Weight loss occurs when energy expenditure exceeds energy intake. The differential is broad, but two classic endocrine causes produce weight loss despite increased appetite:

Diabetes mellitus and Hyperthyroidism — these are the two endocrine conditions causing weight loss despite increased appetite. ^[6]

Other major causes of severe weight loss include:

• Malignancy (increased metabolic demand, cytokines, anorexia)
• Chronic infections (e.g. TB — especially if a diabetic patient has marked weight loss)
• Malabsorption (coeliac, chronic pancreatitis, inflammatory bowel disease)
• Psychiatric (anorexia nervosa, depression)
• Chronic organ failure (cardiac cachexia, COPD, CKD)
• Hypermetabolic states post-surgery/sepsis (amino acid and fatty acid mobilisation from muscle and fat) ^[7]

The thyroid gland produces predominantly the prohormone T4 together with a small amount of the bioactive hormone T3. Most T3 is produced by enzymatic outer ring deiodination (ORD) of T4 in peripheral tissues. ^[1]

HPT Axis:

1. Hypothalamus → releases TRH (thyrotrophin-releasing hormone)
2. Anterior pituitary → releases TSH (thyroid-stimulating hormone)
3. Thyroid gland → synthesises and releases T4 (predominant) and T3
4. T4/T3 exert negative feedback on both hypothalamus and pituitary

Steps of Thyroid Hormone Synthesis (7-step pathway from lecture): ^[1]

Key molecules:

• Thyroglobulin — backbone protein for making and storing thyroid hormone ^[1]
• Thyroid peroxidase (TPO) — previously known as thyroid microsomal enzyme; catalyses organification and coupling ^[1]

Mechanism of Thyroxine Action:

T3 has avid cellular uptake → binds intracellular protein receptor (T3 > T4 affinity) → modulates nuclear RNA → enzyme synthesis + protein synthesis + mitochondrial oxidative phosphorylation. ^[1]

This is why thyroid hormone affects virtually every organ system — it increases basal metabolic rate by driving mitochondrial ATP production, protein turnover, and enzymatic activity.

Circulating thyroid hormones:

• > 99% protein-bound (to TBG primarily, also TBPA/transthyretin and albumin) ^[1]
• Only the free fraction is biologically active
• 0.02% of T4 and 0.2% of T3 exist as free forms ^[1]

TSH is used to screen for primary thyroid dysfunction because of the inverse log/linear relationship between fT4 and TSH — small alterations in fT4 lead to a large response in serum TSH. In early thyroid dysfunction, TSH abnormality will precede the development of abnormal fT4. ^[1]

Prerequisites for TSH-centred screening: ^[1]

1. Intact hypothalamic-pituitary axis (otherwise TSH may be inappropriately normal/low in central hypothyroidism)
2. Stable thyroid status (no recent anti-thyroid therapy initiation — TSH takes weeks to equilibrate)

Symptoms of Hyperthyroidism: Weight loss, palpitations, nervousness, easy fatiguability, excessive sweating, heat intolerance, hyperkinaesia, increased bowel motions, hair loss, visual complaints. ^[1]

Signs of Hyperthyroidism: Goitre, tachycardia, sweaty palms, hand tremor, pretibial myxoedema, periorbital edema, lid lag, lid retraction, exophthalmos (proptosis), ophthalmoplegia, corneal involvement, sight loss. ^[1]

Understanding "why" each symptom/sign occurs:

Causes: Graves' disease, toxic multinodular goitre, toxic solitary adenoma, thyroiditis (subacute / painless / medications including immune checkpoint inhibitors), TSH-secreting pituitary adenoma, molar hyperthyroidism, factitious causes. ^[1]

Autoimmune disease: lymphocytes produce thyrotropin-receptor antibody (TRAb) that stimulates the TSH receptor on the thyroid gland → stimulates thyroid cell hyperplasia and increases thyroid hormone release → hyperthyroidism, which in turn suppresses TSH release from the pituitary. ^[1]

Female preponderance F:M = 4.8:1. Highest incidence 20–50 years. Diffuse goitre with thyroid bruit. Symptoms and signs of hyperthyroidism. Graves' ophthalmopathy. Pretibial myxoedema. ^[1]

Associated autoimmune diseases: myasthenia gravis, type 1 diabetes mellitus ^[1]

Complications: AF, heart failure, thyroid storm, thyrotoxic periodic paralysis ^[1]

Clinical Diagnosis! Diffusely enlarged thyroid gland (not nodular). Raised fT4/fT3 and suppressed TSH. Positive anti-TSHR antibody. Diffusely increased uptake on radioiodine scintillation scan. Diffusely increased vascularity on ultrasound. ^[1]

Prognostic indicator: positive TRAb at end of therapy → higher relapse chance. Negative TRAb → prolonged remission likely. Forecasting neonatal Graves' disease: high TRAb → transplacental passage causes neonatal Graves'. Aids diagnosis (nearly 100% positive in active Graves'). Level decreases with anti-thyroid drug treatment. ^[1]

Ultrasound: useful for palpable thyroid nodules to evaluate suspicious sonographic features. Thyroid scan: suggested when thyroid nodularity co-exists with hyperthyroidism, or if thyroiditis is suspected. ^[1]

Anti-thyroid drugs (thiouracil derivatives: methimazole, carbimazole, propylthiouracil; lithium). Surgery. Radioactive iodine therapy. Ancillary: beta-blockers, iodide (Lugol's iodine), sedatives. ^[1]

Mechanisms of thiouracil derivatives (MMZ/CMZ/PTU): (1) Inhibit organification of iodide, (2) Inhibit coupling of iodotyrosines, (3) PTU also inhibits peripheral T4→T3 conversion, (4) Immunosuppressive effects on thyroid autoantibodies. ^[1]

Pharmacological Properties:

Pregnancy management: Change MMZ/CMZ to PTU if planning conception and remain until end of first trimester. Change back to MMZ/CMZ in second trimester for less hepatotoxicity. ^[1]

Block-and-replace therapy: Sometimes thiouracil + T4 supplementation to prevent hypothyroidism swings ^[1]

Rash (5%). Agranulocytosis (0.1%) — idiosyncratic, reversible with discontinuation + G-CSF, usually in first 2–3 months, increased with age > 40 and high doses. Usual presenting symptoms: fever, sore throat. Rare: cholestatic jaundice, hepatotoxicity, acute arthralgia, ANCA-induced vasculitis. ^[1]

Larger goitre, positive family history, higher fT3 or fT3/fT4 ratio, shorter treatment course, failure to normalise TSH during treatment, high anti-TSHR levels. ^[1]

Indications:

Young age, failed medical treatment, intolerance/contraindications to ATD, refused RAI, significant Graves' ophthalmopathy, expecting pregnancy, large goitre especially with compressive effects. ^[1]

Preoperative Optimisation:

Anti-thyroid medications until euthyroid. Beta-blockers for at least 2 weeks. (Lugol's iodine — to reduce thyroid vascularity and size). ^[1]

The Lugol's iodine works via the Wolff-Chaikoff effect: supraphysiological iodide transiently inhibits thyroid hormone synthesis and reduces gland vascularity, making surgery safer. It should not be given for > 10–14 days as the thyroid "escapes" the effect. ^[10]

Complications of Thyroid Surgery:

Primary hypothyroidism (lifelong T4 replacement needed), vocal cord dysfunction (RLN injury — transient vs permanent; external branch of SLN), hypoparathyroidism (transient vs permanent), bleeding, tracheomalacia, wound complications (seroma, hypertrophic scar), precipitation of thyroid storm, GA risks. ^[1]

In use since late 1940s. Low relapse rate (15% after 1 dose). Simple and economical. No immediate complications. ^[1]

Indications:

Relapsed thyrotoxicosis (especially after previous surgery), thyrotoxic heart disease, thyrotoxic periodic paralysis, contraindications to surgery, toxic multinodular goitre. ^[1]

Mechanism:

Beta emission almost completely absorbed → necrosis of follicular cells, fibrosis, disappearance of colloid. Non-destroyed cells have limited replication. ^[1]

Complications and Precautions:

Primary hypothyroidism: transient 3.5–28%, permanent 10–15% in first 2 years then 3%/year. Fetal risk definite: transient radiation-induced changes in gametes — avoid pregnancy for 6–12 months; crosses placenta concentrated by fetal thyroid > 12 weeks; excreted in milk → CONTRAINDICATED in pregnant and lactating women. NO increase in thyroid carcinoma, leukaemia, or transmissible genetic damage. Increased risk of de novo or exacerbation of Graves' ophthalmopathy. May precipitate thyroid storm from radiation thyroiditis. ^[1]

Orbital fibroblasts are the target cells. A subpopulation can differentiate into adipocytes with increased TSH receptor expression. TSH stimulates orbital adipogenesis. TRAb stimulates orbital adipocytes. TRAb level correlates with clinical scores of GO. ^[1]

Histological changes: ^[1]

• Extraocular muscles: oedema, mononuclear cell infiltration, mucopolysaccharide accumulation, fibrosis
• Retrobulbar fat: lymphocytic infiltration, fibrous tissue, hyaluronic acid accumulation
• Optic nerve: atrophy, replaced by fibrous/fatty connective tissue

Key clinical points:

Patients can be hyper-, hypo-, or euthyroid. 80% develop eye signs within 18 months of thyrotoxicosis diagnosis. ^[1]

Assessment of GO: ^[1]

• Comprehensive ophthalmological exam: VA, IOP, colour vision, optic nerve function, extraocular movements
• Radiological: MRI orbit preferred (or CT) — crowding of orbital apices, extraocular muscle enlargement, optic nerve calibre

F/30, malaise, feeling cold, constipation, weight gain, central neck swelling. Low thyroid hormone and high TSH. ECG: sinus bradycardia. ^[1]

Symptoms: fatigue, weakness, cold intolerance, dry skin, hair loss, constipation, weight gain with decreased appetite, difficulty concentrating, hoarseness, menorrhagia (later oligo/amenorrhoea), paraesthesia, impaired hearing ^[1][8]

Signs: dry/cold skin, puffiness of face/hands/feet (myxoedema — non-pitting), bradycardia, alopecia, delayed tendon reflex relaxation, hyporeflexia, carpal tunnel syndrome, periorbital oedema, macroglossia ^[1][8]

Delayed reflexes in hypothyroidism — the "slow-relaxing ankle jerk" is a classic clinical finding. ^[1]

Primary: autoimmune (atrophic thyroiditis, Hashimoto's), post-RAI, post-subtotal thyroidectomy, subacute thyroiditis, medications (e.g. immune checkpoint inhibitors), congenital, excessive iodide intake, iodine deficiency (borderline iodine intake in Hong Kong). Central/secondary hypothyroidism. ^[1]

Lymphocytic thyroiditis, atrophic thyroiditis, Hashimoto's thyroiditis (enlarged thyroid with lymphocytes), postpartum thyroiditis. Variable prognosis depending on residual thyroid reserve. ^[1]

Autoimmune disease. Common cause of primary hypothyroidism. Low T4, high TSH. Positive anti-TPO antibody. Enlarged goitre due to fibrosis and lymphocytic infiltration. Common in middle-aged women. May be associated with other autoimmune diseases. ^[1]

Also called giant cell thyroiditis. Fever, acute neck pain, tender goitre. Leucocytosis with high ESR. NSAIDs or corticosteroids in severe cases. Histology: giant cells and lymphocytes. ^[1]

The natural history of subacute thyroiditis is: painful thyrotoxic phase (preformed hormone leak) → hypothyroid phase → recovery to euthyroid (most patients). This explains why the thyroid scan shows decreased uptake despite elevated thyroid hormones — the gland is inflamed and leaking, not actively synthesising.

Local (HK) incidence 1:3000. Neonatal cord blood TSH screening. Suspicious at 2 weeks if fT4 < 12 pmol/L and TSH > 7 mIU/L. Early treatment to preserve brain development. ^[1]

Newborn findings: cretinism, mental retardation, puffy face, deafness, mutism, protuberant abdomen, umbilical hernia ^[1]

Causes: athyroesis, dyshormonogenesis, ectopic thyroid, associated syndromes (Down syndrome, trisomy 18, CHD), hypothalamic-pituitary hypothyroidism, transient (maternal ATD use, maternal blocking Ab, neonatal iodine deficiency, prematurity) ^[1]

With little residual thyroid function: ~1.6 μg/kg/day of L-thyroxine. ^[1]

For patients with known/suspected coronary heart disease: ^[1]

• Hypothyroidism causes hyperlipidaemia → atherosclerosis
• Starting T4 ↑ cardiac output → may worsen cardiac symptoms
• Manage coronary atherosclerosis first, then start T4 at low dose (12.5–25 μg daily)

Practical points:

• TSH may decline within 1 month of starting
• Separate from iron/calcium supplements by ≥ 4 hours (they impair absorption)
• After dose changes, wait 4–6 weeks before rechecking TSH
• Pregnancy targets: TSH < 2.5 (1st trimester), < 3.0 (2nd), < 3.5 mIU/L (3rd) ^[1]

Low TSH with normal fT4. Investigate with thyroid antibodies, ultrasound, and/or thyroid scan. Management: assess for AF, osteoporosis; regular TFT monitoring. ^[1]

High TSH with normal fT4. Investigate with thyroid antibodies. Management: assess lipid levels and hypothyroid symptoms; regular TFT monitoring. Start T4 replacement if persistent TSH > 10 mIU/L. ^[1]

Can cause hyper- or hypothyroidism. Be cautious interpreting TFTs if contrast given in last 2–3 months. Due to supraphysiological iodine concentrations. Prevalence 1–15%. Hyperthyroidism: mainly in iodine-deficient regions or underlying nodular goitre/latent Graves'. Hypothyroidism: at-risk patients with autoimmune thyroiditis in iodine-sufficient areas. Most cases mild and transient. ^[1]

Most common immunotherapy-related adverse event (IRAE). Incidence: anti-CTLA4 monotherapy 25%, anti-PD-1/PD-L1 monotherapy 38%, dual therapy 56%. Most develop within 6 weeks but can occur years into therapy. Large majority of ICI-related thyrotoxicosis is due to thyroiditis (self-limiting) — acute immune-mediated destruction of follicular cells. Can evolve into hypothyroidism or resolve to euthyroid within 6 weeks. If central hypothyroidism found, must exclude concomitant secondary cortisol insufficiency. ^[1]

1. Which disturbance gives rise to sweating, palpitation, and weight loss? → Hyperthyroidism (not hypoglycaemia — which causes transient sweating/palpitation but not sustained weight loss) ^[3]

2. A patient on carbimazole presents with fever and sore throat. What is the most important investigation? → Urgent CBC (to exclude agranulocytosis) ^[1]

3. Which of the following is contraindicated in a pregnant patient with thyrotoxicosis? → Radioactive iodine ^[1]

4. A patient with thyrotoxicosis has a thyroid scan showing decreased uptake. What is the most likely diagnosis? → Thyroiditis (subacute or painless) ^[1]

5. What is the MOST LIKELY cause of weight loss in a post-surgical patient with septic complications? → Mobilisation of amino acid and fatty acid from muscle and fat ^[7]

2023 SAQ Q6: ^[4]

• (a) Diagnosis: Graves' disease (bilateral proptosis + diffuse goitre with bruit + heat intolerance + weight loss)
• (b) Important immunological investigation: TRAb (anti-TSHR antibody)
• (c) Most appropriate medication: Carbimazole (or methimazole); life-threatening side effect: Agranulocytosis
• (d) Two definitive therapies: Total thyroidectomy and Radioactive iodine therapy

2021 SAQ Q11: ^[5]

• (a) Most likely diagnosis: Hypothyroidism
• (b) Two conditions causing hypothyroidism: Hashimoto's thyroiditis, post-radioactive iodine therapy (or post-thyroidectomy, iodine deficiency, etc.)
• (c) Additional symptoms: cold intolerance, constipation, hair loss, menorrhagia, dry skin, hoarseness
• (d) Physical exam signs: delayed tendon reflex relaxation, bradycardia, non-pitting oedema/myxoedema, dry skin, goitre
• (e) Best initial lab test: Serum TSH

2019 Minicase Case 2: Patient with thyroid nodule, weight loss, palpitations, tremor, HR 130. Blood test: TSH < 0.03, fT4 45. Thyroid scan: focal increased uptake left lower pole → Toxic adenoma. ^[11]