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Thyroid Disorders: Hyperthyroidism and Hypothyroidism

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Overview of Thyroid Hormones

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HYPERTHYROIDISM (Thyrotoxicosis)

Causes

• Subacute (de Quervain's) thyroiditis
• Silent/postpartum thyroiditis
• Amiodarone, cytokines, immune checkpoint inhibitors
• Thyrotoxicosis factitia (excess exogenous thyroid hormone)

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Graves' Disease - Deep Dive

1. Thyrotoxicosis (diffuse goiter)
2. Ophthalmopathy (proptosis, lid lag, lid retraction, periorbital edema)
3. Dermopathy (pretibial myxedema - rare, ~1-2%)

Clinical Features of Hyperthyroidism

Diagnosis of Hyperthyroidism

• Primary hyperthyroidism: TSH suppressed (<0.1 mIU/L) + elevated free T4 and/or T3
• T3 toxicosis: TSH suppressed, T4 normal, only T3 elevated (2-5% of Graves'; more common with borderline iodine intake)
• Subclinical hyperthyroidism: TSH suppressed, T4 and T3 normal, no symptoms
• Secondary (pituitary): TSH NOT suppressed + elevated T4

Treatment of Hyperthyroidism

• Methimazole (MMI) - preferred; blocks thyroid peroxidase, given once daily
• Propylthiouracil (PTU) - preferred in first trimester of pregnancy and thyroid storm (also blocks T4→T3 conversion); higher hepatotoxicity risk
• Side effects: agranulocytosis (0.2-0.5%) - must warn patients to stop drug and get WBC if fever/sore throat develops

• First-line in most adults (US preference)
• Contraindicated in pregnancy
• Can worsen Graves' ophthalmopathy (especially in smokers)
• Most patients become hypothyroid within months-years and need LT4

• For large goiters, compressive symptoms, malignancy concern, pregnant patients failing PTU
• Patient must be rendered euthyroid pre-operatively

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Thyroid Storm (Thyrotoxic Crisis)

⚠️ Iodine MUST be given at least 1 hour AFTER the thionamide - if given first, it can precipitate thyroid storm by providing substrate for more hormone synthesis (Wolff-Chaikoff escape failure).

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HYPOTHYROIDISM

Causes

• Pituitary adenoma, Sheehan's syndrome, hypothalamic disease

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Hashimoto's Thyroiditis - Deep Dive

• Anti-TPO (anti-thyroid peroxidase) - most sensitive, >90% positive
• Anti-thyroglobulin (anti-Tg) - less specific

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Clinical Features of Hypothyroidism

"The signs and symptoms of hypothyroidism all lack sensitivity and specificity individually - TSH is the best screening test." - Symptom to Diagnosis, 4th Ed.

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Diagnosis of Hypothyroidism

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Treatment of Hypothyroidism

• Full replacement: 1.6 μg/kg/day (typically 100-150 μg/day) in patients without residual thyroid function
• Start low (50-100 μg/day) in patients <60 years without cardiac disease; go even lower (25 μg/day) in elderly or patients with known cardiac disease
• Goal: TSH in the normal range, ideally lower half of reference range
• Recheck TSH at 6-8 weeks after any dose change
• Follow-up TSH annually once stable

• Calcium supplements, ferrous sulfate, PPIs, cholestyramine, sucralfate
• Rifampicin, phenytoin, carbamazepine, amiodarone (increase T4 metabolism)
• Estrogens (increase TBG binding)

• Treat if: TSH >10 mIU/L, OR patient is pregnant/wants to conceive, OR symptomatic
• Observe if: TSH 4-10 mIU/L with no symptoms

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Myxedema Coma

• IV levothyroxine (T4) 200-400 μg loading dose, then 50-100 μg/day
• Some add IV T3 (liothyronine) given slow T4-to-T3 peripheral conversion in critically ill
• IV hydrocortisone (concurrent adrenal insufficiency must be assumed and treated)
• Supportive: rewarming, ventilation, treat precipitant
• Begin IV T4 once clinical diagnosis is made - do NOT wait for lab confirmation (Plum & Posner's; Harrison's 22E)

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Quick Comparison Table

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Diseases of the Pituitary Gland

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Anatomy & Hormones - Quick Review

1. Hypersecretion - from functioning adenomas
2. Hyposecretion - hypopituitarism
3. Mass effects - from tumors pressing on adjacent structures

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PITUITARY ADENOMAS - Overview

• Microadenoma - <10 mm diameter; usually intrasellar, non-invasive
• Macroadenoma - ≥10 mm diameter; may invade parasellar structures

• Functioning (secreting): Prolactinoma (most common), GH-secreting, ACTH-secreting, TSH-secreting, Gonadotropin-secreting
• Non-functioning (clinically silent): Cause mass effects only

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MASS EFFECTS OF SELLAR LESIONS

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HYPERSECRETION SYNDROMES

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1. PROLACTINOMA (Most Common Functioning Adenoma)

• Accounts for ~50% of all functioning pituitary tumors
• Prevalence: ~10/100,000 men; ~30/100,000 women
• Female:male ratio = 20:1 for microadenomas; ~1:1 for macroadenomas

• PRL level >200 μg/L = very likely prolactinoma
• PRL <100 μg/L = may be microadenoma OR stalk compression by another lesion (stalk effect)
• MRI pituitary (with gadolinium) in ALL patients with hyperprolactinemia
• Note: dopamine agonists can suppress PRL from ANY cause, not just prolactinoma

• Dopamine agonists = first-line (suppress PRL synthesis + reduce tumor size)
  • Cabergoline - long-acting (twice weekly dosing), higher D2 affinity, ~80-90% efficacy, preferred
  • Bromocriptine - shorter-acting, preferred when pregnancy is desired
• Surgery (transsphenoidal) - for macroadenomas resistant or intolerant to dopamine agonists
• ~20% of patients (especially males) are dopamine agonist-resistant; surgery or radiation required
• Microadenomas that normalize on treatment may have dopamine agonist withdrawn after 2 years with close monitoring

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2. ACROMEGALY / GIGANTISM (GH-Secreting Adenoma)

• Gigantism = GH excess before epiphyseal closure (children) → tall stature
• Acromegaly = GH excess after epiphyseal closure (adults) → characteristic soft tissue and bony changes

• Screening: Random IGF-1 (elevated, age-matched)
• Confirmation: Oral glucose tolerance test (OGTT) - GH should suppress to <1 ng/mL after 75g glucose; failure to suppress confirms acromegaly
• MRI pituitary to localize the adenoma

1. Transsphenoidal surgery - first-line; cure rate ~80% for microadenomas, ~50% for macroadenomas
2. Somatostatin receptor ligands (SRLs) - octreotide LAR or lanreotide (normalize GH/IGF-1 in ~50%); also used as primary therapy if surgery not feasible
3. Pegvisomant - GH receptor antagonist; normalizes IGF-1 in >90%; used in SRL-resistant cases
4. Cabergoline - for mild residual disease post-surgery
5. Radiotherapy - last resort; slow effect over years, causes hypopituitarism

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3. CUSHING'S DISEASE (ACTH-Secreting Pituitary Adenoma)

Note: Cushing's DISEASE = pituitary ACTH-secreting adenoma specifically Cushing's SYNDROME = any cause of hypercortisolism (adrenal tumor, ectopic ACTH, exogenous steroids)

• 24-hour urinary free cortisol (UFC) - best screening test
• Overnight 1 mg dexamethasone suppression test - failure to suppress cortisol (<50 nmol/L) = positive
• Midnight serum/salivary cortisol - elevated (loss of normal diurnal rhythm)
• Inferior petrosal sinus sampling (IPSS) with CRH - gold standard to distinguish pituitary vs. ectopic ACTH when MRI is negative

• Transsphenoidal surgery - first-line (cure rate ~80% for microadenomas)
• Medical options (pre-op or when surgery fails): ketoconazole, metyrapone, osilodrostat, mifepristone, pasireotide (SST analogue effective specifically for Cushing's)
• Bilateral adrenalectomy - for refractory cases (risk of Nelson's syndrome: enlarging corticotrope adenoma post-adrenalectomy with extreme hyperpigmentation)
• Radiation - for recurrent/residual disease

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4. TSH-SECRETING ADENOMA (Rare, ~1% of adenomas)

• Causes secondary hyperthyroidism with a NORMAL or ELEVATED TSH (paradoxically)
• Presents as hyperthyroidism + goiter + non-suppressed TSH
• Distinguish from thyroid hormone resistance syndrome
• Treatment: transsphenoidal surgery + octreotide (SST suppresses TSH)

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5. NON-FUNCTIONING PITUITARY ADENOMAS

• No hormonal hypersecretion; often secrete gonadotropins (FSH, LH subunits) without clinical effect
• Present late with mass effects: visual field loss (bitemporal hemianopia), headache, hypopituitarism from compression
• Treatment: surgery (transsphenoidal) when causing symptoms; surveillance with serial MRI for small, asymptomatic lesions

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HYPOPITUITARISM

Causes

Key principle (hormone loss order): GH → FSH/LH → TSH → ACTH (GH fails first, ACTH last) In children: growth retardation is the presenting feature In adults: hypogonadism (menstrual irregularities in women, impotence in men) is the earliest symptom

Sheehan's Syndrome

Pituitary Apoplexy

• Sudden severe headache, visual changes, ophthalmoplegia, meningism
• Cardiovascular collapse in severe cases
• Management: High-dose glucocorticoids (acute adrenal insufficiency); urgent surgical decompression if visual loss or altered consciousness

Clinical Features of Hypopituitarism by Hormone

Laboratory Diagnosis

• "Low trophic hormone + low target hormone" pattern
• e.g., Low free T4 + low/normal TSH = secondary hypothyroidism
• e.g., Low testosterone + low/normal LH = hypogonadotropic hypogonadism
• Insulin tolerance test (ITT): gold standard for GH and ACTH reserve (glucose <2.2 mmol/L with peak GH <3 ng/mL = GH deficiency; peak cortisol <500 nmol/L = ACTH deficiency)

Treatment of Hypopituitarism (Hormone Replacement)

⚠️ Always replace cortisol before thyroid hormone - giving T4 in unrecognized ACTH deficiency can precipitate adrenal crisis.

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POSTERIOR PITUITARY DISORDERS

Arginine Vasopressin Deficiency (AVP-D) / Central Diabetes Insipidus

• Causes: Pituitary/hypothalamic surgery, tumors (craniopharyngioma), trauma, sarcoidosis, histiocytosis X, metastases (posterior pituitary), idiopathic (~30%)
• Features: Polyuria (>3 L/day), polydipsia, dilute urine (low specific gravity <1.005), normal serum glucose
• Diagnosis: Water deprivation test - failure to concentrate urine, corrected by DDAVP (confirms central vs. nephrogenic DI)
• Treatment: Desmopressin (DDAVP) - synthetic AVP analogue, given intranasally, orally, or IV

SIADH (Syndrome of Inappropriate ADH Secretion)

• Excess AVP secretion: euvolemic hyponatremia, concentrated urine in the setting of dilute plasma
• Causes: CNS disease, ectopic (small cell lung cancer), drugs (carbamazepine, SSRIs, vincristine), postoperative state
• Treatment: fluid restriction; severe/symptomatic: hypertonic saline; tolvaptan (V2 receptor antagonist) for chronic SIADH

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Summary Table: Pituitary Tumors at a Glance

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ADH (Antidiuretic Hormone) Physiology - Simple Explanation

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What is ADH?

• "Anti" = against
• "Diuretic" = making urine
• So ADH literally means: "hormone that prevents excess urine production"

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Where is it Made and Stored?

Hypothalamus (makes it)
        ↓
Travels down the pituitary stalk
        ↓
Posterior Pituitary (stores & releases it)

• Supraoptic nucleus
• Paraventricular nucleus

Think of it like a water factory (hypothalamus) connected to a warehouse (posterior pituitary) via a delivery pipe (pituitary stalk).

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The Big Idea: Why Does the Body Need ADH?

• If you get dehydrated (not enough water) → blood becomes too concentrated (high osmolality) → DANGER
• If you drink too much water → blood becomes too dilute (low osmolality) → also DANGER

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What Triggers ADH Release? (Stimuli)

1. High Blood Osmolality (Most Sensitive Trigger)

• Special sensors called osmoreceptors in the hypothalamus detect this
• Even a 1-2% rise in blood osmolality is enough to trigger ADH release
• ADH is released → kidneys hold onto water → urine becomes dark and concentrated → osmolality returns to normal

2. Low Blood Volume / Low Blood Pressure

• Baroreceptors (pressure sensors) in the carotid artery and aorta detect the drop
• They signal the hypothalamus to release ADH
• But this requires a much bigger stimulus - a 5-10% drop in blood volume is needed (less sensitive than osmolality)

3. Other Stimulants

• Nausea (very powerful ADH trigger - this is why vomiting can cause water retention)
• Pain
• Stress
• Nicotine
• Hypoglycemia (low blood sugar)
• Some drugs (opioids, carbamazepine, cyclophosphamide)

What SUPPRESSES ADH?

• Drinking lots of water (low osmolality)
• Alcohol (alcohol blocks ADH → you urinate more after drinking → dehydration and hangover)
• Atrial natriuretic peptide (ANP)

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How Does ADH Work on the Kidney?

ADH released into blood
        ↓
Travels to kidney collecting duct
        ↓
Binds to V2 receptors on collecting duct cells
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Activates adenylate cyclase → ↑ cAMP
        ↓
cAMP moves water channels (Aquaporin-2) to cell surface
        ↓
Water flows from urine back into blood
        ↓
Urine becomes concentrated, less volume produced

Imagine the collecting duct is a pipe with lots of tiny "water doors" (aquaporins) stored in a closet. Normally the doors are locked away. When ADH arrives, it sends a signal that opens the closet and installs water doors into the pipe wall. Now water can flow from the pipe (urine) back into the body (blood). When ADH is gone, the doors get taken off the wall and put back in the closet.

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The ADH-Osmolality Relationship

Without ANY ADH: urine output can reach 800-1000 mL per hour! (18-24 L/day) - this is what happens in untreated Diabetes Insipidus.

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The Role of THIRST

Dehydration → Blood osmolality rises
        ↙               ↘
ADH released           Thirst activated
(kidney saves water)   (you drink water)

• ADH is the first line of defense - tries to fix the problem quietly (retaining water)
• Thirst is the backup - makes you actively seek water when dehydration is more severe

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ADH's Other Receptors (Beyond the Kidney)

At normal blood levels, ADH mainly works on V2 (kidney). It only causes significant vasoconstriction at HIGH (pharmacologic) doses - which is why vasopressin is used as a drug in septic shock.

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ADH and Clotting Factor VIII

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What Happens When ADH Goes Wrong?

Too LITTLE ADH (or kidney ignores it) = Diabetes Insipidus (DI)

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Too MUCH ADH = SIADH (Syndrome of Inappropriate ADH)

• Low serum sodium (<135 mmol/L)
• Low plasma osmolality
• Urine osmolality inappropriately HIGH (>100 mOsm/kg) - kidney still concentrating because of excess ADH
• Urine sodium >20 mmol/L

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Quick Summary Diagram

DEHYDRATION / HIGH OSMOLALITY / LOW BP
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   Hypothalamus osmoreceptors / baroreceptors
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   ADH released from posterior pituitary
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   ADH → V2 receptor on kidney collecting duct
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   ↑ cAMP → AQP2 water channels inserted
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   Water saved from urine → back into blood
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   Blood osmolality normalizes, urine becomes concentrated
              
WELL-HYDRATED / LOW OSMOLALITY
              ↓
   ADH suppressed
              ↓
   AQP2 channels removed from membrane
              ↓
   Water passes out as dilute urine

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