ENDOKRINOLOGI :

HORMON TIROID DAN INSULIN

May Fanny Tanzilia, dr., Sp.PK(K)

Surabaya 2023

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 Anatomi dan Histologi Kelenjar Tiroid

Kelenjar tiroid terletak pada leher bagian depan, di bawah laring, terdiri dari 2 lobus yaitu lobus kanan
dan kiri yang dipisahkan oleh isthmus. Tiap lobus memiliki lobuli yang mengandung folikel dan
parafolikuler. Di dalam folikel terdapat rongga yang berisi koloid tempat hormon tiroid disintesis

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 Sintesis Hormon Tiroid
1. Transport aktif iodium ke dalam sel tiroid
2. Oksidasi iodium dan iodinasi tirosil dalam
tiroglobulin (Tg) oleh Thyroidal
1 Peroxidase (TPO) dengan stimulasi TSH (
Thyroxine Stimulating Hormone =
Thyrotropin)
2 3. Coupling iodotyrosine dalam Tg → T3
(Triiodotyronine) → T4
(Tetraiodotyronine= Thyroxine)
4. Proteolisis Tg melepas iodotyronine bebas iodothyrosine
3 5. Deiodinasi iodotyrosine dan menggunakan iodium Kembali
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6. Deiodinasi T4 → T3
7 Sel Parafollicular:
→Hasilkan thyrocalcitonin (metabolisme kalsium )

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Axis Hipotalamus – Hipofisis - Tiroid
▪ Hipotalamus mensekresi thyrotropin releasing hormone (TRH)
yang kemudian menstimulasi kelenjar pituitari untuk
memproduksi thyroid stimulating hormone (TSH)
▪ TSH akan menstimulasi kelenjar tiroid untuk mensekresi tiroksin
(T4) dan juga sedikit triiodotironin (T3)
▪ Kadar T3 dan T4 akan memberikan umpan balik negatif terhadap
produksi TRH dan TSH

Kadar T4 serum > T3

Aktivitas T4 < T3

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 Hormon Tiroid dalam Darah
T3, T4 :
▪ T4 hanya dihasilkan kelenjar tiroid, sedangkan T3 dihasilkan kelenjar tiroid (20%)
dan dari deiodinisasi T4 di jaringan ekstranodal perifer (hati dan ginjal)
▪ Hormon tiroid terikat protein (TBG=Thyroid Binding Globulin)
▪ TBG meningkat pada : kehamilan, pemakai estrogen
▪ Efek biologis T3 >4x dibandingkan T4

FT3, FT4 :
▪ Bentuk bebas (Free T3, Free T4)

TSH :
▪ Bergantung pada umpan balik negatif
▪ Paling sensitif dalam deteksi awal kelainan hormon tiroid, namun kadarnya tidak
mudah berubah
▪ Nilai rujukan : 0,5 – 5,0 mU/L
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 Fungsi Hormon Tiroid
• Merangsang metabolisme → Basal Metabolic Rate
(BMR) ↑, konsumsi O2 ↑, produksi panas ↑
• Hipertiroid : BMR > 100 %
• Hipotiroid : BMR < 50 %
Metabolisme karbohidrat :
• Langsung
• Tak Langsung (efek potensiasi hormon lain) →
absorpsi glukosa GIT meningkat→ glukosa darah
segera meningkat setelah beban glukosa
• Uptake glukosa sel perifer meningkat
Metabolisme lemak :
• Lipolisis ↑ → Asam lemak bebas ↑
• Lipogenesis ↑
Metabolisme protein :
• Utama → pertumbuhan dan perkembangan
• Hipotiroid (anak) : kretinisme
• Hipertiroid : pertumbuhan cepat, tetapi
cepat terhenti karena epifisis tulang panjang
cepat menutup
Metabolisme vitamin :
• Proses metabolisme ↑ → Kebutuhan vitamin
↑
• Hipertiroid : defisiensi vitamin merangsang
sintesis vitamin A dari karoten
• Hipotiroid : karoten plasma → kulit
kekuningan, defisiensi vitamin A
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Efek Hormon Tiroid

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 Kelainan Fungsi Tiroid

• Hipertiroid :
Kelainan fungsi kelenjar tiroid yang menghasilkan terlalu banyak hormon
tiroid sehingga kelenjar tiroid menjadi terlalu aktif (Hipertiroidisme)

• Hipotiroid :
Kelainan fungsi kelenjar tiroid yang tidak menghasilkan cukup hormon
tiroid sehingga kelenjar tiroid menjadi kurang aktif (Hipotiroidisme)

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Screening & Diagnosis
Congenital Hypothyroidism
• Intrauterine life is supported by maternal TH. Nonetheless, overtime the
fetus will be able to synthesize and secrete his own TH
• After birth, colder temperature outside the mother’s womb induces TSH
surge on the newborn, hence elevation of T3 and T4 → decrease over
several weeks
• TSH level is measured after the TSH surge phenomenon → if TSH level is
high, hypothyroidism is suspected
• Study the screening method → Indonesia:
• Measure TSH at age 3-5 days
• Result TSH values (cut-off = 20 mU/L → if > 20 mU/L, screening is (+))
• If TSH is high and FT4 is low → confirm congenital hypothyroidism

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Endemic Goitre (GAKI=Gangguan Akibat Kekurangan Iodium)

• Hipotiroid : penyebab paling sering di Indonesia

• Etiologi : tersering defisiensi yodium
(penduduk pegunungan)
• Klinis : → mudah lelah, irama jantung lambat, otot jantung lemah,
anemia, rambut rontok,
• peningkatan berat badan, menorrhagia, impotensia
• Lab : → T3 ↓ , T4 ↓
→ TSH ↑
→ Hb ↓ (pada ♀)
→ Hiperkolesterol
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Tiroiditis Hashimoto
• Hipotiroid karena proses imunologik
• Prognosis kurang baik krn proses otoimun
• Lab : → T3 ↓ / T4 ↓
→ TSH ↑
→ antibodi anti-tiroid positif

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Grave’s Disease (Basedow)
• Hipertiroid : sering terjadi pada wanita
• Etiologi : → autoimun , HLA DR3. Sel B sintesis Thyroid stimulating
immunoglobulin
• Gejala : - berat badan menurun, intoleransi hawa panas, tremor
- tachycardia, arhythmia → gagal jantung
- keringat banyak
- exophthalmos, diplopia
- amenorrhoea, osteoporosis

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• Pada kasus berat → thyroid
crisis (febris, kesadaran ↓ ,
arrythmia → kematian )

• Lab : T4 ↑,T3 ↑
• (hipertiroid ringan: T3
↑)

TSH ↓
antibodi anti-tiroid
positif

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Autoimunitas Tiroid
• Auto Ag : → thyroglobulin (Tg)
→ TPO = Microsomal Ag
→ TSH – R
→ G4 – kDa protein Ag
(klj. Tiroid / sel orbita)
• Auto Ab : → marker penyakit autoimmune tiroid
- Ab anti Tg
- Ab anti TPO
- Ab anti-TSH-R : - blocking
- -stimulating

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Tes Stimulasi TRH
• Indikasi :
1. T3 borderline, TSH rendah
2. Diagnosis kelainan di luar tiroid
• Cara : → periksa TSH basal
→ suntik i.v 200 μg TRH
→ periksa TSH setelah 20 & 60 menit
• Interpretasi :
Normal : basal < 5 mU/L
20 mnt: minimal 3mU/L

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 Hipertiroid Hipopituarism
Basal <2 3
20 menit <2 3
6o menit <2 3

Kelainan hipofisis:→TSH flat (hipotiroid sekunder)

Kelainan hipotalamus:→TSH meningkat (hipotiroid tersier)

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 TSH
T4 (mU/L)
(nmol/L)

Batas atas
TSH normal

Batas bwh
T4 normal

Pasca Operasi (bulan)

• Pemeriksaan tiroglobulin digunakan untuk evaluasi terapi keganasan tiroid .

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Disorders of Glucose

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Diabetes mellitus
• Kelompok penyakit metabolik yang ditandai dengan hiperglikemia
karena defek insulin absolut (sekresi insulin)/ relative (kerja dari
insulin), atau keduanya (ADA, 2012)
• merupakan keadaan hiperglikemia dengan gangguan metabolisme
karbohidrat, protein & lemak serta penyulit makro/mikrovaskular

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Penyebab Diabetes Mellitus
1. Kerusakan sel β pankreas: insulin ↓ (kuantitas dan kualitas)
2. Resistensi reseptor insulin
3. Gangguan pasca reseptor insulin (enzim)
4. Inhibitor anti insulin: insulin autoantibodi, counter regulatory
hormones of insulin

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Fungsi Insulin:
• Metabolisme Karbohidrat→ Langsung: menurunkan kadar glukosa darah
1. Uptake Glukosa (otot, hati, jaringan lemak)
2. Sintesa Glikogen (glikogenesis, disimpan dalam hepar + otot)
3. Glikogenolisis (pemecahan glikogen menjadi glukosa untuk digunakan sebagai
energi)
4. Glukoneogenesis (pembentukan glukosa dari as. amino, laktat, piruvat)
• Metabolisme Protein :
1. Rangsang transport aktif as. amino ke dalam sel
2. Rangsang sintesis protein
• Metabolisme Lemak :
1. Rangasang lipogenesis (konversi karbohidrat menjadi asam lemak) dalam sel
hepar dan jaringan lemak
2. Menghambat lipolisis (pemecahan lemak)
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Klasifikasi Diabetes Mellitus (ADA, 2004)

• DM tipe 1 : defisiensi insulin absolut akibat destruksi sel beta

● Penyebab :
○ immune mediated atau autoimun
○ idiopatik
• DM tipe 2:
• predominantly insulin resistance with relative insulin deficiency
• predominantly secretory defect with insulin resistance

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Klasifikasi D.M (2)
• D.M tipe lain :
1. Defek genetik fungsi sel beta :
- MODY (Maturity Onset Diabetes of the Young): kromosom 12, 7, 20, 13, 17, 2
- Mutasi mitokondria DNA 3243
2. Penyakit eksokrin pankreas :
- pankreatitis
- pankreatektomi/ trauma, dll
3. Endokrinopati :
- Akromegali
- Cushing’s syndrome
- Hipertiroid

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Klasifikasi D.M (3)
• 4. Akibat obat :
- glukortikoid
- hormon tiroid
- Dilantin
5. Infeksi :
- CMV, rubella
6. Imunologi : (jarang)
- antibodi anti insulin
7. Sindrom genetik lain :
- Sindrom Down, Klinefelter, Turner

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Karakteristik Laboratorium
DM Tipe 1 (IDDM) DM Tipe 2 (NIDDM)
1. Berhubungan dengan Tidak
HLA DR 3 & DR 4
2. Islet Cell Ab + (ICA)(proses autoimun, (-). Genetic disorder and environmental
infeksi virus) factor
3. Riwayat kel. DM (+) 30 %

4. Kembar identik 30-50 % terkena ± 100 %

5. Insulin serum rendah Normal / tinggi

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Diagnosis *) Catatan : - GTG = Gangguan Toleransi Glukosa
- 1 mmol/L glukosa = 18 mg/dL glukosa

• Glukosa Darah Puasa (GDP) dan 2 jam post prandial (2JPP) > normal
atau sesudah beban glukosa 75 gram (2 JSB) atau acak (GDA)
Vena
DM GDP > 126 mg/dL = 7 mmol/L
2JPP/GDA ≥ 200 mg/dL = 11 mmol/L
GTG GDP 100 – 125 mg/dL
2JSB 140 – 199 mg/dL
NORMAL GDP < 100 mg/dL
2JSM < 140 mg/dL
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 DIAGNOSIS OF DIABETES CRITERIA
(ADA 2010)
• A1c > 6.5%
• Fasting plasma glucose (FPG) > 126 mg/dL
• Fasting is defined as no caloric intake for at least 8h
• 2h Plasma Glucose > 200 mg/dL during OGTT
using 75 g glucose dissolved in water
• A Random Plasma Glucose > 200 mg/dL in patients with
hyperglyemic classic symptoms

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2004 ADA Diagnostic Criteria
• Diabetes Mellitus criteria:
• Diabetes symptoms plus Casual Plasma Glucose> 200 mg/dL(11.1
mmol/L), or
• Fasting Plasma Glucose> 126 mg/dL (7.0 mmol/L), or
• A 2-hour PG > 200 mg/dL (11.1 mmol/L) during an OGTT using 75 g
anhydrous glucose dissolved in water

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 2004 ADA Diagnostic Criteria
• Normal FPG < 110 mg/dL (2004: <100 mg/dL)
• FPG between 110-125 mg/dL categorized as “impaired fasting
glucose” (IFG)
• If the 2-hour PG>140 mg/dL during OGTT categorized as IGT
(“impaired glucose tolerance”)

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Indikasi 2JSB (TTGO)
Tes Toleransi Glukosa Oral
• GDP : 100 – 125 mg/dL
• 2JPP : < 200 mg/dL
• DM keluarga (+)
• Gejala DM (+)
• Hamil : bayi > 4 kg, toksemia, hidramnion, abortus spontan

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.: Syarat TTGO :.
• Ambulatoir, exercise minimal
• Bebas kopi, alkohol, rokok, kortikosteroid, diuretika, obat hipoglikemik
oral
• Tidak stress / sakit berat
• Tidak ada gangguan absorbsi
• Diet karbohidrat > 100 kal / hari selama 3 hari

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Tes Toleransi Glukosa Oral :
Glukosa darah (mg/dL)

240

200

160

120

30 60 90 120 Waktu (menit)

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Pemeriksaan Glukosa Urine (screening) :

1.Reduksi : Fehling / Benedict

kurang spesifik
positif palsu karena reduktor : fruktosa, maltosa, laktosa, vit. C,
salisilat, INH, PAS, penicillin
2.Enzimatik : clinistix, glukotest
lebih spesifik
Negatif Palsu :
Usia lanjut → glomerulosklerosis → nilai ambang ginjal terhadap
glukosa meningkat
Infeksi saluran kemih (glukosa dikonsumsi kuman /sel radang)

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Monitoring :
• Glukosa urine : banyak kelemahan
• 2JPP (+OAD/Insulin) : monitor terapi
• GDP :sangat penting untuk regulasi insulin long acting
• Fruktosamin/Hemoglobin A1C : status regulasi glukosa jangka panjang
• Fruktosamin/Hemoglobin A1C terjadi karena proses glikosilasi
irreversible dari glukosa dengan protein (albumin/globin)
• Fruktosamin/Hemoglobin A1C berubah (meningkat/menurun) setelah
perubahan glukosa minimal selama 2 minggu atau 6 minggu
• Protein urine : Diagnosis nefropati diabetik (albumin > 300 mg/hr)
• Microalbuminuria (ekskresi albumin 30-300 mg/hr): diagnosis dini
nefropati diabetic
• Albumin:creatinine ratio (estimasi eksresi albumin 30-300 mg/hr)

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Nilai bergantung pada tiap
laboratorium.
Semakin tinggi HOMA IR,
semakin besar resistensi
insulin
Semakin tinggi HOMA B,
semakin baik fungsi sel
beta pancreas.

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Diagnosis DM tipe 1
1. C. Peptide / Insulin serum
2. Tes Autoimmune :
● I.C.A (Islet Cell Ab)
● I.A.A (Insulin Auto Ab)
● Ab Glutamic Acid Decarboxylase

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DM Tipe 2
• Resistensi Insulin
• Defek Reseptor / Pasca Reseptor

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 Defisiensi Insulin

Glukosa Uptake Proteolisis Lipolisis

As. Amino Nitrogen Gliserol FFA

Loss

Ketogenesis
Glukoneogenesis
Hiperglikemi +
Ketonemia
Glikogenolisis
Ketonuria
Osmotic Diuresis → electrolyte depletion

Hyptonic Loss → dehydration

Asidosis
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Faktor-faktor yang mempengaruhi HbA1c
Faktor HbA1c tinggi palsu
Eritropoiesis Defisiensi besi
Kehamilan trimester 3
Defisiensi vit B12
Gangguan glikasi Gagal ginjal kronik
Destruksi eritrosit Peningkatan masa hidup eri:
Splenektomi
Assay Hiperbilirubinemia
Alkoholisme
Aspirin dosis tinggi
HbA1c rendah palsu
Terapi eritropoietin, besi, vit B12
Penyakit hati kronik
Anemia hemolitik
Aspirin, vit C, vit E
Penurunan masa hidup eritrosit:
Anemia hemolitik, perdarahan masif
Transfusi
Gagal ginjal kronik
Hemodialisis
Hemoglobinopati
Splenomegali
Rheumatoid arthritis
Antiretrovirus, ribavirin, dapsone
hipertrigliseidemia
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Proses pembentukan Glycated Albumin
• Glycated Albumin:
albumin yang berikatan
dengan glukosa melalui
reaksi oksidasi non
enzimatik.

• Merupakan index kontrol

glikemik intermediet yang
tidak dipengaruhi oleh
metabolisme hemoglobin.

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ORAL ANTIDIABETIC AGENTS

• Increasing insulin availability (secretagogues : sulfonyl- urea)

• Supressing excessive hepatic glucose output(biguanide i.e. metformin)
• Improving insulin sensitivity(thiazolidinediones or glitazones)
• Delaying gastrointestinal glucose absorption(acarbose)
• Objectives (ADA):FPG 90-130 mg/dL, postprandial plasma glucose <180
mg/dL,HbA1c < 7%

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DIABETIC KETOACIDOSIS (DKA)
PATHOGENESIS
DKA : a complex metabolic disturbance of glucose, fat and protein
metabolism
Hyperglycemia → hyperosmolality : caused by glucose overproduction
by the liver and under utilization of glucose by peripherial tissue
When blood glucose concentration>threshold for tubular reabsorption
of glucose→glucosuria→osmotic diuresis→water loss + electrolyte
excess
Extracell osmolality↑→glomerular filtration↑→hypo
volemia→glomerular filtration and glucose losses↓→severe
hyperglycemia

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PATHOGENESIS OF DKA (2)

Ketoacidosis is primarily due to the overproduction of ketoacids by the

liver
→loss of bicarbonate and other body buffers
→metabolic acidosis
DKA develops as consequence of insulin deficiency and
counterregulatory hormone excess (cortisol, catecholamines,
glucagon, growth hormone)
Counterregulatory hormone excess as a result of physical and
emotional stress/illness

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PATHOGENESIS OF DKA (3)

Glucagon influence gluconeogenesis and ketogenesis.

FFA (free fatty acid) is necessary to support glucagon stimulated
hepatic ketogenesis
Glucagon can directly increase ketogenesis without FFA release from
adipose tissue by activating lipolysis of hepatic triglyceride
Cortisol and epinephrine can increase hepatic glucose production
through glycogenolysis andgluconeogenesis

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DIAGNOSIS OF DKA

1. Traditional criteria: blood glucose  300 mg/dL, HCO3 - <18mEq/L,

pH<7.30
2. pH in DKA depends on degree of respiratory compensation and acid
base disturbances
3. Metabolic acidosis → anion gap↑
Anion gap= [Na+ - (Cl- + HCO3-)]
Normal : 8-14 mEq/L
Increase of anion gap usually equal to the reduction in HCO3-

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DIAGNOSIS OF DKA (2)

Coexistence of other acid-base disturbances,such

as metabolic alkalosis(nausea,vomiting,diuretics),
respiratory alkalosis(fever,sepsis) and hyperchlore
mic acidosis(diarrhea)- can confound the diagnosis
of DKA.
Substantial deficits of sodium,magnesium,phosphorus and water can
develop in DKA. However,most patients have normal/elevated plasma
concentration of Na, Mg and P.

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DIAGNOSIS OF DKA (3)

*The presence of normal/increased electrolyte

should not be interpreted as normal/increased of
these elements in the body.
*Hyperkalemia in DKA is usually atributed to a shift
of hydrogen ion from extracellular to intracellular
and of potassium from intracellular to extracellular.
*Insulin deficiency is the major cause of hyperkalemia in DKA.

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DIAGNOSIS OF DKA (4)

Serum potassium concentration decrease rapidly

during therapy due to direct action of insulin on
cellular potassium uptake, alterations in systemic
pH, reduction in serum glucose and associated
hyperosmolality and enhanced renal potassium
excretion.
Hyponatremia due to osmotic diuresis and loss of
water in excess of electrolyte.

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DIAGNOSIS OF DKA (5)

• Magnesium deficiency impairs secretion and action of parathyroid

hormone→hypocalcemia if patient receive phosphate supplements.
• Phosphate reduces plasma ionized-calcium, which cannot be restored
to normal because of magnesium deficiency.
• Patient require calcium and magnesium.

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DIAGNOSIS OF DKA (7)

In DKA there are increment of β-hydroxybutyrate (B), acetoacetate (A)

and acetone.
Nitroprusside reagent for detecting plasma and urinary ketones does
not react with β-hydroxybutyrate but reactive with acetoacetate &
acetone.
Β-hydroxybutyrate 3-4 x >acetoacetate & acetone
This test correlates poorly with degree of ketonemia.

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Tes Keton Uria (Nitroprusid)

• Hanya deteksi aceton/acetoacetic acid

• Tidak dapat mendeteksi ß hydroxy butiric acid
• Positif palsu pada :
- starvation, diet tinggi lemak, alcoholic ketoasidosis, fever
▪ Pada diabetik ketoasidosis mayoritas ß OH butiric acid, sehingga tes
keton uria sering negatif

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HYPERGLYCEMIC HYPEROSMOLAR SYNDROME (HHS)

Previous name hyperosmolar non ketotic coma (HONK)

Definition:
severe hyperglycemia(600 mg/L or 34 mmol/dL),
hyperosmolarity(320 mOsm/L), dehydration in the absence of
significant ketoacidosis (some ketonuria/mild ketonemia,pH 7.3 or
bicarbonate as low as 15 mEq/L do not preclude the diagnosis)
Occurs frequently in the elderly, T2DM.

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HHS (2)

Typically associated with severe fluid depletion and renal function

impairment, high mortality
Eosm=2[Na++K+(mEq/L)]+blood glucose(mg/dL)
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HHS : Blood glucose  600 mg/dL or  34 mmol/L
Eosm  320 mOsm/L
Arterial pH  7.30
SERUM BICARBONATE  15 mEq/L

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PATHOGENESIS OF HHS

Critical initiating event: persistent glicosuric diuresis→massive losses of

water & electrolytes
→”latent shock of dehydration”
If plasma glucose falls rapidly,the intracellular space severely depleted
with water and in osmotic equilibrium with extracellular compart-
ment, takes up water freed by metabolism of glucose along an
osmotic gradient favouring water movement from extracell→intracell
space

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PATHOGENESIS OF HHS (2)

This leaves behind a contracted intravascular space with hypotension

and oliguria.
Prevention: infusion of crystalloid solution early
In elderly: renal-concentrating ability decreased associated with a low –
grade ADH resistance.
Decreased in GFR, RBF, kidney mass, total body water, decreased
sense to thirst→ more vulnerable to loss of free water

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LABORATORY FINDINGS IN HHS

H2O : loss → dehydration, hypovolemia, and hyperosmolarity

Na+ : loss → for every 100 mg/dL increase in plasma glucose may
decrease Na+ by 2.4 mEq/L
Cl- : loss
K+ : loss. Initial levels may be high even with total body depletion.
Symptoms of hypokalemia : neuromuscular weakness, cardiac
conduction abnormalities, rhabdomyolysis, respiratory muscle
paralysis, cardiac arrest

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LABORATORY FINDINGS IN HHS (2)

Mg2+ : losses paralel those of K+. Severe depletion interferes with K+

repletion. Symptoms of hypo- magnesemia: lethargy, altered mental
status, convulsions, stupor, coma, nausea, vomiting,
refractory arrhythmias
Ca2+ : loss. Symptoms of hypocalcemia are rare (tetany,cramps
cardiac,conduction abnormalities
and mental status changes).

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LABORATORY FINDINGS IN HHS (3)

P : loss. Initial levels usually high, may falls to low levels with insulin
and glucose even if total body stores are normal. Symptoms of
hypophosphate
Symptoms: weakness, rhabdomyolysis, convulsions, coma,
hyporeflexia, hemolysis.

Plasma glucose : > 600 mg/dL

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Daftar Pustaka
• Sam HA, Meeran K. 2009.Lecture Notes in Endocrinology and
Diabetes
• Desai SP, Pratt SI.2000. Clinician’s Guide to Laboratory Medicine
• Soehita S. Hormon Tiroid. FK UNAIR
• Soehita S. Diabetes Mellitus. FK UNAIR
• Immanuel S. Laboratory Aspect of Thyroid and Parathyroid Gland. FK
UI

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