghasil kortisol kortisol

DIAGNOSISDIAGNOSIS

Visualisasi langsung Kelenjar Endokrin (Imaging Visualisasi langsung Kelenjar Endokrin (Imaging Radiologi)Radiologi)

- melihat ukuran dan bentuk kelenjar hipofisis dan - melihat ukuran dan bentuk kelenjar hipofisis dan adrenal serta menentukan jika ada tumor.adrenal serta menentukan jika ada tumor.

- dengan CT ( Computerized Tomography) scan dan - dengan CT ( Computerized Tomography) scan dan MRI (Magnetic Resonance Imaging).MRI (Magnetic Resonance Imaging).

Sampling Sinus PetrosalSampling Sinus Petrosal - test terbaik utk membedakan penyebab Cushing’s - test terbaik utk membedakan penyebab Cushing’s

syndrome antara hipofisis dengan ektopik.syndrome antara hipofisis dengan ektopik. Test Dexametason – CRH Test Dexametason – CRH - membedakan Cushing’s syndrome dengan Pseudo - membedakan Cushing’s syndrome dengan Pseudo

Cushing’s Syndrome secara cepat.Cushing’s Syndrome secara cepat. - Peningkatan kadar kortisol selama test menunjukkan - Peningkatan kadar kortisol selama test menunjukkan

adanya Cushing’s Syndromeadanya Cushing’s Syndrome

Pseudo-Cushing's syndromePseudo-Cushing's syndrome is a is a medical condition in which patients display medical condition in which patients display the the signssigns, , symptomssymptoms, and abnormal , and abnormal hormone levels seen in Cushing's hormone levels seen in Cushing's syndrome. Pseudo-Cushing's syndrome, syndrome. Pseudo-Cushing's syndrome, however, is not caused by a problem with however, is not caused by a problem with the hypothalamic-pituitary-adrenal axis as the hypothalamic-pituitary-adrenal axis as Cushing's is. It is an idiopathic condition. Cushing's is. It is an idiopathic condition.

Pemeriksaan lab Pseudo Cushing Pemeriksaan lab Pseudo Cushing SyndrommeSyndromme

Levels of cortisol and ACTH are both high Levels of cortisol and ACTH are both high 24-hour urinary cortisol levels are high 24-hour urinary cortisol levels are high Dexamethasone suppression test fails to Dexamethasone suppression test fails to suppress serum cortisol suppress serum cortisol Loss of diurnal variation in cortisol levels- Loss Loss of diurnal variation in cortisol levels- Loss of Diurnal Variation is seen only in true of Diurnal Variation is seen only in true Cushing's Syndrome or Disease. Cushing's Syndrome or Disease. High mean corpuscular volume and gamma-High mean corpuscular volume and gamma-glutamyl transferase may be clues to alcoholism glutamyl transferase may be clues to alcoholism Polycystic Ovarian Syndrome should be ruled Polycystic Ovarian Syndrome should be ruled out, since PCOS has similar symptoms. out, since PCOS has similar symptoms.

Diagnosis banding=Differential Diagnosis banding=Differential diagnosisdiagnosis

Differentiation from Cushing's is extremely Differentiation from Cushing's is extremely difficult difficult

Causes of Cushing's should be excluded with Causes of Cushing's should be excluded with imaging of the lungs, adrenal glands, and imaging of the lungs, adrenal glands, and pituitary gland - but these often appear normal in pituitary gland - but these often appear normal in Cushing's anyway Cushing's anyway

In the alcoholic patient with pseudo-Cushing's, In the alcoholic patient with pseudo-Cushing's, admission to hospital (and avoidance of alcohol) admission to hospital (and avoidance of alcohol) will result in normal midnight cortisol levels will result in normal midnight cortisol levels within 5 days, excluding Cushing's[1] within 5 days, excluding Cushing's[1]

Diagnosa kerja utk menegakkan Diagnosa kerja utk menegakkan Cushing’s SyndromeCushing’s Syndrome

MRI pada adrenal tumorMRI pada adrenal tumor

Test utk mendiagnosa Cushing’s Test utk mendiagnosa Cushing’s syndromesyndrome

TestTest NormalNormal HyperplasiaHyperplasia AdenomaAdenoma CarcinomaCarcinoma

PlasmaPlasma

Kortisol Kortisol ((μμg/dL, g/dL, AM/PM)AM/PM)

17/817/8 / / / / / /

After low-After low-dose DSTdose DST

NormalNormal NormalNormal NormalNormal

After high-After high-dose DSTdose DST

/ Normal/ Normal NormalNormal NormalNormal

ACTH ACTH (pg/mL)(pg/mL)

10 - 8010 - 80

UrineUrine

Kortisol Kortisol ((μμg/24 h)g/24 h)

20 - 9020 - 90

Sasaran terapiSasaran terapi

Karena terjadi hiperkortisolisme Karena terjadi hiperkortisolisme maka maka sasaran terapinya adl menurunkan kadar sasaran terapinya adl menurunkan kadar kortisol plasmakortisol plasma

TERAPI TERAPI tergantung etiologi / penyebabtergantung etiologi / penyebab

Terapi farmakologi Terapi farmakologi obatobat

Terapi non farmakologiTerapi non farmakologitindakan bedah / tindakan bedah / operasi dan radiasioperasi dan radiasi

TERAPITERAPI

TreatmentTreatment

DosingDosing

EtiologyEtiology Non drugNon drug DrugDrug InitialInitial UsualUsual MaxMax

EctopicEctopic

ACTH ACTH syndromesyndrome

SurgerySurgery

ChemotherapyChemotherapy

IrradiationIrradiation

Metyrapone Metyrapone tabstabs

250 mg 250 mg

AminoglutetAminoglutethimide tabs, himide tabs, 250 mg 250 mg

1 – 1, 5 g/d, 1 – 1, 5 g/d, divided q4-6 hdivided q4-6 h

0,5-1 g/d, 0,5-1 g/d, divided 96 bid divided 96 bid – qid x 2 – qid x 2 weeksweeks

1 – 6 g/d, 1 – 6 g/d, divided q4-divided q4-6 h6 h

1 g/d, 1 g/d, divided q6divided q6

6 g/d6 g/d

2 g/d2 g/d

Pituitary Pituitary dependentdependent

SurgerySurgery

IrradiationIrradiationCyproheptadCyproheptadine, 2 mg/5 ine, 2 mg/5 mL syrup or mL syrup or 4 mg tabs4 mg tabs

Mitotane Mitotane tabs 500 mgtabs 500 mg

MetyraponeMetyrapone

4 mg bid4 mg bid

1-6 g/d, 1-6 g/d, increased by increased by 1-2 g/d q3-7d1-2 g/d q3-7d

See aboveSee above

24 – 32 24 – 32 mg/d., mg/d., divided qiddivided qid

9 – 10 g/d, 9 – 10 g/d, divided tid divided tid – qid– qid

See aboveSee above

32 mg/d32 mg/d

16 g/d16 g/d

See aboveSee above

Adrenal Adrenal adenomaadenoma

Surgery + Surgery + postoperative postoperative replacementreplacement

KetokonazolKetokonazole, tabs 200 e, tabs 200 mgmg

200 mg qd - 200 mg qd - bidbid

600 – 800 600 – 800 mg/d, mg/d, divided biddivided bid

1200 mg/d1200 mg/d

Adrenal Adrenal carcinomacarcinoma

SurgerySurgery MitotaneMitotane See aboveSee above See aboveSee above See aboveSee above

Terapi farmakologiTerapi farmakologi

Steroid inhibitorSteroid inhibitor

Adrenolitik agent Adrenolitik agent mitotanmitotan

Neuromodulator Neuromodulator agentagent

Antagonis reseptor Antagonis reseptor glukokortikoidglukokortikoid

Steroid InhibitorSteroid Inhibitor

Inhibitor steroid : metyrapone, aminogluthetimide, Inhibitor steroid : metyrapone, aminogluthetimide, ketokonazoleketokonazoleMetyrapone dan aminogluthetimide bila tdk kontinu, Metyrapone dan aminogluthetimide bila tdk kontinu, mempunyai efikasi terbatas mempunyai efikasi terbatas → shg digunakan sesudah → shg digunakan sesudah operasi.operasi.Metyrapone : menghambat aktivitas 11 – hydroxylase, Metyrapone : menghambat aktivitas 11 – hydroxylase, sehingga sintesis kortisol terhambat.sehingga sintesis kortisol terhambat.Setelah terapi akan diikuti dg peningkatan kadar ACTH Setelah terapi akan diikuti dg peningkatan kadar ACTH plasma, karena tjd penurunan mendadak kortisol.plasma, karena tjd penurunan mendadak kortisol.ES : mual, muntah, vertigo, sakit kepala, bingung, sakit ES : mual, muntah, vertigo, sakit kepala, bingung, sakit

perut, perut, rash.rash.

KetokonazoleKetokonazole

Antifungal derival imidazoleAntifungal derival imidazole

Mempunyai efektivitas tinggi menurunkan Mempunyai efektivitas tinggi menurunkan kortisolkortisol

Mek kerja : menghambat enzim sit P450 (11 – Mek kerja : menghambat enzim sit P450 (11 – hydroxylase dan 17- hydroxylase)hydroxylase dan 17- hydroxylase)

ES : ginekomastia & penurunan kadar ES : ginekomastia & penurunan kadar testoterone plasma testoterone plasma

ES umum : peningkatan transaminase hepatik ES umum : peningkatan transaminase hepatik (reversibel), ginekomastia, gangguan GI(reversibel), ginekomastia, gangguan GI

AminoglutethimideAminoglutethimide Pertama digunakan utk epilepsi, kmd sbg Pertama digunakan utk epilepsi, kmd sbg

inhibitor sintesis kortisol yg poteninhibitor sintesis kortisol yg poten Mek. Kerja : menghambat konversi Mek. Kerja : menghambat konversi

kolesterol mjd pregnenolon. Penurunan kolesterol mjd pregnenolon. Penurunan kortisol plasma sampai dg 50%kortisol plasma sampai dg 50%

ES : sedasi, mual, ataksia, dan skin rash.ES : sedasi, mual, ataksia, dan skin rash. Interaksi : dg warfarin akan menurunkan Interaksi : dg warfarin akan menurunkan

efek antikoagulan.efek antikoagulan. Indikasi : penggunaan jangka pendek Indikasi : penggunaan jangka pendek

Cushing’s disease dg sindrom ACTH Cushing’s disease dg sindrom ACTH ektopik, digunakan sbg kombinasi dg ektopik, digunakan sbg kombinasi dg metyrapone metyrapone → efektif pd cushing yg tdk dpt → efektif pd cushing yg tdk dpt dioperasi.dioperasi.

Adrenolytic agent mitotane (orto-para-Adrenolytic agent mitotane (orto-para-dichlorodiphenyl dichloroethane)dichlorodiphenyl dichloroethane)

Menghambat 11-hidroksilasi dari 11-desoksikortisol Menghambat 11-hidroksilasi dari 11-desoksikortisol dan 11-desoksikortikosteron pada korteks.dan 11-desoksikortikosteron pada korteks.

Menurunkan sekresi kortisol plasma, urin, 17-Menurunkan sekresi kortisol plasma, urin, 17-substitued kortisol.substitued kortisol.

Mitotane secara selektif menghambat fs Mitotane secara selektif menghambat fs adrenokortikal tanpa menyebabkan destruksi seluler.adrenokortikal tanpa menyebabkan destruksi seluler.

Karena tjd penurunan besar kortisol, perlu monitoring Karena tjd penurunan besar kortisol, perlu monitoring penurunan kortisol di RS.penurunan kortisol di RS.

ES : 80% pasien mengalami lethargi dan somnolen, ES : 80% pasien mengalami lethargi dan somnolen, 40% pasien dg ES CNS lainnya, hiperkolesterolemia.40% pasien dg ES CNS lainnya, hiperkolesterolemia.

Neuromodulator agentNeuromodulator agent

CyproheptadineCyproheptadine

BromocriptineBromocriptine

Valproic acidValproic acid

OctreotideOctreotide

CyproheptadineCyproheptadine

Menurunkan sekresi ACTHMenurunkan sekresi ACTH

Perlu monitoring kadar kortisol pada urin Perlu monitoring kadar kortisol pada urin 24 jam bebas kortisol24 jam bebas kortisol

ES : sedasi & hiperfagiaES : sedasi & hiperfagia

Respon Rate (RR)Respon Rate (RR) tidak lebih 30%, jadi tidak lebih 30%, jadi perlu dipantau kekambuhannyaperlu dipantau kekambuhannya

Antagonis reseptor glukokortikoidAntagonis reseptor glukokortikoid

RU-486 (mifepristone) adl antagonis RU-486 (mifepristone) adl antagonis reseptor progesteron dan reseptor progesteron dan glukokortikoid menghambat supresi glukokortikoid menghambat supresi deksametason dan deksametason dan

kortisol endogen.kortisol endogen.

SpironolactoneSpironolactoneantagonis kompetitif antagonis kompetitif aldosteron, memperbaiki hipertensi aldosteron, memperbaiki hipertensi & hipokalemia pada Cushing’s & hipokalemia pada Cushing’s syndromesyndrome

Terapi adenoma hipofisisTerapi adenoma hipofisis

1. 1. Dg pembedahan Dg pembedahan →transsphenoidal adenomectomy →transsphenoidal adenomectomy (tkt (tkt

keberhasilan 80%), penurunan ACTH sampai 2 tingkat keberhasilan 80%), penurunan ACTH sampai 2 tingkat di bwh Normaldi bwh Normal

Jk tjd penurunan drastis →suplai kortisol sintetik Jk tjd penurunan drastis →suplai kortisol sintetik (hidrokortison/prednison)(hidrokortison/prednison)

Jika pembedahan gagal → radioterapi (> 6 mgu), tkt Jika pembedahan gagal → radioterapi (> 6 mgu), tkt keberhasilan 40 – 50% pada dws, > 80% pada anak.keberhasilan 40 – 50% pada dws, > 80% pada anak.

2. Kombinasi radiasi dg Mitotane (Lysodren)2. Kombinasi radiasi dg Mitotane (Lysodren)Mitotane menekan produksi kortisol & menurun Mitotane menekan produksi kortisol & menurun

kadarnyakadarnya dlm plasma dan urine, 30 – 40 % pasien berhasildlm plasma dan urine, 30 – 40 % pasien berhasil3. Aminoglutethimide, Metyrapone, Trilostane & 3. Aminoglutethimide, Metyrapone, Trilostane &

Ketokonazole → ada ESKetokonazole → ada ES

Terapi sindroma ACTH ektopikTerapi sindroma ACTH ektopik

Prinsip terapi : eliminasi semua Prinsip terapi : eliminasi semua jaringan kanker penghasil ACTH jaringan kanker penghasil ACTH (misal sel kanker paru)(misal sel kanker paru)

PembedahanPembedahanRadioterapiRadioterapiKemoterapiKemoterapi ImunoterapiImunoterapiKombinasi Kombinasi →tgt tipe dan luas kanker→tgt tipe dan luas kanker

Tumor adrenalTumor adrenal

Dg :Dg : Pembedahan Pembedahan

adrenolectomyadrenolectomy Pada Primary Pada Primary

Pigmented Pigmented Micronodular Adrenal Micronodular Adrenal Disease dan Carney’s Disease dan Carney’s Complex dg Complex dg pembedahan kel. pembedahan kel. Adrenal.Adrenal.

Learn How to Treat Cushing's SyndromeLearn How to Treat Cushing's Syndrome

1Cushing's syndrome may be caused in different ways and 1Cushing's syndrome may be caused in different ways and categorized accordingly. Long-term use of steroids (such as categorized accordingly. Long-term use of steroids (such as prednisone) or adrenal abnormalities can cause the disease to prednisone) or adrenal abnormalities can cause the disease to surface. However, pituitary adenomas (benign tumors) are to blame surface. However, pituitary adenomas (benign tumors) are to blame in most cases, and this condition is referred to as Cushing's in most cases, and this condition is referred to as Cushing's disease. In other cases, ectopic ACTH syndrome is at disease. In other cases, ectopic ACTH syndrome is at workwork, which , which means malignant tumors have formed on the pituitary, causing a means malignant tumors have formed on the pituitary, causing a domino reaction of ACTH and cortisol release.domino reaction of ACTH and cortisol release.2The exact reason your body is producing too much cortisol will 2The exact reason your body is producing too much cortisol will determine how to treat the disease. Conventional treatments include determine how to treat the disease. Conventional treatments include radiation, chemotherapy, administration of cortisol-inhibiting drugs radiation, chemotherapy, administration of cortisol-inhibiting drugs and/or surgery.and/or surgery.3Pituitary adenomas are usually treated by a surgical procedure 3Pituitary adenomas are usually treated by a surgical procedure called a transsphenoidal adenomectomy, which has a better than 80 called a transsphenoidal adenomectomy, which has a better than 80 percent success rate. The pituitary gland is accessed through the percent success rate. The pituitary gland is accessed through the nose via a thin tube containing a microscope, and tiny instruments nose via a thin tube containing a microscope, and tiny instruments are used to remove the tumor.are used to remove the tumor.

Cont’dCont’d

4Be aware that surgery on the pituitary may cause ACTH levels to 4Be aware that surgery on the pituitary may cause ACTH levels to fall below normal, which is typical. Therefore, it may become fall below normal, which is typical. Therefore, it may become necessary to follow up with administration of a synthetic form of necessary to follow up with administration of a synthetic form of cortisol, such as hydrocortisone or prednisone.cortisol, such as hydrocortisone or prednisone.5Expect that radiotherapy or a combination of radiation therapy and 5Expect that radiotherapy or a combination of radiation therapy and medication may be necessary if you're not a good candidate for medication may be necessary if you're not a good candidate for surgery. While radiation works to shrink tumors, drugs such as surgery. While radiation works to shrink tumors, drugs such as mitotane (Lysodren) help to inhibit cortisol production.mitotane (Lysodren) help to inhibit cortisol production.6Know that there are several medications used to control cortisone 6Know that there are several medications used to control cortisone secretion, including mitotane, aminoglutethimide, metyrapone, secretion, including mitotane, aminoglutethimide, metyrapone, trilostane and ketoconazole.trilostane and ketoconazole.

Read more: Read more: How to Treat Cushing's Syndrome | How to Treat Cushing's Syndrome | eHow.comeHow.com http://www.ehow.com/how_2048201_treat-cushings-syndrome.htmlhttp://www.ehow.com/how_2048201_treat-cushings-syndrome.html#ixzz12pFKoNXq#ixzz12pFKoNXq

Monitoring terapiMonitoring terapi

Kadar kortisol serum pada pemeriksaan Kadar kortisol serum pada pemeriksaan urin 24 jam bebas kortisolurin 24 jam bebas kortisol

Perbaikan gejala & manifestasi klinik Perbaikan gejala & manifestasi klinik Cushing’syndromeCushing’syndrome

Risiko kekambuhan terutama utk obat2 dg Risiko kekambuhan terutama utk obat2 dg RR yg rendahRR yg rendah

Penderita Cushing’s sebelum pembedahanPenderita Cushing’s sebelum pembedahan

Penderita Cushing’s sesudah pembedahanPenderita Cushing’s sesudah pembedahan

Sesudah pembedahan & sebelum Sesudah pembedahan & sebelum pembedahanpembedahan

Adrenocortical carcinoma in infantAdrenocortical carcinoma in infant

The patient is a Caucasian female born at term with a The patient is a Caucasian female born at term with a birth weight of 3.06 kg; pregnancy and delivery were birth weight of 3.06 kg; pregnancy and delivery were uncomplicated. At six months of age, she was referred to uncomplicated. At six months of age, she was referred to pediatric endocrine clinic due to features of Cushing pediatric endocrine clinic due to features of Cushing syndrome. She had a three month history of progressive syndrome. She had a three month history of progressive Cushingoid facies, acne and irritability. Her linear growth Cushingoid facies, acne and irritability. Her linear growth apparently had been arrested between three and six apparently had been arrested between three and six months of age, although she gained weight at an months of age, although she gained weight at an accelerated rate. Prior to referral, laboratory evaluation accelerated rate. Prior to referral, laboratory evaluation by her primary care physician revealed serum cortisol of by her primary care physician revealed serum cortisol of 240240 mcg/dl (normal, 4.5–22.7 mcg/dl); total testosterone  mcg/dl (normal, 4.5–22.7 mcg/dl); total testosterone of 185 ng/dl (normal, 6–77ng/dl), and DHEA-S of 401 of 185 ng/dl (normal, 6–77ng/dl), and DHEA-S of 401 mcg/dl (normal, 16–96 mcg/dl). Serum ACTH was less mcg/dl (normal, 16–96 mcg/dl). Serum ACTH was less than 5 pg/ml (normal, 10–60 pg/ml). than 5 pg/ml (normal, 10–60 pg/ml).

Her weight at initial evaluation in our clinic at six months of age was 7.52Her weight at initial evaluation in our clinic at six months of age was 7.52 kg  kg (60–75th percentile) and length was 59.1 cm (< 5th percentile). Blood (60–75th percentile) and length was 59.1 cm (< 5th percentile). Blood pressure was 110/70 mmHg. Physical examination showed Cushingoid pressure was 110/70 mmHg. Physical examination showed Cushingoid facies, buffalo hump, facial acne, and poor muscle tone (Figure 2). There facies, buffalo hump, facial acne, and poor muscle tone (Figure 2). There were no signs of virilization. Family history was noncontributory. were no signs of virilization. Family history was noncontributory. Physical examination of the patient revealed features of Cushing Syndrome Physical examination of the patient revealed features of Cushing Syndrome including round facies, acne, plethora, central obesity, and poor muscle including round facies, acne, plethora, central obesity, and poor muscle tone; she lacked clitoromegaly, hirsutism or other signs of virilization.tone; she lacked clitoromegaly, hirsutism or other signs of virilization.An MRI of the abdomen showed a heterogeneous right adrenal mass An MRI of the abdomen showed a heterogeneous right adrenal mass measuring 3.6×5.4×3.8 cm; this mass was found to extend as a tumor measuring 3.6×5.4×3.8 cm; this mass was found to extend as a tumor thrombus into the inferior vena cava. The tumor thrombus appeared to thrombus into the inferior vena cava. The tumor thrombus appeared to extend to approximately 2 cm from the right atrium. There were no extend to approximately 2 cm from the right atrium. There were no metastases seen in the liver or lungs on MRI. A Doppler ultrasound showed metastases seen in the liver or lungs on MRI. A Doppler ultrasound showed minimal, but present flow around the IVC tumor thrombus which measured minimal, but present flow around the IVC tumor thrombus which measured 2.5×0.9×1 cm. Laboratory evaluation showed serum cortisol 70.8 mcg/dl 2.5×0.9×1 cm. Laboratory evaluation showed serum cortisol 70.8 mcg/dl (normal, 4.5–22.7 mcg/dl); aldosterone 4.2 ng/dl (normal 6.5–86.0 ng/dl); (normal, 4.5–22.7 mcg/dl); aldosterone 4.2 ng/dl (normal 6.5–86.0 ng/dl); testosterone 59 ng/dl (normal, 6–77 ng/dl); ACTH <5 (normal, 10–60 pg/ml).testosterone 59 ng/dl (normal, 6–77 ng/dl); ACTH <5 (normal, 10–60 pg/ml).