Thyroid disorders – Hypothyroidism/Hyperthyroidism
Thyroid function
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Euthyreoidism: normal TSH (0.4-4.5 mU/L),
fT4 (12-22 pmol/L) és fT3 (2.5-6.5 pmol/L)
Primary thyroid dysfunction:
Subclinical hypothyroidism:
elevated TSH, normal fT4
Overt hypothyroidism:
elevated TSH, decreased fT4
Subclinical hyperthyroidism:
Very low TSH (<0.1), normal fT4 és fT3
Overt hyperthyroidism:
Very low TSH, increased fT4 és/vagy fT3
fT4: free thyroxine, fT3: free triiode-thyronine TSH: thyreotropin, TRH: thyreotropin-releasing hormone
Hypothyroidism
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Hypothyroidism frequency
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Overt hypothyroidism: 2 – 3 %,
Subclinical hypothyroidism: 6 – 8 %,
Most frequently: female patients around 40Y
Congenital hypothyroidism: 1 : 4000
Autoimmun hypothyroidism:
female: 4 : 1000 man: 1 : 1000
Hypothyroidism causes
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Primary: (98-99%) Definitive: Transient: - thyreoiditis (Hashimoto) - thyreoiditis (subacut, postpartum)
- iatrogen - iodine excess ((sub)totalis thyreoidectomy - medical therapy Irradiation) - drug induced (lithium és amiodarone , interferon, mitotane)
- iodine-deficiency - congenitale - infiltration
Secundary:
- Pituitary disorders (cancer, OP, irradiation)
Tertier: - Hypothalamic disorders
Symptoms
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
fatigue weakness
slowly Increased sleepness
Muscle weakness Cold intolarence
Weight gain Hairloss, skin dryness
Concentration/memory deficits
depression hoarseness
infertility Libido loss
galactorrhe Menstrual irregularity
bradycardy hypertension
obstipation hyporeflexia
Check-up
• Typical symptoms (in elderly just few symptoms)
• anamnestic: thyroid OP/irradition, drugs, co-morbidities
• Lab-tests: TSH, fT4, aTPO
• Thyroid ultrasound
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Thyroid ultrasound
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Normális thyroid Hashimoto-thyreoiditis
Hashimoto-thyreoiditis
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Chronic lymphocyte-infiltration in the thyroid tissue. Local inflammation, irreversible destruction of the tissue – definitive hypothyroidism
Autoantibodies
- anti-peroxidase AB
- Thyroglobulin AB
Co-morbidities:
Type 1 diabetes mellitus, Morbus Addison, vitiligo, atropic gastritis, myasthenia gravis, Sjörgen syndrome
Hashimoto-thyreoiditis histology
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Normal follicules Hashimoto-thyreoiditis
Treatment
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Levothyroxine-substitution: Levothyroxine half life time 7-8 day. Once a day Dosage: 1,6-1,7 mg/ ttkg TSH-control: 4 weeks after dosage change, long-term
yearly/halfyearly Drug intake: fasten, 30 min before breakfast with water (no
coffee)
Hyperthyroidism
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Hyperthyroidism causes Morbus Graves-Basedow
toxic adenom ( Morbus Plummer)
multinodular goiter
iodine-induction
hCG- pregnancy induced
Rare causes:
TSH-secreted pituitary adenom
hCG-secreted tumours
overdosage of thyroxine
struma ovarii
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Transient hyperthyroidism • Distruction of thyroid follicules: T4 and T3 secreted in the
bloodstrem
de Quervain subacut thyroiditis
silent thyreoiditis
postirradiation thyreoiditis
Transient hyperthyroidism with overt hypothyroidism
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Hyperthyroidism frequency
II. sz. Belgyógyászati Klinika
Morbus Graves-Basedow 5-10/100000
Toxic goiter or toxic adenom in advanced age
Amiodarone induced hyperthyroidism 2%
Role of iodine:
Iodine-rich region: relative lower incidency of hyperthyroidism, with high prevalence of Morbus Graves-Basedow
Iodine-arm region, relative higher frequency with higher prevalence of toxic goiter
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Hyperthyroidism signs
irritability Emotional lability
Tremor, hyperreflexia Increased body temperature
Tachycardy Atrial fibrillation
Congestive heart failure Myopathy
Osteoporosis Increased appetite with weight loss
Diarrhoe Elevated liver function lab test
Opthalmopathy Increased sweating
Infertility Menstrual disorders
increased libido with ED Accelerated metabolism
Hypertension Hairloss
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Diagnostic
• Anamnestic, physical examination
• Hormone-test: TSH, fT4, fT3
• Ultrasound
• Antibody (TRAb)
• Thyroid-scan: diffuse increased Tc-uptake
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Morbus Basedow Merseburg-triade: exophthalmus, goiter, tachycardy
• Thyroid dermopathy
• Endocrine ophthalmopathy
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Ultrasound and scan
Tc-uptake increased
ultrasound Scan
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Endokrin opthalmopathy
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Morbus Basedow treatment
30-40% has definitive treatment success
60-70% relapse.
Medical treatment (1-1,5 year long drug therapy
Definitive treatment: in case of relapse, drug-intolerance,
etc
I131-isotope or near-total thyreoidectomx
Adjuvant treatment
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Medical treatment Thyreostatics:
methimazol 30-60 mg/day (Metothyrin, 10 mg)
propylthiouracil 300-600 mg/day (Propycil, 50 mg)
Alternative medical treatmen:
lithium
iodine (Wolff-Chaikov-effect),
(potassium-perchlorate)
Adjuvant treatment
propranolol 120-320 mg/day, inhibit of T4-T3 conversion
steroid (in severe hyperthyroidism)
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Side effects of drugs
frequency: 3-12%, avarage: 4.3%
pruritus 2.2%
urticaria 0.5%
granulocytopenia 1.6%
agranulocytosis 0,1-0,5%
toxic hepatitis
cholestatic icterus
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Radio-iodine treatment
• In USA 70%, in Europe 10-20%.
• Long term hypothyroidism
• No pregnancy in the next 6-12 months
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Operation
• Near-total thyreoidectomy, no relapse (~ 100% hypothyroidism)
• Indication: large goiter with local press symptoms, nodular goiter, ophthalmopathy, planned pregnancy in 1 year
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Toxic nodular goiter
Ultrasoung Scana
Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Toxic nodular goiter
• Over hyperthyroidism – treatment indicated
• Subclinical hyperthyroidism „wait and see”.
• Drug treatment has transient success.
• Definitive treatment: I131-isotope or operation
II. sz. Belgyógyászati Klinika Semmelweis Egyetem II. sz. Belgyógyászati Klinika
Thyroid cancer
Peter Reismann
Thyroid nodule
- Thyroid nodule is a discrete lesion within the thyroid gland that is radiologically distinct from the surrounding thyroid parenchyma. - Only nodules >1 cm should be evaluated - No universal screening advice - Tastbar nodule: 5% female, 1% man - US found nodule: 19-67% up to many studies,
more frequent with age and in female gender - 3-5% of the nodules are malignant
Diff. Diagnostic possibilities • Thyroid
– Benign nodule • Folliculare adenoma • Lipoma • Dermoid cysts • Teratoma
– Malignant • Papillary, follicular, medullary, anaplastic cancer • Lymphome, metastatic tumors
– Others • Focal thyroiditis • Granulomatic • Cyst
• Non-thyroid – Parathyroid adenoma – Ductus thyreoglossus cysts – Lymph nodes
Medical check-up in case of thyroid nodule
1. Thyroid ultrasound
2. TSH measurement
3. (Tc-thyroid scan)
4. FNA of suspected lesions
5. (Calcitonin measurement)
6. (Genetic analysis)
Thyroid ultrasound
Lymph nodes
Fine needle aspiration
FNA cytology
Papillary cancer cytology
Thyroid cancer
• Papillary cancer
• Follicular cancer
• Hürthle-cells variant
• Medullar cancer
• Anaplastic cancer
• Metastases
• Lymphom
Thyroid cancer
Thyroid cancer
• 3-15% have initial metastatic disease
• 6-20% will have metastatic disease during follow-up
• Papillary cancer : lymphatic metastatic: lymph nodes
• Follicular cancer: hematogen metastatic: bones, lung
• Medullary cancer: hematogen metastatic: liver, bones, lung, lymph nodes
Preoperative Study
• Neck ultrasound
– Initial diameter, solitaer/ multiplex
– Lymph nodes
• FNA
• NO: Thyreoglobulin Serum-level, aTG, CT, MR, PET/CT
Mutation
• BRAF T1799A- Val600Glu 44% in papillary cancer
• RET/PTC rearrangement 10-30% in papillary cancer
• MAPK-kinase longlasting activation
• N/K RAS, PAX8/PPARgamma in follicular cc.
• TERT, TP53 other mutations
MAPK
• Activation of MAPK prohihibits thyroid hormone synthesis and the gene settlement of Na-I-transporter and TPO.
Tumor development
Therapy
• Surgical: near-total thyreoidectomy or lobectomy
• Lymph nodes removal
– Central – therapeutical indication
– Latera – positive FNA or prophylactic indication
Follow-up
• Neck ultrasound
• Thyreoglobulin and aTG serum level
– Perfect tumormarker, < 0.2 ng/ml
• Whole-body RAI (123/131)-scan
• CT
Additional treatment
• Radio-iodine therapy
– Adjuvant - tumor remnant
– Remnant ablation
- follow up
• TSH-suppression
• TKI-inhibitor
• Study drugs
• Etc…
RAI
• Iodine-Uptake TSH > 30 mU/L
– Levothyroxine-off for 4-6 weeks
– Recombinant TSH (Thyrogen)
• Indications:
– Metastatic disease
– Primary tumor > 4 cm
– Primary tumor is out of thyroid bed
– Lymph nodes metastates
– Histology: aggresive behaviour
RAI
TSH-Suppression
• TSH has proliferative effect on thyroid cells
• Supraphysiologic levothyroxine dose
– High risk patient TSH < 0.1 mU/L
– Intermediate risk patient TSH: 0.1-0.5 mU/L
– Low risk patient TSH: 0.2-2.5 mU/L
Beyond standard therapy
• RAI-refracter disease
• No external beam radiation
• No routine systematic adjuvant chemotherapy
• Local recurrence:
– Surgical removal
– Ethanol injection
– Radiofrequency ablation
• TKI: sorafenib (Nexavar)
• Iodine-uptake enhancement: selumetinib
Follow-up
• Excellent response: 10 years survival > 90%
• 6 months US, Tg+aTG
• After 1 year: re-stratifications
– T4-off Tg, aTG measurement and US
• 5 years TSH-suppression
Thank You!