PENYAKIT KELENJAR

ADRENAL
- Cushing’s Syndrome -
OLEH :
Woro Harjaningsih
 Definisi
adalah kondisi klinik sebagai akibat dari paparan
kronik glukokortikoid menyebabkan kadar
glukokortikoid dlm sirkulasi berlebihan.
disebut juga sebagai
hiperadrenokortikalisme
Hiperadrenalkortikalisme
Hiperkortisolisme
Penyebab paling umum : sekresi berlebih ACTH
dari kelenjar hipofisis anterior (Cushing’s
disease)
 ETIOLOGI
A. Cushing’s disease :
Dapat tjd :
secara spontan  cushing’s syndrome
spontaneous atau , merupakan penyebab
terbesar, kejadian kira2 2 – 4 kasus / juta
populasi dan pd wanita 9 X lebih banyak drpd
laki-laki
sebagai hasil pemberian kronik (jangka
panjang) kortikosteroid  Cushing’s syndrome
iatrogenic
Spontaneous cushing’s syndrome / Cushing’s
disease bisa tjd akibat :
Adenoma hipofisis sekresi berlebih ACTH (>
90%)
Hiperplasia difuse / pituitary corticotroph cells yg
bertanggung jawab thdp hipersekresi ACTH
Hiperplasia kmk krn hipersekresi CRH oleh
hipotalamus atau tumor pensekresi CRH (CRH-
secreting tumors)
Hipersekresi kronik CRH tidak menyebabkan
adenoma hipofisis
B. Ectopic ACTH Syndrome
Tumor non hipofisis mensintesis &
mensekresikan secara berlebih
(hipersekresi) ACTH yg aktif secara biologi
atau peptida menyerupai ACTH (ACTH-
like peptide)
Biasanya karsinoma sel kecil dari paru
atau tumor karsinoid dari bronkhial
Lebih banyak menyerang laki-laki
C. ECTOPIC CRH Syndrome
Sangat jarang menyebabkan Cushing’s
Syndrome
Sebagian besar kasus berhub dg tumor
karsinoid bronkhial
D. Functioning Adrenocortical Tumors
Baik adrenocortical adenoma dan
carcinoma menyebabkan Cushing’s
syndrome melalui pengeluaran kortisol
secara autonom
Adenoma memp vaskuler yang tinggi,
dengan area nekrosis, perdarahan,
degenerasi kista dan kalsifikasi bisa
metastase ke ginjal, retroperitoneum, liver
dan paru
E. Adrenal Micronodular Hyperplasia
Jarang menyebabkan Cushing’s
Syndrome
Sekitar separuh kasus timbul secara
mendadak pada anak2 dan dewasa muda
F. Adrenal Macronodular Hyperplasia
Jarang menyebabkan Cushing’s
Syndrome
Beberapa pasien dg macronodular
hyperplasia tidak menunjukkan gambaran
cushingoid tipikal
Patofisiologi
 Patofisiologi
Penyebab dapat dibagi 2 kategori :
ACTH-dependent peningkatan kadar
kortisol tergantung pada ACTH dan tidak
dapat menekan sekresi ACTH dari
hipofisis
ACTH-independent peningkatan kadar
kortisol tidak tergantung ACTH (autonom)
dan dapat menekan sekresi ACTH dari
hipofisis
 Klasifikasi

 ACTH dependent
Cushing’s disease
Ectopic ACTH syndrome
Ectopic corticotropin-releasing hormone syndrome*
 ACTH independent
Iatrogenic
Adrenal adenoma
Micronodular hyperplasia*
Macronodular hyperplasia*

Ket : ACTH : Adrenocorticotropin hormone

* : accounts per 1 percent or less of cases
(Adapted with permission from Orth DN Cushing’s Syndrome. N Engl. J.
Med, 1995 ; 332 : 791 – 803)
 ACTH-dependent Cushing’s syndrome :
~ Cushing’s disease 80% kasus ACTH-
dependent
~ Ectopic ACTH hypersecretion 20%
~ Ectopic CRH secretion jarang
Dimana kesemuanya ditandai dg
hipersekresi ACTH kronik dan
peningkatan sekresi kortisol
 ACTH-independent Cushing’s syndrome :
~ Glucocorticoid-secreting adrenocortical
adenoma dan carcinoma
~ Adrenal micronodular dan macronodular
hyperplasia
Kesemuanya ditandai dg sekresi secara
autonom kortisol dan penekanan ACTH
hipofisis
 Adrenal tumor
Carcinoma dan adrenal
adenoma primer tidak di
bawah kendali
hipotalamus-hipofisis dan
kmd secara autonom
mensekresikan lebih
kortisol
Hiperkortisol menekan
produksi ACTH hipofisis
menyebabkan atrofi
korteks adrenal
Manifestasi Klinik
 FUNGSI KORTISOL

 Memelihara tekanan darah dan fungsi kardiovaskuler.

 Menurunkan respon inflamasi sistem imun.
 Menyeimbangkan efek insulin dalam memecah glukosa
untuk energi.
 Mengatur metabolisme protein, karbohidrat, dan lemak.
 Fungsi terpenting : membantu tubuh terhadap respon
stress.
(kadar kortisol wanita pada kehamilan 3 bln terakhir dan
atlit secara normal tinggi).
dmk juga pada orang2 dg depresi, alkoholisme, malnutrisi
dan gangguan panik.
 GEJALA

 Obesitas tubuh bagian atas, muka bulat, peningkatan lemak sekitar

leher, lengan dan kaki kurus, pada anak-anak pertumbuhan lambat.
 Gejala lain : kulit fragile, kurus, memar dan tidak sehat, kulit warna
ungu pink pada perut, paha, lengan dan payudara.(striae)
 Tulang rapuh dan bengkok, patah tulang (fraktur) pada tulang rusuk
(iga) dan tulang belakang.
 Sangat lelah, otot lemah, tek. darah dan kadar gula darah tinggi,
irritabilitas, ansietas, depresi.
 Pertumbuhan rambut pada muka, leher, dada, perut dan paha (pada
wanita)
Periode menstruasi tidak teratur/ terhenti.
 Penurunan libido sex pada laki-laki
Penderita Cushing’s Syndrome
Penderita Cushing’s Syndrome anak
 Gejala Cushing’s Syndrome
Striae pada abdomen dan payudara
Moonface
Moonface
Striae pada stomach
Striae
Pertumbuhan rambut pada dada
Striae pada lengan
Striae pada siku
Buffalohump (punggung menebal)
Buffalohump (punggung menebal)
Exogenous Cushing Syndromme
 DIAGNOSIS

 Berdasarkan tinjauan riwayat medis pasien, pemeriksaan fisik, dan

test lab.
X ray : utk menentukan lokasi tumor.
 24 urin 24 jam bebas kortisol
paling spesifik, kadar > 50 – 100 µg / hari utk dewasa cushing’s
syndrome
 Test Supresi Dexametason
utk membedakan peningkatan ACTH karena adenoma hipofisis dan
tumor ektopik.
 Test Stimulasi CRH
utk membedakan antara adenoma hipofisis dengan sindroma ACTH
ektopik atau tumor adrenal penghasil kortisol
 DIAGNOSIS

 Visualisasi langsung Kelenjar Endokrin (Imaging Radiologi)

- melihat ukuran dan bentuk kelenjar hipofisis dan adrenal serta
menentukan jika ada tumor.
- dengan CT ( Computerized Tomography) scan dan MRI
(Magnetic Resonance Imaging).
 Sampling Sinus Petrosal
- test terbaik utk membedakan penyebab Cushing’s syndrome
antara hipofisis dengan ektopik.
 Test Dexametason – CRH
- membedakan Cushing’s syndrome dengan Pseudo Cushing’s
Syndrome secara cepat.
- Peningkatan kadar kortisol selama test menunjukkan adanya
Cushing’s Syndrome
Pseudo-Cushing's syndrome is a
medical condition in which patients display
the signs, symptoms, and abnormal
hormone levels seen in Cushing's
syndrome. Pseudo-Cushing's syndrome,
however, is not caused by a problem with
the hypothalamic-pituitary-adrenal axis as
Cushing's is. It is an idiopathic condition.
Pemeriksaan lab Pseudo Cushing
Syndromme
Levels of cortisol and ACTH are both high
24-hour urinary cortisol levels are high
Dexamethasone suppression test fails to
suppress serum cortisol
Loss of diurnal variation in cortisol levels- Loss
of Diurnal Variation is seen only in true
Cushing's Syndrome or Disease.
High mean corpuscular volume and gamma-
glutamyl transferase may be clues to alcoholism
Polycystic Ovarian Syndrome should be ruled
out, since PCOS has similar symptoms.
 Diagnosis banding=Differential
diagnosis
Differentiation from Cushing's is extremely
difficult
Causes of Cushing's should be excluded with
imaging of the lungs, adrenal glands, and
pituitary gland - but these often appear normal in
Cushing's anyway
In the alcoholic patient with pseudo-Cushing's,
admission to hospital (and avoidance of alcohol)
will result in normal midnight cortisol levels
within 5 days, excluding Cushing's[1]
Diagnosa kerja utk menegakkan
Cushing’s Syndrome
MRI pada adrenal tumor
 Test utk mendiagnosa Cushing’s
syndrome
Test Normal Hyperplasia Adenoma Carcinoma

Plasma

Kortisol 17/8 /  /   /

(μg/dL, 
AM/PM)
After low-  Normal Normal Normal
dose DST
After high-   / Normal Normal Normal
dose DST
ACTH 10 - 80   
(pg/mL)
Urine

Kortisol 20 - 90   
(μg/24 h)
 Sasaran terapi
Karena terjadi hiperkortisolisme maka
sasaran terapinya adl menurunkan kadar
kortisol plasma

TERAPI tergantung etiologi / penyebab

Terapi farmakologi obat
Terapi non farmakologitindakan bedah /
operasi dan radiasi
 TERAPI
Treatment

Dosing
Etiology Non drug Drug Initial Usual Max
Ectopic Surgery Metyrapone 1 – 1, 5 g/d, 1 – 6 g/d, 6 g/d
ACTH syndrome Chemotherapy tabs divided q4-6 h divided q4-6
250 mg h
Irradiation
Aminoglutethi 0,5-1 g/d, 1 g/d,
2 g/d
mide tabs, 250 divided 96 bid – divided q6
mg qid x 2 weeks
Pituitary Surgery Cyproheptadin 4 mg bid 24 – 32 32 mg/d
dependent Irradiation e, 2 mg/5 mL mg/d.,
syrup or 4 mg divided qid
tabs
Mitotane tabs
500 mg 1-6 g/d, 16 g/d
increased by 1-2 9 – 10 g/d,
g/d q3-7d divided tid –
Metyrapone See above qid
See above See above

Adrenal Surgery + Ketokonazole, 200 mg qd - bid 600 – 800 1200 mg/d

adenoma postoperative tabs 200 mg mg/d,
replacement divided bid
Adrenal Surgery Mitotane See above See above See above
 Terapi farmakologi
Steroid inhibitor
Adrenolitik agent
mitotan
Neuromodulator
agent
Antagonis reseptor
glukokortikoid
 Steroid Inhibitor

Inhibitor steroid : metyrapone, aminogluthetimide,

ketokonazole
Metyrapone dan aminogluthetimide bila tdk kontinu,
mempunyai efikasi terbatas → shg digunakan sesudah
operasi.
Metyrapone : menghambat aktivitas 11 – hydroxylase,
sehingga sintesis kortisol terhambat.
Setelah terapi akan diikuti dg peningkatan kadar ACTH
plasma, karena tjd penurunan mendadak kortisol.
ES : mual, muntah, vertigo, sakit kepala, bingung, sakit perut,
rash.
 Ketokonazole
Antifungal derival imidazole
Mempunyai efektivitas tinggi menurunkan
kortisol
Mek kerja : menghambat enzim sit P450 (11 –
hydroxylase dan 17- hydroxylase)
ES : ginekomastia & penurunan kadar
testoterone plasma
ES umum : peningkatan transaminase hepatik
(reversibel), ginekomastia, gangguan GI
Aminoglutethimide
 Pertama digunakan utk epilepsi, kmd sbg inhibitor
sintesis kortisol yg poten
 Mek. Kerja : menghambat konversi kolesterol mjd
pregnenolon. Penurunan kortisol plasma sampai
dg 50%
 ES : sedasi, mual, ataksia, dan skin rash.
 Interaksi : dg warfarin akan menurunkan efek
antikoagulan.
 Indikasi : penggunaan jangka pendek Cushing’s
disease dg sindrom ACTH ektopik, digunakan sbg
kombinasi dg metyrapone → efektif pd cushing yg
tdk dpt dioperasi.
 Adrenolytic agent mitotane (orto-para-
dichlorodiphenyl dichloroethane)

 Menghambat 11-hidroksilasi dari 11-desoksikortisol dan

11-desoksikortikosteron pada korteks.
 Menurunkan sekresi kortisol plasma, urin, 17-substitued
kortisol.
 Mitotane secara selektif menghambat fs adrenokortikal
tanpa menyebabkan destruksi seluler.
 Karena tjd penurunan besar kortisol, perlu monitoring
penurunan kortisol di RS.
 ES : 80% pasien mengalami lethargi dan somnolen, 40%
pasien dg ES CNS lainnya, hiperkolesterolemia.
 Neuromodulator agent
Cyproheptadine
Bromocriptine
Valproic acid
Octreotide
 Cyproheptadine
Menurunkan sekresi ACTH
Perlu monitoring kadar kortisol pada urin
24 jam bebas kortisol
ES : sedasi & hiperfagia
Respon Rate (RR) tidak lebih 30%, jadi
perlu dipantau kekambuhannya
 Antagonis reseptor glukokortikoid

RU-486 (mifepristone) adl antagonis

reseptor progesteron dan glukokortikoid
menghambat supresi deksametason dan
kortisol endogen.
Spironolactoneantagonis kompetitif
aldosteron, memperbaiki hipertensi &
hipokalemia pada Cushing’s syndrome
 Terapi adenoma hipofisis
1. Dg pembedahan →transsphenoidal adenomectomy (tkt
keberhasilan 80%), penurunan ACTH sampai 2 tingkat di bwh
Normal
Jk tjd penurunan drastis →suplai kortisol sintetik
(hidrokortison/prednison)
Jika pembedahan gagal → radioterapi (> 6 mgu), tkt
keberhasilan 40 – 50% pada dws, > 80% pada anak.
2. Kombinasi radiasi dg Mitotane (Lysodren)
Mitotane menekan produksi kortisol & menurun kadarnya
dlm plasma dan urine, 30 – 40 % pasien berhasil
3. Aminoglutethimide, Metyrapone, Trilostane &
Ketokonazole → ada ES
 Terapi sindroma ACTH ektopik
Prinsip terapi : eliminasi semua jaringan kanker
penghasil ACTH (misal sel kanker paru)
 Pembedahan
 Radioterapi
 Kemoterapi
 Imunoterapi
 Kombinasi →tgt tipe dan luas kanker
 Tumor adrenal
Dg :
 Pembedahan
adrenolectomy
 Pada Primary
Pigmented Micronodular
Adrenal Disease dan
Carney’s Complex dg
pembedahan kel.
Adrenal.
 Learn How to Treat Cushing's Syndrome

1Cushing's syndrome may be caused in different ways and

categorized accordingly. Long-term use of steroids (such as
prednisone) or adrenal abnormalities can cause the disease to
surface. However, pituitary adenomas (benign tumors) are to blame
in most cases, and this condition is referred to as Cushing's
disease. In other cases, ectopic ACTH syndrome is at work, which
means malignant tumors have formed on the pituitary, causing a
domino reaction of ACTH and cortisol release.
2The exact reason your body is producing too much cortisol will
determine how to treat the disease. Conventional treatments include
radiation, chemotherapy, administration of cortisol-inhibiting drugs
and/or surgery.
3Pituitary adenomas are usually treated by a surgical procedure
called a transsphenoidal adenomectomy, which has a better than 80
percent success rate. The pituitary gland is accessed through the
nose via a thin tube containing a microscope, and tiny instruments
are used to remove the tumor.
 Cont’d
4Be aware that surgery on the pituitary may cause ACTH levels to
fall below normal, which is typical. Therefore, it may become
necessary to follow up with administration of a synthetic form of
cortisol, such as hydrocortisone or prednisone.
5Expect that radiotherapy or a combination of radiation therapy and
medication may be necessary if you're not a good candidate for
surgery. While radiation works to shrink tumors, drugs such as
mitotane (Lysodren) help to inhibit cortisol production.
6Know that there are several medications used to control cortisone
secretion, including mitotane, aminoglutethimide, metyrapone,
trilostane and ketoconazole.

Read more: How to Treat Cushing's Syndrome | eHow.com

http://www.ehow.com/how_2048201_treat-cushings-syndrome.html
#ixzz12pFKoNXq
 Monitoring terapi
Kadar kortisol serum pada pemeriksaan
urin 24 jam bebas kortisol
Perbaikan gejala & manifestasi klinik
Cushing’syndrome
Risiko kekambuhan terutama utk obat2 dg
RR yg rendah
Penderita Cushing’s sebelum pembedahan
Penderita Cushing’s sesudah pembedahan
Sesudah pembedahan & sebelum pembedahan
Adrenocortical carcinoma in infant
The patient is a Caucasian female born at term with a
birth weight of 3.06 kg; pregnancy and delivery were
uncomplicated. At six months of age, she was referred to
pediatric endocrine clinic due to features of Cushing
syndrome. She had a three month history of progressive
Cushingoid facies, acne and irritability. Her linear growth
apparently had been arrested between three and six
months of age, although she gained weight at an
accelerated rate. Prior to referral, laboratory evaluation
by her primary care physician revealed serum cortisol of
240 mcg/dl (normal, 4.5–22.7 mcg/dl); total testosterone
of 185 ng/dl (normal, 6–77ng/dl), and DHEA-S of 401 
mcg/dl (normal, 16–96 mcg/dl). Serum ACTH was less
than 5 pg/ml (normal, 10–60 pg/ml).
Her weight at initial evaluation in our clinic at six months of age was 7.52 kg
(60–75th percentile) and length was 59.1 cm (< 5th percentile). Blood
pressure was 110/70 mmHg. Physical examination showed Cushingoid
facies, buffalo hump, facial acne, and poor muscle tone (Figure 2). There
were no signs of virilization. Family history was noncontributory.
Physical examination of the patient revealed features of Cushing Syndrome
including round facies, acne, plethora, central obesity, and poor muscle
tone; she lacked clitoromegaly, hirsutism or other signs of virilization.
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
thrombus into the inferior vena cava. The tumor thrombus appeared to
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
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
(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).