Hyperthyroidism

Common causes

• Graves disease: diffuse autoimmune thyroid stimulation, often with eye disease and pretibial myxedema
• Toxic multinodular goiter
• Toxic adenoma
• Thyroiditis: subacute painful, painless/postpartum, or drug-induced. This produces thyrotoxicosis through hormone leakage, not increased synthesis.
• Iodine or amiodarone-induced thyrotoxicosis
• Excess exogenous thyroid hormone
• Rare: TSH-secreting pituitary adenoma

Clinical features

General and metabolic

• Weight loss despite normal or increased appetite
• Heat intolerance and excessive sweating
• Fatigue, weakness, especially proximal muscle weakness
• Increased thirst
• Warm, moist skin; fine hair; onycholysis

Neuropsychiatric

• Nervousness, irritability, anxiety
• Insomnia
• Fine tremor of outstretched hands
• Brisk deep-tendon reflexes

Cardiovascular

• Palpitations
• Sinus tachycardia
• Atrial fibrillation, particularly in older adults
• Systolic hypertension, flow murmur
• Angina or heart failure may worsen

Gastrointestinal and reproductive

• Increased bowel frequency or diarrhea
• Oligomenorrhea, amenorrhea, reduced fertility
• Reduced libido and erectile dysfunction in men

Eye and thyroid signs

• Diffuse or nodular goiter
• Thyroid bruit or thrill in Graves disease
• Stare, lid retraction and lid lag
• Graves orbitopathy: proptosis, diplopia, chemosis, restrictive eye movements
• Pretibial myxedema: specific to Graves disease

Special presentations

• Older people may present mainly with weight loss, weakness, atrial fibrillation, or heart failure rather than obvious adrenergic symptoms.
• Thyroid storm: fever, marked tachyarrhythmia, agitation/delirium, vomiting/diarrhea, heart failure, and hepatic dysfunction. This is an emergency.

Investigations

1. Confirm biochemical hyperthyroidism

1. Serum TSH: best initial test
   • Usually suppressed/undetectable
2. Free T4 and free T3
   • Overt hyperthyroidism: low TSH with raised free T4 and/or T3
   • T3 toxicosis: low TSH, raised T3, normal free T4
   • Subclinical hyperthyroidism: low TSH with normal free T4 and T3

2. Identify the cause

• TSH-receptor antibody (TRAb) or thyroid-stimulating immunoglobulin (TSI)
  • Supports/establishes Graves disease.
• Radioactive iodine uptake (RAIU) and thyroid scan, if not pregnant or breastfeeding:
  • Diffuse high uptake: Graves disease
  • Patchy/multiple focal uptake: toxic multinodular goiter
  • Single focal uptake: toxic adenoma
  • Very low uptake: thyroiditis, iodine exposure, or exogenous thyroid hormone
• Thyroid ultrasound with color Doppler
  • Useful if radioisotope scanning is unsuitable or if nodules are present.
  • Graves typically has diffuse enlargement and increased vascularity.
• ESR/CRP
  • Often raised in painful subacute thyroiditis.
• Serum thyroglobulin
  • Low in factitious thyrotoxicosis from exogenous hormone; usually raised in endogenous thyroid hormone release/production.

3. Assess complications and treatment safety

• ECG: sinus tachycardia or atrial fibrillation
• CBC and liver function tests before antithyroid drugs
• Pregnancy test before radioiodine
• Eye assessment if Graves orbitopathy is suspected
• Bone-density assessment in selected patients with persistent/subclinical disease or fragility risk

Management

A. Immediate symptomatic control

• Beta-blocker, unless contraindicated
  • Propranolol is commonly used for tremor, palpitations, anxiety, and tachycardia. It also reduces peripheral conversion of T4 to T3 at higher doses.
  • Alternatives: atenolol/metoprolol; diltiazem or verapamil if beta-blockers cannot be used.
• Correct dehydration, treat arrhythmia or heart failure, and address triggers such as infection.

B. Antithyroid drugs

• Methimazole/carbimazole: preferred in most non-pregnant patients.
• Propylthiouracil (PTU):
  • Preferred in the first trimester of pregnancy
  • Preferred in thyroid storm because it also inhibits peripheral T4-to-T3 conversion
  • Avoid prolonged use where possible because severe hepatotoxicity can occur.

C. Definitive therapy

D. Cause-specific points

• Graves disease: antithyroid drugs, RAI, or surgery. Avoid smoking because it worsens orbitopathy. Refer promptly if reduced visual acuity, impaired color vision, corneal exposure, or optic neuropathy is suspected.
• Toxic adenoma/multinodular goiter: RAI or surgery is generally definitive; antithyroid drugs control hormone excess but do not cure autonomy.
• Thyroiditis: antithyroid drugs are not useful because synthesis is not increased. Use beta-blocker; NSAIDs or corticosteroids may be needed for painful subacute thyroiditis.
• Exogenous thyroid hormone: stop/reduce the source and give beta-blockade as required.
• Amiodarone-induced thyrotoxicosis: specialist management, as the mechanism and treatment differ by type.

E. Thyroid storm

• Beta-blocker
• PTU or methimazole
• Iodine solution after antithyroid medication
• Hydrocortisone
• Fluids, cooling, oxygen, treatment of precipitating cause, and close cardiac monitoring

Follow-up

• Monitor free T4 and T3 during early therapy. TSH may stay suppressed for weeks to months and is not reliable initially for dose adjustment.
• After RAI or surgery, monitor for hypothyroidism and start levothyroxine when indicated.
• Persistent untreated hyperthyroidism increases the risk of atrial fibrillation, heart failure, osteoporosis, and fractures.

Hypothyroidism

• Primary: thyroid gland failure, causing high TSH
• Central (secondary/tertiary): pituitary or hypothalamic disease, causing low or inappropriately normal TSH with low free T4

Causes

Primary hypothyroidism

• Autoimmune thyroiditis: Hashimoto or atrophic thyroiditis
• Previous radioactive iodine treatment or thyroid surgery
• Drugs: amiodarone, lithium, antithyroid drugs, interferon, immune checkpoint inhibitors, tyrosine-kinase inhibitors
• Neck irradiation
• Iodine deficiency or iodine excess
• Subacute, painless, or postpartum thyroiditis, sometimes transient
• Congenital thyroid dysgenesis/dyshormonogenesis
• Infiltrative disease: amyloidosis, sarcoidosis, hemochromatosis, Riedel thyroiditis

Central hypothyroidism

• Pituitary or hypothalamic tumor
• Pituitary surgery or irradiation
• Sheehan syndrome
• Head injury or infiltrative disease
• Drugs such as bexarotene or mitotane

Clinical features

General and metabolic

• Fatigue, lethargy, excessive sleepiness
• Weight gain despite reduced appetite
• Cold intolerance
• Reduced sweating
• Slow speech and movements

Skin, hair, and face

• Dry, coarse, cool, pale skin
• Coarse or brittle hair, hair loss especially lateral eyebrows
• Puffy face and periorbital edema
• Non-pitting edema, termed myxedema
• Brittle nails

Neuropsychiatric and neuromuscular

• Poor concentration, memory impairment, depression
• Slow thinking, delayed relaxation of deep-tendon reflexes
• Paresthesia/carpal tunnel syndrome
• Myalgia, cramps, proximal muscle weakness
• Hoarse voice, macroglossia in severe disease

Cardiovascular and respiratory

• Bradycardia
• Reduced exercise tolerance
• Diastolic hypertension
• Pericardial effusion, low-voltage ECG, hypercholesterolemia
• Dyspnea, pleural effusion, hypoventilation in severe disease

Gastrointestinal and reproductive

• Constipation
• Menorrhagia or irregular menstruation
• Infertility and recurrent miscarriage
• Reduced libido, erectile dysfunction
• Galactorrhea may occur due to increased TRH and prolactin

Thyroid findings

• Firm, diffuse goiter may occur in Hashimoto thyroiditis.
• The gland may be small or impalpable in atrophic autoimmune disease or after ablation.

In infants and children

• Prolonged jaundice, poor feeding, constipation, hypotonia, large tongue
• Delayed growth and neurodevelopment if untreated congenital hypothyroidism

Investigations

1. Thyroid function tests

• TSH is the preferred initial screening test for suspected primary hypothyroidism.
• Measure free T4 to confirm disease and assess severity.
• TSH alone is unreliable in suspected central hypothyroidism.

2. Determine the cause

• Anti-thyroid peroxidase antibodies (anti-TPO): supports autoimmune/Hashimoto thyroiditis.
• Anti-thyroglobulin antibodies: may be supportive, but are less commonly necessary.
• Review previous thyroid surgery, radioiodine, radiation, and medication history.
• Pituitary hormone profile and MRI pituitary if central hypothyroidism is suspected.
• Thyroid ultrasound is not routinely needed merely to diagnose hypothyroidism. Use it for a palpable goiter, nodule, or suspected structural disease.

3. Assess complications and associated conditions

• Full blood count: normocytic or macrocytic anemia may occur.
• Lipid profile: raised LDL cholesterol and triglycerides are common.
• Creatine kinase: may be raised with hypothyroid myopathy.
• Serum sodium: may be low in severe disease.
• ECG: bradycardia, low voltage, or other cardiac abnormalities.
• Check for associated autoimmune disease where clinically indicated, for example type 1 diabetes, celiac disease, pernicious anemia, or adrenal insufficiency.

Management

A. Overt primary hypothyroidism

• Typical full replacement requirement in healthy adults with little/no residual thyroid function: approximately 1.6 micrograms/kg/day.
• Younger adults without cardiac disease can often start at a near-full dose.
• In older adults, frail patients, or those with coronary artery disease, start at a low dose and titrate slowly to avoid angina, arrhythmia, or ischemia.
• Take LT4 consistently, preferably on an empty stomach, at least 30 minutes before breakfast.

Important interactions and administration advice

• Iron salts
• Calcium supplements
• Aluminium-containing antacids
• Sucralfate
• Bile-acid sequestrants
• Some proton-pump inhibitors
• Food, coffee, and high-fiber intake in some patients

B. Central hypothyroidism

• Treat with levothyroxine, but monitor free T4 rather than TSH for dose adjustment.
• Assess for concomitant adrenal insufficiency first. If suspected, give glucocorticoid replacement before LT4 to avoid precipitating adrenal crisis.

C. Subclinical hypothyroidism

• TSH is persistently 10 mIU/L or higher
• Symptoms are convincing
• Anti-TPO antibodies are positive
• Goiter is present
• Pregnancy, infertility, or planned conception is relevant
• There is cardiovascular risk or dyslipidemia, especially in younger patients

D. Pregnancy

• Women with established hypothyroidism should have TSH checked before conception and as soon as pregnancy is confirmed.
• LT4 requirements commonly increase during pregnancy.
• Levothyroxine alone is used. T3-containing combinations and desiccated thyroid extract should be avoided in pregnancy.

E. Treatments generally not routine

• Liothyronine (T3) is not standard long-term monotherapy.
• LT4 plus T3 combination therapy is not routinely supported by prospective evidence.
• Desiccated thyroid extract is not recommended routinely because its T3:T4 ratio is nonphysiologic and hormone levels can fluctuate. Harrison’s Principles of Internal Medicine 22E, p. 3075.

Myxedema coma: emergency

• Altered mental status
• Hypothermia
• Bradycardia and hypotension
• Hypoventilation and carbon dioxide retention
• Hyponatremia or hypoglycemia
• Pericardial or pleural effusions

1. Starting levothyroxine dose

2. Dose adjustment for a patient already on levothyroxine

3. Important exceptions

• Pregnancy or attempting conception: do not use this table alone. Dose requirements often rise promptly, and TSH is monitored about every 4 weeks.
• Central hypothyroidism: TSH cannot guide dosing reliably. Adjust to free T4, usually targeting the upper half of the reference range after excluding/treating adrenal insufficiency.
• Elderly people or those with ischemic heart disease: never rapidly escalate solely because TSH is markedly high.
• Myxedema coma: requires hospital/ICU management with IV therapy, not outpatient tablet dosing.
• If TSH remains high despite a seemingly adequate dose, first check missed doses, whether it is taken fasting, and interactions with iron, calcium, antacids, sucralfate, bile-acid sequestrants, food, and some PPIs.

Common effects of excessive dose

• Palpitations, fast pulse, or pounding heartbeat
• Tremor, nervousness, anxiety, irritability
• Insomnia
• Headache
• Heat intolerance and sweating
• Increased appetite and weight loss
• Diarrhea or abdominal cramps
• Muscle weakness or cramps
• Menstrual irregularity

Important or serious effects

• Tachyarrhythmias, especially atrial fibrillation
• Worsening angina, myocardial ischemia, or heart failure in susceptible patients
• Raised blood pressure
• Long-term over-replacement with a suppressed TSH can contribute to reduced bone density and fractures, particularly in postmenopausal women
• Worsening glucose control in diabetes, sometimes requiring adjustment of insulin or other glucose-lowering medication

Allergy-like reactions

• Rash, itching, hives, flushing
• Nausea, vomiting, abdominal pain
• Wheeze or facial/lip swelling, which needs urgent care

Children

• Irritability, poor sleep, fast heartbeat
• Pseudotumor cerebri
• Premature closure of growth plates with prolonged overtreatment

Seek urgent medical care for

• Chest pain
• New irregular or very fast heartbeat
• Fainting, severe breathlessness
• Facial/throat swelling or difficulty breathing

Possible causes

1. Sympathetic nerve dysfunction

• Harlequin syndrome: one side of the face, neck, upper chest, or occasionally arm flushes and sweats with heat, exercise, or emotion, while the other side does not.
• Horner syndrome, especially if there is:
  • Drooping upper eyelid
  • Smaller pupil on one side
  • Reduced facial sweating on that same side

2. Local nerve injury or disease

• Prior neck/chest/shoulder surgery or trauma
• Cervical disc/spine disease or spinal cord lesion
• Herpes zoster affecting nerves
• Diabetes-related autonomic neuropathy
• Tumor compressing/invading a nerve pathway, including an apical lung lesion
• Thoracic outlet pathology, although this is uncommon

3. Localized skin/sweat-gland conditions

• Idiopathic localized unilateral hyperhidrosis
• Local skin tumors/vascular lesions, rarely
• Complex regional pain syndrome, usually with pain, color/temperature change, swelling, or altered sensation

4. Less likely systemic causes

When to seek urgent care

• New drooping eyelid, unequal pupils, double vision, or visual loss
• Severe new headache, neck pain, or facial pain
• Weakness, numbness, facial droop, imbalance, speech difficulty, or confusion
• New chest pain, shortness of breath, persistent cough, coughing blood, or unexplained weight loss
• Symptoms after neck trauma or manipulation

Evaluation

1. Distribution
   • Face only, face and upper chest, one arm, trunk, or entire half of body?
   • Is the other side truly dry?
2. Triggers
   • Heat, exercise, emotion, meals, sleep, pain, or no trigger?
3. Associated signs
   • Flushing, color or temperature difference
   • Ptosis or unequal pupils
   • Altered sensation, weakness, pain, headache
   • Previous shingles, diabetes, surgery/trauma, medications
4. Examination
   • Full neurologic examination
   • Pupils and eyelids for Horner syndrome
   • Neck, chest, lungs, spine, and skin examination
5. Possible tests, guided by findings
   • Blood glucose/HbA1c, thyroid tests, medication review
   • Chest X-ray or CT if chest/apical lung pathology is a concern
   • MRI brain, cervical spine, or chest/neck if neurologic signs or unexplained new-onset symptoms exist
   • CT/MR angiography if acute painful Horner syndrome is suspected
   • Specialized sweat tests, such as thermoregulatory sweat testing or QSART, in selected cases

Management

• Treat an identified underlying condition: for example, diabetes optimization, treating a nerve lesion, addressing a spine/chest/neck cause, or stopping a causative medicine where appropriate.
• If testing is normal and this is idiopathic localized hyperhidrosis, symptom treatment may include:
  • Aluminum chloride antiperspirant for a small accessible area
  • Topical anticholinergic treatment in selected areas
  • Botulinum toxin injections for focal troublesome sweating
  • Oral anticholinergics only under clinician supervision, as they can cause dry mouth, constipation, blurred vision, urinary retention, and confusion, particularly in older adults
• Harlequin syndrome is frequently benign and may need reassurance only, but this should follow an appropriate evaluation when it starts in adulthood.