Thyroid Disease Flashcards by James Turner

What does TSH stand for and where is it released from?

Thyroid stimulating hormone + anterior pituitary

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What hormone stimulates TSH secretion?

Where is this hormone secreted?

TRH - thyroid releasing hormone

Paraventricular nuclei of hypothalamus

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How are TSH secretion levels controlled?

Via negative feedback from T4/T3

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Which 3 proteins transport T4/T3 in the blood?

Thyroxine Binding Globulin (TBG) - transports most (70%) T4/T3
Transthyretin
Albumin

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What is the function of TPO (thyroid peroxidase)?

It oxidises Iodide ions (I^-) to iodine –> which then combine with tyrosine residues on thyroglobulin to produce moniodotyrosine or diiodotyrosine –> which is used to produce T3/T4

Thyroglobulin in produced by thyroid follicular cells and secreted into the thyroid colloid follicles (the same space where iodine ions are transported to)
Sodium-iodide-symporters on the basolateral membrane of thyrocytes (thyroid d cells)cells import sodium + iodide
Iodide ions are transported into the colloid via Pendrin at the apical thyrocyte membrane (adjacent colloid)

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Interspersed between thyroid follicles are parafollicular cells called C-cells - what do they produce?

Calcitonin

Function:
- Acts to ↓ blood [Ca²⁺] - thus opposing PTH
- Inhibits osteoclast activity in bones
- Inhibits renal tubular reabsorption of Ca²⁺ and phosphate [PO₄^3-] –> thus ↑ urine [Ca²⁺] + [PO₄^3-]
Regulation:
- Stimulated by ↑ blood [Ca²⁺]
- Stimulated by Gastrin + pentagastrin (synthetic gastin)
Treatment for:
- Hypercalcaemia (calcitonin has faster effect than bisphosphonates)
- Osteoporosis

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Which is a better marker of thyroid function Free T4 or Free T3?

Free T4

Thyroid secretes T4 and T3 in 20:1 ratio (easier to detect T4)
T3 is primarily produced peripherally in tissues via the conversion of T4 –> T3 by deiodinase enzymes

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When giving pharmcological intervention for thyroid conditions, how long should you wait to re-test a patient’s TFTs to monitor response to treatment?

6-8 weeks

T4 half-life is ~1 week

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Which is more common Hypothyroidism or Hyperthyroidism?

Are they more common in women or men?

Hypothyroidism is more common

Thyroid conditions are significantly more common in women

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What are the symptoms of Hyperthyroidism?

General:
- Weight loss
- Goitre
- ↑ appetite (if ↑↑ then paroxysmal weight gain in 10%)
- ‘Manic’ restlessness - overactive, irritable
- Heat intolerance
- Exopthalmos (Grave’s)
Skin:
- ↑ Sweating
- Palmar erythema
- Pretibial myxoedema (Grave’s)
- Thyroid acropachy (Grave’s)
Heart:
- Palpitations - can produce AF
- ↑ HR (tachy)
GI:
- Diarrhoea
Gynaecological:
- Oligomenorrhea (infrequent / light menstruation)
Neurological:
- Proximal myopathy
- Anxiety
- Tremor

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What are some causes of Primary Hyperthyroidism?

Grave’s Disease - most common:
- Autoimmune antibodies which stimulate; TSH-receptor (90%), TPO (75%)
- Features:
  - Hyperthyroid symptoms
  - Diffuse smooth goitre
  - Orbitopathy (lid retraction, exopthalmos, optic neuropathy, opthalmoplegia)
  - Pretibila myxoedema
  - Thyroid acropachy
- Typical age = 30-50yrs
- Associated with other autoimmune conditions: vitiligo (loss of skin pigmentation), T1DM and Addison’s
Toxic multinodular goitre:
- Goitre is composed of multiple autonomously functioning nodules
- Hyperplastic response to thyroid gland stimulus
- Commonly caused by iodine deficiency
- Can cause dysphagia if goitre is significant
Toxic thyroid adenoma:
- Benign neoplasm that can function autonomously
Subacute (painless) lymphocytic thyroiditis:
- Autoimmune
- NO pain
- Triphasic course: Hyperthyroid –> hypothyroid –> euthyroid (phases can last months)
De Quervain’s Thyroiditis (subacute granulomatous thyroiditis):
- Period of acute viral like illness (fever, myalgia, neck pain) + hyperthyroid symptoms –> tender, firm goite, ↑ ESR, ↑ CRP + flu symptoms + hyperthyroid
- PAIN is key symptom (can be in jaw, neck, teeth)
- Triphasic course: Hyperthyroid –> hypothyroid –> euthyroid
Drugs:
- Levothyroxine excess, amiodarone, lithium (hypo- is more common with lithium)

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What tests might be ordered for suspected Hyperthyroidism?

What might they show?

TFTs
- ↓ TSH (more sensitive that T4 levels for pts with existing thyroid condition - used to guide treatment)
- ↑ T4
- ↑ T3 (this can be measured but is only useful clinically in a small no. of cases)
Thyroid antibodies:
- TSH-receptor
- TPO
- Thyroglobulin
FBC:
- Mild normocytic anaemia
- Mild neutropenia (Grave’s)
- ↑ ESR (marker of inflammation)
U+Es:
- Mild ↑ Ca²⁺ (thyroid hormones have role in bone metabolism)
Radioactive iodine uptake test (scintigraphy)
- ↑ uptake diffusely –> Grave’s
- ↑ uptake in specifc areas –> toxic multinodular goitre or adenoma
- ↓ uptake –> thyroiditis

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Why can Amiodarone cause Hyper- or Hypo- thyroidism?

It is an Iodine-rich drug (structurally similar to T4)

Half life ~80 days –> hence if patient has amiodarone induce thyroid pathology, cessation of the drug won’t resolve symptoms quickly

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How can Amiodarone cause Hypothyroidism?

Wolff-Chaikoff Effect

Effect involves ↓ in T4/T3 following administration of iodine/iodide (amiodarone is rich in this)
In normal pt, this effect causes transient ↓ in T4/T3 (~10 days) –> after which the thyroid gland escapes from this suppression and returns to normal
In pts with autoimmune conditions the suppresive effect can persist
This effect can be used in thyroid storm via infusion of large amounts of iodine to suppress the thyroid gland

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How does Amiodarone cause Hyperthyroidism?

Jod-Basedow Effect

Involves ↑ T4/T3 following iodine/iodide/amiodarone
This DOES NOT occur in people with a healthy thyroid gland
In pts with; Grave’s disease, toxic multinodular goitre or toxic thyroid adenoma there is an ↑ risk of ↑ T4/T3 following intake of excess iodine (e.g. amiodarone)

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What are the differences between AIT 1 and 2 (Amiodarone induced thyrotoxicosis)?

AIT type 1:

A form of iodine-induced hyperthyroidism
Usually occurs when the patient has abnormal thyroid glands
Thyroid radioactive iodine-uptake (RAIU) levels cam be low/normal/raised
Multinodular or diffuse goitre

AIT type 2:

A type of drug-induced destructive thyroiditis
Usually occurs in normal thyroid glands
Thyroid radioactive iodine-uptake (RAIU) levels are usually low/very low
Usually absent but can be small, firm and sometimes tender goitre

How is Hyperthyroidism treated?

Carbimazole / Thiazmazole:
- 1st line hyperthyroid medication
- MoA: pro-drug which is converted to methimazole –> which inhibits thyroid peroxidase (TPO) –> thus inhibits iodination of thyroglobulin
- Often given for 12-18 months
- Relapse to hyperthyroid state is common –> if it occurs consider another cours of carbimazole or other treatments
- Side effects: Rash, itchy, arthralgia, nausea/vomiting, agranulocytosis
- 10mg carbimazole = 100mg PTU
Propylthiouracil (PTU):
- Is 2nd line
- Given when pt is intolerant of carbimazole + during 1^st trimester of pregnancy due to association with congenital defects
- MoA: inhibits TPO + 5’-deiodinase (which converts T4 –> T3)
- Side Effects: hepatic reactions (can become toxic), agranulocytosis, aplastic anaemia (hematopoietic stem cells damaged –> deficiency in RBC, WBCs and platelets i.e. pancytopenia)
Radioactive sodium iodide (¹³¹I):
- Pts are recommended to maintain 1-2m distance away from people post treatment due to radiation (most of which dissipates within 1 week, but some is used to make thyroid hormones thus hangs around)
- Can aggravate thyroid eye disease
- Does NOT cause infertility (but pt not to get pregnant for 6 months post treatment)
- Does NOT ↑ risk of cancer
Propranolol
- MOA: Is a non-selective (both β1 and β2) beta-blocker
- Contraindications: pts with bronchospasms (asthma), hypotension, Prinzmetal’s angina, 2^nd and 3^rd degree AV block
- Side effects: bradycardia, bronchospasm, constipation, diorrhoea, vomiting, dizziness, dry eyes, erectile dysfunction, heart failure, syncope
Surgery:
- Popular in; women planning pregnancy in < 6 months, malignancy, coexisting hyperparathyroid, low radioactive iodine uptake
- Not liked because of potential scar
- Risks: hypoparathyroidism (2-4%) and vocal cord paralysis (recurrent laryngeal nerve dmg – 1%) and pts require lifelong levothyroxine therapy due to permanent hypothyroidism

What dose of Carbamizole is usually given for hyperthyroid?

Dose: 15-40mg daily until pt is euthyroid (~4-8 weeks) then reduced to maintenance doses of 5-15mg daily – therapy usually given for 12-18 months

What dose of Propylthiouracil is given for Hyperthyroid?

Dose: 200-400mg daily in divided doses, until pt is euthyroid, then 50-150mg daily divided

Whilst Secondary Hyperthyroidism is rare (<1% of cases) - how would it present on TFTs?

High TSH
High free T4

What does ‘Block and Replace’ regime refer to in the treatment of Hyperthyroidism?

Using anti-thyroid drugs (e.g. carbimazole) to produce hypothyroid/euthyroid state and then use levothyroxine titration to maintain euthyroid

E.g. Carbimazole started at 40mg –> Levothyroxine added when pt is euthyroid (treatment lasts 6-9 months)

What are the symptoms of Hypothyroidism?

General:
- Weight gain
- Lethargy
- Cold intolerance
- Hoarse voice
- Goitre
- Myalgia + Weakness
Skin:
- Dry (anhydrosis)
- Non-pitting oedema e.g. face, hands, feet
- Course scalp hair
- Loss of lateral 1/3rd of eyebrow
Heart:
- ↓ HR (brady)
GI:
- Constipation
Gynaecological:
- Menorrhagia (heavy menstrual bleeding) –> can cause iron-deficient anaemia
Neurological:
- Reflex relax slowly
- Depression
- Myxoedema coma = most severe hypothyroid state (close to death)

What are some causes of Primary Hypothyroidism (95% of cases)?

Hashimoto’s Thyroiditis
- Most common cause in developed world
- Autoimmune - diffuse T-lymphocytic infiltration of thyroid
- May cause firm diffuse goitre
- Antibodies against; TPO (95%), TSH-receptor or thyroglobulin (60%)
- Peak age onset: 30-50 yrs
Iodine deficiency
- Most common cause developing world
Thyroidectomy
Radioactive iodine treatment (for hyperthyroidism)
Drugs:
- Anti-thyroid medication (e.g. carbimazole), amiodarone, lithium, interferon-alpha, tyrosine kinase inhibitors (e.g. imatinib)
Phasic Thyroid conditions:
1. N.B. Triphasic thyroid pathologies: Hyperthyroid –> hypothyroid –> euthyroid
2. Subacute (painless) lymphocytic thyroiditis = triphasic
3. De Quervain’s Thyroiditis (subacute granulomatous thyroiditis) = triphasic
4. Postpartum thyroiditis = can be triphasic or primarily hypo

What are some causes of Secondary Hypothyroidism (1-5% cases)?

Pituitary pathology:
1. Pituitary Adenoma (most common)
2. Surgery / radiation
3. Rathke’s cleft cyst - benign mucus filled cyst growingin in anterior pituitary
4. TB
5. Sheehan’s syndrome (postpartum pituitary gland necrosis) - – ischaemic necrosis due to blood loss and hypovolemic shock during and after childbirth
Hypothalamic pathology:
1. Tumour
2. Surgery / radiation

What tests might be ordered for suspected Hypothyroidism? What might they show?

* TFTs * ↑ TSH * ↓ T4 * ↓ T3 (this can be measured but is only useful clinically in a small no. of cases) * Thyroid antibodies: * TSH-receptor * TPO (Hashimoto's) * Thyroglobulin * FBC: * Eliminate other causes of tiredness e.g. anaemia * ↑ MCV (macrocytosis) * ↑ ESR (marker of inflammation) * Glucose: * May have ↑ glucose as Primary hypothyroidism is associated with T1DM * Lipid Profile: * ↑ Cholesterol / triglycerides * U+Es: * Na⁺ may be reduced (incidental finding) * Radioactive iodine uptake test (scintigraphy) * ↑ uptake diffusely --\> Grave's * ↑ uptake in specifc areas --\> toxic multinodular goitre or adenoma * ↓ uptake --\> thyroiditis

How is Primary Hypothyroidism treated?

1. **Levothyroxine** * Is manufactured form of T4 * Taken **30 min before breakfast**/other medication * Lower initial dose in: elderly (\>50yrs) + ischaemic heart disease * May need to ↑ dose during 1st trimester pregnancy due to ↑ T4/T3 demands * **Side Effects:** - mainly symptoms of hyperthyroid * **Exacerbate angina** in CAD pts * **Atrial fibrillation** * Osteoporosis (due to suppression of TSH – associated with osteoporosis) * Diarrhoea * Nausea / vomiting * Anxiety, agitation * Weight loss * ↑appetite * Muscle weakness * Tremor * **Liothyronine** * Man made T3 * Given when there is impaired conversion of T4 --\> T3 (e.g. deiodinase deficiency) * e.g. ↑ TSH, ↑ T4 and ↓ T3

What dose of Levothyroxine is given for 18-49 year olds without cardiac disease?

**50-100** **micrograms** once daily, adjust in 25-50 microgram steps every 3-4 weeks, maintenance 100-200 micrograms once daily * Take before breakfast, caffeine or other medication

Which 3 Thyroid pathologies can present with a mixed/phasic combination of hyperthyroid and hypothyroid?

1. Subacute (painless) lymphocytic thyroiditis 2. De Quervain's Thyroiditis (subacute granulomatous thyroiditis) 3. Postpartum thyroiditis

What advice should you give to a patient taking a medication with a risk of Agranulocytosis?

* Report signs of infection; sore throat (especially), fever, bad flu symptoms * If the case --\> FBC --\> check for infection * Stop Carbimazole if WBC count is high!

What is the mechanism of neonatal Hyperthyroidism?

TSH-receptor antibodies (Grave's disease in mother) can cross placenta and stimulate thyroid of the foetus

How do you know that a hypothyroid patient is being sufficiently treated with Levothyroxine?

1. Resolution of hypothyroid symptoms 2. TSH level within normal range

What are some 'Red-Flags' for Thyroid Cancer?

1. Rapid growth (several months) 2. Dysphagia 3. Neck pain 4. Hoarse voice, cough, stridor 5. FHx of thyroid cancer 6. Multiple enlarged cervical lymph nodes 7. Tethering of mass to surround structures

What are the 2 best investigations for suspected Thyroid Cancer?

1. Ultrasound 2. Fine-needle aspiration of lump

What are the 5 main histological types of Thyroid carcinoma?

1. Papillary carcinoma 70% 2. Follicular carcinoma 20% 3. Medullary cell carcinoma 5% 4. Anaplastic carcinoma 3% 5. Lymphoma 2% * Papillary + follicular carcinomas are derived from the follicular epithelium and are well differentiated and have a good prognosis * Medullary cell carcinomas arise from the calcitonin-producing (C-cells) in the thyroid

What 3 steps are involved in treatment of Thyroid Cancer treated?

1. Surgery - total thyroidectomy or lobectomy 2. Post-operative radioactive iodine treatment (selected cases) 3. Thyroid hormone suppression (to suppress TSH so that tumour growth is not stimulated)

Susan Preston has noticed a lump in the left side of her neck for the last few weeks. When the GP examines her, he detects a solid lump 2cm in diameter in the left lobe of hte thyroid and enlarged left-sided cervical lymph nodes. Susan volunteers that her brother had one adrenal gland removed last year due to a tumour. What is the most likely diagnosis? 1. Follicular carcinoma 2. Papillary carcinoma 3. Medullary cell carcinoma 4. Lymphoma

3. Medullary cell carcinoma * Papillary carcinoma is the most common thyroid cancer and frequently metastasises to the cervical lymph nodes * HOWEVER, medullary cell carcinoma can be inherited (genetic) * When medullary cell carcinoma is present with phaepchromocytoma (adrenal medulla tumour) and hyperparathyroidism --\> it is called Multiple endocrine neoplasia type IIa (MEN type IIa)