1 PEMERIKSAAN LABORATORIUM DAN INTERPRETASI PADA GROWTH RETARDATION Prof. dr. Burhanuddin Nst. SpPK (K)

2 Pendahuluan Masa anak-anak adalah waktu untuk tumbuh, merupakan proses komplek dan melibatkan interaksi banyak faktor. Pertumbuhan adalah biasa untuk organisme multicellular dan terjadi dengan cara pembelahan sel dan pembesaran sel dan organ differensiasi

3 Perkembangan morfologi secara menyeluruh dan kecepatan pembelahan sel pada berbagai organ pada waktu yang berbeda dan outcome yang diperoleh ditentukan oleh komposisi genetik dari seseorang dan berinteraksi dengan faktor-faktor eksternal, termasuk nutrisi, psikososial dan faktor ekonomi

4 Fase-fase pertumbuhan normal Pertumbuhan terjadi pada kecepatan berbeda-beda selama masa : - Intra uterine - Masa awal dan pertengahan Childhood dan - Masa adolescene Pertumbuhan pre-natal rata-rata 1,2-1,5 cm/minggu

5 Midgestational length growth velocity dari 2,5 cm/minggu turun menjadi 0,5 cm/minggu, segera akan lahir Kecepatan pertumbuhan rata-rata ± 15 cm/tahun, selama 2 tahun pertama kehidupan, dan perlahan menjadi 6 cm/tahun selama middlle childhood

6 Growth Retardation (GR) GR diklasifikasikan sbb: I.Primary Growth Abnormalities A. Osteochondrodysplasia B. Chromosomal abnormalities C. Intra Uterine Growth Retardation

7 II. Secondary Growth Disorders A. Malnutrition B. Chronic Disease C. Endocrine Disorders

8 Sambungan..... C. Endocrine Disorders 1. Hypothyroidism 2. Cushing’s Syndrome 3. Pseudohypo Parathyroidism 4. Rickets a vitamin D resistant rickets 5. IGF deficiensy a. GHD due to Hypothalamic dysfunction b. GHD due to pituitary GH deficiency

9 c. GH resistance 1. Primary GH insensitivity 2. Secondary GH insensitivity d. Primary defects of IGF transport& clearance e. IGF Insensitivity 1. Defect of the type I/GF receptor 2. Post receptor defect III. Idiopathic Short Stature Sambungan.....

10 Excess Growth and Tall Stature Fetal IGF II Post natal Excess GH secretion Hyperthyroidism Adult androgen or estrogen deficiency Testicular feminization Excess GH

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12 Hypothyroidism Hypothyroidism is the disease caused by insufficient production of thyroid hormone by the thyroid gland. Cretinism is a form of hypothyroidism found in infants.

13 How To Diagnostic Hypothyroidism ? To diagnose hypothyroidism, – TSH↑, FT4↓  Primary Hipothyroidism – TSH↓, FT4↓, FT3 N ↓  Secondary Hipothyroidism – TSH↓, FT4 N, FT3↓  Secondary Hipothyroidism – Suppression of thyrotropin-releasing hormon ( TRH )  ( Tertiary Hipothyroidism ) If the TSH is normal and hypothyroidism is still suspected. blood testing ; – Free triiodothyronine (fT3) – Free levothyroxine (fT4) – Total T3 – Total T4

14 The following measurements may be needed: 24 hour urine free T3 Antithyroid antibodies — for evidence of autoimmune diseases that may be damaging the thyroid gland Serum cholesterol — which may be elevated in hypothyroidism Prolactin — as a widely available test of pituitary function Testing for anemia, including ferritin Basal body temperature

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16 Hipotiroid (FF), Laboratorium - T3 menurun - T4 menurun - TSH normal Hipertiroid : - T3 meningkat → T3 Tirotoksikosis - T4 meningkat → T4 Tirotoksikosis

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18 Pendekatan untuk penderita Hypothyroidism (FF) Sign/symtoms Hypothyoridism TSH Level FT4 or FT4I TSH  FT4  or FT4I TSH (N) or  FT4  or FT4I  TSH (N) FT4(N) or FT4I(N) TSH  FT4(N) or FT4I(N) Primary Hypothyroidism Consider Central Hypothyroidism Consider other Causes of patients Sign & symtoms Subclinical Hypothyroidism Yes

19 Sign & Symtoms Hypothyroidism Weakness Dry skin Edema Eye Lids Cold skin Memory  Constipation Weight gain Loss of hair Anorexia Nervousness Sweating  Parasthesia

20 Hyperthyroidism Hyperthyroidism is the term for overactive tissue within the thyroid gland, resulting in overproduction and thus an excess of circulating free thyroid hormones: thyroxine (T4), triiodothyronine (T3), or both

21 TSH↓, FT4↑  Hiperthyroidism. – Excessive iodide intake – Overmedication  chronic oral thyroxine – Graves’ desease / toxic goiter TSH↓, FT4 normal, FT3↑  Thyrotoxicosis TSH↑, FT4 ↑  TSH secreting tumor anti-TSH-receptor antibodies anti-thyroid-peroxidase How To Diagnostic Hyperthyroidism ?

22 Pendekatan untuk penderita Hyperthyroidism Sign/symtoms Hyperthyoridism TSH Level FT4 or FT4I TSH  FT4  or FT4I  TSH  FT4  or FT4I  TSH (N) FT4(N) or FT4I(N) TSH  FT4(N) or FT4I(N) Hyperthyroidism Consider TSH Producing Adenoma Consider other Causes of patients Sign & symtoms T3 Yes N  Subclinical Hiperthyroid T3 Thyrotoxicosis Diffuse goiter + bruit Opthalmopathy Pretibial oedema YesNo Gvave Disease Perform Radioactive Iodine Uptake test

23 Sign & Symptoms Hyperthyroidism Nervousness Emotional lability Tremor Palpitations Fatigue Weight loss Tachycardia Atrial Fibrilasi  diff systole & diastole BP Diarrhea Prox. Muscle weakness Heart intolerance Moist skin Fine hair Hair loss Weakness Increase appetite

24 Cushing's syndrome Cushing's syndrome (hyperadrenocorticism or hypercorticism) is a hormone (endocrine) disorder caused by high levels of cortisol (hypercortisolism) in the blood. There are several possible causes of Cushing's syndrome. – Hormones that come from outside the body are called exogenous ( glucocorticoid drugs ) – hormones that come from within the body are called endogenous. ( tumors that produce cortisol or adrenocorticotropic hormone (ACTH). )

25 The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH)  Pituitary gland to release adrenocorticotropin (ACTH)  Adrenal gland (zona fasciculata )  (cortisol). Elevated levels of cortisol exert negative feedback on the pituitary.

26 Laboratory Diagnostic Dexamethasone suppression test 24-hour urinary measurement for cortisol Cortisol in saliva over 24 hours

27 Cushing Syndrome (CS) CS results prolong Exposure to excessive amounts of endogenous or exogenous corticosteroids Kadar Cortisol plasma lebih besar dari 7 ug/dl (200nmol/L) pada midnight Organ normal : - Paling tinggi pagi hari, malam meningkat sedikit (2ug/dl)

28 - False positif : Stress (vena puncture), Penyakit berulang-ulang, takut Free Cortisol urin : - Metabolisme cortisol di urin : 17 hydrocorticosteroid atau 17 exogenicsteroid - Normal ug/24 jam - Bisa normal 8-15% penderita Sambungan.....

29 Dexamethazon Suppression Test 1 mg dexamethazon diberi tengah malam Pada jam antara 08-09, bila response normal kadar plasma cortisol < 5 ug/dl Cushing Syndrome ACTH dependent ACTH independent

30 Kadar ACTH antara PM > 23 pg/dl → ACTH dependent Pemeriksaan ACTH dgn Imunoradiometric Klinis : - Centripetal Obesity + Buffalo Hump - Moonface - Hirsutism

31 Cushing’s Syndrome Sign & Symtoms Present Perform Screening test for CS 24 hours urin collection for Cortisol or Over night 1 mg DST 24 hours urin CortisolPerform over night 1 mg DST Cortisol > 5 ug/dl Cushing’s Syndromel Plasma ACTH Cortisol (N) Cortisol ↑ But not > 3.5X Upper limit normal Consider Alternative diagnosis Cortisol ↑ > 3.5X Upper limit normal Futher evaluation To differentiate Cushing’s from pseudocushing Cushing’s Syndrome Perform one of the following: -Dexamethazon-CHR test -Midnight serum cortisol -Late night salivary cortisol Results consistent with Cushing’s Results consistent with pseudocushing’s Stop >10-15 pg/dl  A < 5 pg/dl, consider Adrenal causes of CS Perform CT / MRI Adrenal Gland

32 A. Plasma ACTH Plasma ACTH Perform High Dose DST (8 mg Dexamethazon) > pg/dl Ectopic ACTH Screening tumor Cushing’s Disease Suppression (+) Suppression (-)

33 Sign & Symtoms CS Central Obesity Proximal Muscle Weakness( hips, shoulders ) Hypertension buffalo hump moon face Acne Hyperpigmentasion Hirsutism (male-pattern hair growth in a female ) Hyperglicemia Hypokalmic metabolik Acidosis

34 Pseudo hypoparathyroid Hipercalcemic Hiperphosphatemic Klinis : - Short stature - Rounded face - Obesitas - Subcutan Calcification - Shortened fourth metacarpal Laboratorium Albright’s Hereditary Osteodystrophy (AHO)

35 Rickets Gangguan mineralisasi dari organik matrik tulang Anak-anak gangguan terjadi pada : - Growth plate - Mineralisasi kartilago → terjadi deformitas

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37 Vitamin D is required for proper calcium absorption from the gut. In the absence of vitamin D, dietary calcium is not properly absorbed, resulting in hypocalcemia, leading to skeletal and dental deformities and neuromuscular

38 Laboratorium (Rickets) Infants dengan Vit. D Deficiency Serum Calcium selalu rendah Serum Phosphat batas normal serum alkaline phosphatase meningkat

39 Disorder of the Pituitary & Hypothalamus Anterior Pituitary mensintesa : - Growth Hormon - Prolactin - TSH - FSH - LH Hypothalamus mensekresi tropik hormon untuk masing-masing

40 Pituitary hormon excess Prolactinoma Cushing;s Syndrome Acromegaly and Gigantism TSH Secreting Adenoma

41 Pituitary hormon deficiency Hypoadrenalism Hypothyrodism Hypogonadism Somatomedin deficiency (IGF Deficiency)

42 Laboratory tests for diagnosis of disorders of pituitary and hypothalamus Growth Hormon (GH) Dihasilkan & disekresi oleh pituitary somatotrope cells sebagai respons terhadap GHRH hypotha- lamus Effek kerja dimediasi melalui Insulin Like Growth Faktor (IGF) Kegunaan : - Differential diagnosis : Short Stature, Slow Growth - Evaluasi Pituitary Function

43 Insulin-like growth factor Regulation of growth and development in mammals. Stimulation of cellular proliferation and growth, IGF-I has important effects on carbohydrate, protein and bone metabolism

44 Meningkat Acromegaly, karena adenoma pituitary tertentu Laron dwarfism (kekurangan GH receptor) GH resistance Renal Failure Uncontrol DM Obat-obatan : Estrogen, Kontrasepsi oral Stravation 2 jam sesudah tidur

45 Menurun Gangguan pada hypothalamus (tumor, infeksi, hemokromatosis) Hypopituitarism (tumor, infeksi, granuloma, radiasi) Dwarfism Corticosteroid therapy Obesity