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

Reading the synthesis diagram (follicular cell between blood and colloid): ^[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)

Also ask about biotin supplements, which can produce misleading immunoassay results, and interpret discordant results in the context of acute non-thyroidal illness, pregnancy, drugs, and possible assay interference. If TSH is low, measure both fT4 and fT3; if central disease is suspected, request TSH and fT4 together. ^[11]

Interpretation during changing thyroid status: after starting anti-thyroid drugs or radioactive iodine, TSH may remain suppressed while fT4 is changing; during this transition, fT4 is the more diagnostically useful measure. In the hypothyroid phase, TSH is again most useful, while fT4 is preferred during a further transition after starting levothyroxine. Once TSH and fT4 equilibrium is restored, TSH resumes its role as the principal test. ^[1]

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

Signs of thyrotoxicosis: goitre, tachycardia/atrial fibrillation, warm sweaty palms, fine tremor, lid lag and lid retraction. Proptosis, inflammatory periorbital swelling, restrictive ophthalmoplegia, pretibial myxoedema, and acropachy point specifically toward Graves' disease. Corneal breakdown, reduced colour vision or acuity, and visual-field loss are thyroid-eye emergencies. ^[1][13][14]

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]

Typical Graves' disease combines biochemical primary hyperthyroidism with a diffuse goitre, thyroid bruit, eye/skin signs, and positive TRAb. Nodularity makes another or co-existing diagnosis possible but does not by itself exclude Graves'. Diffuse increased uptake/vascularity supports Graves' when imaging is clinically indicated. ^[1][11]

Modern TRAb assays are highly sensitive but not literally 100% positive. TRAb is the preferred biochemical confirmation of Graves', helps estimate relapse risk at the end of an ATD course, and is crucial during pregnancy because stimulating antibodies can cross the placenta and cause fetal/neonatal hyperthyroidism even after the mother has had surgery or radioiodine. A negative test makes Graves' less likely but does not override a compelling clinical picture. ^[11][12][15]

For confirmed thyrotoxicosis, measure TRAb first to confirm Graves'; consider technetium/radioiodine scanning if TRAb is negative or the aetiology remains unclear. Ultrasound is not routine solely because TFTs are abnormal—use it when there is a palpable nodule, structural concern, or a specific need to assess anatomy. ^[11]

The three disease-directed options for Graves' hyperthyroidism are thionamides, radioactive iodine, and total thyroidectomy. A beta-blocker gives rapid symptomatic relief while definitive control develops. Iodide and lithium are specialist, short-term tools in selected settings; neither lithium nor a sedative is routine first-line Graves' therapy. ^[1][12]

Methimazole (the active metabolite of carbimazole) and PTU are thionamides: both inhibit TPO-mediated organification and coupling; PTU also inhibits peripheral type 1 deiodination of T4 to T3. Reduced autoantibody levels during treatment do not make nonspecific “immunosuppression” their main therapeutic mechanism. ^[1][12]

Pharmacological Properties:

Pregnancy management: seek preconception specialist review. If an ATD is required during organogenesis, PTU is generally preferred in the first trimester because methimazole/carbimazole embryopathy can be severe; after the first trimester, consider changing to methimazole/carbimazole because PTU can cause severe hepatotoxicity. Use the lowest dose that controls maternal hyperthyroidism and avoid block-and-replace in pregnancy. ^[12][15]

Block-and-replace therapy: high-dose ATD plus levothyroxine is an alternative regimen in selected non-pregnant adults, but it increases drug exposure and is not routine first-line therapy; titration monotherapy is usually preferred. ^[11][12]

Lithium mainly inhibits thyroid-hormone release (and can affect iodine handling); it does not work simply by blocking NIS as the slide suggests. Its narrow therapeutic index restricts it to specialist rescue/bridge situations when standard options are unsuitable, with serum-level, renal, and thyroid monitoring. ^[1][12]

Important adverse effects: rash/pruritus; agranulocytosis (rare, often early but possible at any time); methimazole/carbimazole-associated cholestatic injury; PTU-associated severe hepatocellular injury; arthralgia; and ANCA-associated vasculitis. ^[1][12]

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:

Consider total thyroidectomy for a large or compressive goitre, suspicious/malignant nodule, severe or difficult-to-control disease, ATD intolerance or relapse, a need for rapid definitive control, active clinically important thyroid eye disease when definitive treatment is required, pregnancy planning, or informed patient preference. Young age alone is not an indication. Surgery should be performed by a high-volume thyroid surgeon. ^[12][13]

Preoperative Optimisation: Aim for euthyroidism with ATD when feasible and use beta-blockade according to symptoms/heart rate. A short course of potassium iodide immediately before surgery can reduce hormone release and gland vascularity in Graves', but use is protocol- and patient-specific. ^[12]

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]

RAI is convenient and avoids surgery, but response is delayed and a repeat dose may be needed. There can be early radiation thyroiditis or transient worsening of thyrotoxicosis; in Graves', eventual hypothyroidism is an expected treatment outcome rather than a rare complication. Fixed success/failure percentages should not be applied across doses, gland sizes, and aetiologies. ^[12]

Indications:

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

Mechanism: ¹³¹I emits beta particles, which deposit therapeutic energy over a short tissue range and damage iodine-avid follicular cells, and gamma photons, which escape the body and account for external detection/radiation-safety precautions. It is not an alpha emitter. ^[1][16]

Complications and Precautions: RAI is contraindicated in pregnancy and during breastfeeding; follow local nuclear-medicine advice on stopping lactation, radiation precautions, and delaying conception (commonly at least 6 months after treatment). It can provoke or worsen thyroid eye disease, particularly with smoking, high TRAb, or pre-existing active disease; glucocorticoid prophylaxis may be appropriate for selected at-risk patients with mild active disease. Avoid absolute statements of “no cancer risk”: observational data are broadly reassuring at therapeutic doses, but counselling should describe the evidence and uncertainty rather than promise zero risk. ^[12][13]

The pathway diagram centres on orbital fibroblasts expressing TSH receptor and IGF-1 receptor. Autoantibody/cytokine signalling drives inflammation, hyaluronan/glycosaminoglycan production, oedema, adipogenesis, and extraocular-muscle enlargement. Expansion within the fixed bony orbit produces proptosis and venous congestion; posterior muscle swelling can crowd the orbital apex and compress the optic nerve. ^[1][13][14]

Histological changes: ^[1]

• Extraocular muscles: oedema, mononuclear cell infiltration, mucopolysaccharide accumulation, fibrosis
• Retrobulbar fat: lymphocytic infiltration, fibrous tissue, hyaluronic acid accumulation
• Optic nerve: compression at the crowded apex causes dysthyroid optic neuropathy; chronic compression can lead to optic atrophy, but atrophy is not the initiating mechanism

Key clinical points:

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

This is useful for remembering the spectrum but should not replace contemporary, separate assessment of activity (for example CAS) and severity (EUGOGO/ATA–ETA). ^[13][14]

Assessment of GO: ^[1]

• Comprehensive ophthalmological exam: VA, IOP, colour vision, optic nerve function, extraocular movements
• Orbital imaging is not required for every typical bilateral case. Use CT or MRI when disease is atypical/unilateral, dysthyroid optic neuropathy is suspected, another diagnosis is possible, or surgery is planned. CT maps bony anatomy and decompression; MRI characterises soft tissue and inflammation. The classic image shows extraocular-muscle belly enlargement with relative tendon sparing and possible apical crowding. ^[13][14]

Activity and severity assessment:

• A clinical activity score (CAS) < 3 indicates inactive GO; CAS ≥ 3 indicates active GO.
• The activity assessment includes retrobulbar pain, pain on eye movement, eyelid or conjunctival redness, chemosis, and swelling of the eyelids, caruncle, or plica. A 10-item assessment can also incorporate a recent increase in exophthalmos of ≥2 mm, reduced eye motility of ≥8°, or reduced visual acuity over the preceding 1–3 months. ^[1]

Sight-threatening GO algorithm:

1. Refer immediately to a thyroid-eye clinic, avoid radioactive iodine, stabilize thyroid dysfunction with anti-thyroid drugs, and avoid iatrogenic hypothyroidism.
2. Give high-dose IV methylprednisolone on three consecutive or alternate days using a specialist protocol, with close ophthalmic and systemic monitoring.
3. Reassess within days (about 1 week in the EUGOGO pathway). If vision is not clearly improving or deteriorates, arrange urgent orbital decompression; do not wait 1–2 weeks in a worsening optic neuropathy. ^[1][13]

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 causes: autoimmune thyroiditis, radioiodine, thyroidectomy, the hypothyroid phase of thyroiditis, drugs (including amiodarone, lithium and immune checkpoint inhibitors), iodine excess or deficiency, and congenital disorders. Central hypothyroidism reflects hypothalamic–pituitary disease and may have a low or inappropriately normal TSH, so fT4—not TSH alone—guides diagnosis and replacement. ^[1][11]

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

Hashimoto thyroiditis is autoimmune and commonly causes primary hypothyroidism, but patients can initially be euthyroid, subclinically hypothyroid, briefly thyrotoxic, or have an atrophic rather than enlarged gland. Anti-TPO supports autoimmune aetiology but is not required for every diagnosis and should not be repeatedly trended. ^[1][11]

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.

The slide quotes a historical local incidence of about 1:3000 and a cord-blood/2-week threshold. Screening specimen, timing, cut-offs, and recall pathways are programme-specific; many modern programmes use dried blood-spot TSH collected after birth, with serum TSH and fT4 confirmation of an abnormal result. Do not delay treatment in a newborn with clearly low fT4 and markedly raised TSH while completing aetiological imaging. Early levothyroxine protects neurodevelopment. ^[1][18]

If severe disease is missed: prolonged jaundice, poor feeding, lethargy, macroglossia, puffy facies, large fontanelle, hypotonia, protuberant abdomen/umbilical hernia, hearing impairment, and irreversible neurodevelopmental disability. The older labels printed on the slide are obsolete and stigmatising. Most screened infants look normal at birth, which is why biochemical screening matters. ^[1][18]

Causes: thyroid dysgenesis (absent, ectopic or hypoplastic gland), dyshormonogenesis, central hypothyroidism, and transient dysfunction from maternal ATDs, TSH-receptor–blocking antibodies, iodine imbalance, or prematurity. Associated congenital anomalies and syndromes should prompt a broader assessment. ^[1][18]

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

Older adults or patients with cardiovascular disease: start lower (often 25–50 μg/day; sometimes 12.5–25 μg/day for severe coronary disease or marked longstanding hypothyroidism) and titrate gradually while managing coronary disease in parallel. It is unsafe to convert the slide's “manage atherosclerosis first” into a rule to leave overt hypothyroidism untreated. ^[11]

Practical points:

• TSH may decline within 1 month of starting
• Separate from iron/calcium supplements by ≥ 4 hours (they impair absorption)
• Recheck TSH after the new dose has equilibrated (commonly about 6–8 weeks, following local protocol); titrate to the reference range and avoid suppressed TSH ^[11]
• In pregnancy, use population- and trimester-specific reference ranges where available. For a patient already treated with levothyroxine, a common target is the lower half of that range or TSH < 2.5 mIU/L, with prompt dose increase and early repeat testing after pregnancy is confirmed. The slide's fixed second- and third-trimester cut-offs are not universal. ^[15]

Subclinical hyperthyroidism means low TSH with both fT4 and fT3 within range. Confirm persistence and exclude non-thyroidal illness, drugs, pregnancy, recent treatment, pituitary disease, and assay/biotin interference before labelling it. Determine aetiology with TRAb and, when needed, scintigraphy; do not order ultrasound routinely unless there is a palpable nodule. ^[1][11]

When to treat subclinical hyperthyroidism: ^[1]

Here, 0.4 mU/L is the lower limit of the normal TSH range. ^[1]

Subclinical hypothyroidism means raised TSH with normal fT4. Confirm it on a second sample and measure anti-TPO once. NICE advises considering levothyroxine when TSH is ≥10 mIU/L on 2 tests 3 months apart; for symptomatic adults under 65 with persistent TSH above the reference range but below 10, consider a time-limited treatment trial and stop if symptoms do not improve despite a normal TSH. Pregnancy requires separate guidance. ^[11]

Iodinated contrast delivers a very large iodine load. Susceptible patients may develop Jod–Basedow hyperthyroidism (especially autonomous nodular thyroid or latent Graves') or failure to escape the Wolff–Chaikoff effect with hypothyroidism (especially autoimmune thyroiditis). Recent contrast also suppresses radionuclide uptake, so it can confound scintigraphy for several weeks. Most events are mild/transient, and routine post-contrast TFT screening is not recommended for every euthyroid patient; identify high-risk patients, warn about symptoms, and use targeted follow-up. ^[1][20]

Thyroid dysfunction is among the most common endocrine immune-related adverse events, but incidence varies substantially by drug, combination, study definition, and surveillance; the slide's fixed 25/38/56% figures should not be generalised to every regimen. The usual pattern is painless destructive thyroiditis: a brief thyrotoxic phase followed by hypothyroidism or recovery. New central hypothyroidism suggests hypophysitis—assess adrenal function urgently and give glucocorticoid replacement before levothyroxine when adrenal insufficiency is possible. ^[1][21]