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OverviewAetiologyPathophysiologyClinical features and red flagsInvestigationsDifferential diagnosisManagementComplicationsMonitoring and follow-upSpecial situationsCommon pitfallsQuestionsSources
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Educational draft · awaiting clinical reviewThe full textbook explains uncertainty but does not replace live national or local guidance, specialist advice, or current prescribing information.

Primary and central hypothyroidism

Endocrinology and metabolism · UK scope · Sources checked 27 Aug 2026 · Clinical review pending

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Time-critical presentation

Hypothermia, reduced consciousness, hypoventilation, bradycardia, hypotension, hypoglycaemia or severe hyponatraemia in suspected hypothyroidism requires emergency endocrine and critical-care support. In central disease, possible cortisol deficiency is immediately dangerous and glucocorticoid treatment must precede thyroid replacement when clinically indicated.

Overview

Distinguish thyroid-gland failure from pituitary or hypothalamic disease, replace hormone safely, and protect patients with possible adrenal insufficiency or special physiological needs.

Primary hypothyroidism is failure of thyroid hormone production at the gland. Autoimmune disease is common in iodine-sufficient settings, but surgery, radioiodine, medicines such as amiodarone or lithium, iodine imbalance and destructive thyroiditis are important. TSH normally rises as free T4 falls, which makes the biochemical pattern straightforward when pituitary feedback is intact.

Central hypothyroidism reflects hypothalamic or pituitary disease. The TSH concentration may sit inside the laboratory range and can even be mildly raised while lacking appropriate biological activity. A low free T4 in the correct clinical setting therefore carries more weight than a superficially reassuring TSH; other pituitary hormones, visual fields and sellar imaging may reveal the wider diagnosis.

Replacement aims to restore euthyroidism without iatrogenic excess. Persisting symptoms despite a normal TSH merit review of diagnosis, adherence, administration, anaemia, sleep, mental health, menopause and other comorbidity. Specialist consideration of combination therapy is exceptional and follows a confirmed diagnosis plus optimised levothyroxine, not a response to nonspecific symptoms alone.

Aetiology

01

Autoimmune thyroid failure

Immune-mediated thyroid destruction gradually reduces gland reserve and is a common cause of primary hypothyroidism in iodine-sufficient settings.

02

Iatrogenic thyroid loss

Thyroid surgery, radioiodine and neck treatment reduce functioning tissue, often creating a predictable long-term replacement need.

03

Medicine or iodine-related dysfunction

Amiodarone, lithium and iodine imbalance can impair thyroid synthesis or release, sometimes on a background of autoimmune susceptibility.

04

Pituitary or hypothalamic disease

Tumour, surgery, radiotherapy, inflammation or apoplexy can provide inadequate TSH drive and cause central hypothyroidism within broader hypopituitarism.

Pathophysiology

  1. 1
    Thyroid hormone availability falls

    Gland failure or inadequate central stimulation reduces circulating free thyroid hormone and slows tissue metabolic processes.

  2. 2
    Feedback pattern diverges

    Primary failure raises TSH through loss of negative feedback, while central disease leaves TSH low, normal or biologically inadequate for the low free hormone.

  3. 3
    Organ function slows

    Reduced thermogenesis, cardiac output, gut motility, neurological speed and skin turnover produce cold intolerance, constipation, bradycardia and cognitive slowing.

  4. 4
    Severe deficiency decompensates

    Longstanding disease exposed to infection, cold or sedating medicines can progress to hypothermia, hypoventilation, hyponatraemia and cardiovascular failure.

Clinical features and red flags

Established primary failure

Fatigue, cold intolerance, constipation, dry coarse skin, hair loss, bradycardia, delayed reflex relaxation, menstrual disturbance and low mood accompany raised TSH and low free T4, though none is diagnostic alone.

Central endocrine cluesRed flag

Headache, visual-field symptoms, amenorrhoea, infertility, reduced libido, loss of body hair, post-partum haemorrhage history, polyuria or previous pituitary treatment should shift attention from the thyroid gland to the sellar axis.

Possible adrenal deficiencyRed flag

Postural hypotension, weight loss, nausea, abdominal pain, hyponatraemia, hypoglycaemia or unexplained eosinophilia in pituitary disease makes cortisol deficiency a priority; pigmentation usually indicates primary rather than central adrenal failure.

Replacement malabsorption or interaction

Rising dose requirement, fluctuating TSH or failure to normalise despite reported use suggests administration with food, iron or calcium, missed tablets, coeliac disease, gastritis, bariatric surgery or interacting medicines.

Over-replacement

Palpitations, tremor, heat intolerance, sleep disturbance, suppressed TSH, atrial arrhythmia or accelerated bone loss indicate excessive levothyroxine exposure; older adults are particularly vulnerable.

Severe decompensationRed flag

Altered consciousness with hypothermia, hypoventilation, bradycardia, hypotension and metabolic disturbance suggests myxoedema coma, which may occur without literal coma and needs immediate critical care.

Investigations

  1. 01
    TSH and free T4First step
    Why
    Confirm hypothyroidism and locate dysfunction within the axis.
    Interpretation and limitations
    High TSH plus low free T4 indicates overt primary disease. Low free T4 with TSH not appropriately elevated suggests central dysfunction after illness, medicine and assay effects are considered.
  2. 02
    Thyroid peroxidase antibodies
    Why
    Identify autoimmune thyroiditis as the likely primary cause.
    Interpretation and limitations
    Positivity supports autoimmune disease and future progression but does not alter the daily replacement target; NICE advises measuring once rather than serial titres.
  3. 03
    Morning cortisol and pituitary profile
    Why
    Detect corticotroph and other pituitary deficits before thyroid replacement.
    Interpretation and limitations
    Cortisol requires time-, illness- and assay-aware endocrine interpretation. Do not wait for a routine result when adrenal crisis is clinically suspected; treat and test according to the emergency pathway.
  4. 04
    Pituitary MRI and visual assessment
    Why
    Define structural central disease and threat to the optic pathways.
    Interpretation and limitations
    A sellar lesion, haemorrhage or stalk abnormality requires endocrine-neurosurgical planning; acute severe headache, ophthalmoplegia or visual loss is possible apoplexy and demands emergency imaging.

Differential diagnosis

01

Non-thyroidal illness

Acute severe illness can transiently lower TSH or thyroid hormones without primary gland failure; timing and clinical recovery guide repeat interpretation.

02

Depression or sleep disorder

Fatigue, weight change and poor concentration overlap, but a coherent free-hormone and TSH pattern supports hypothyroidism.

03

Anaemia

Breathlessness, tiredness and cold intolerance can reflect low haemoglobin, which is identified by blood count and may coexist.

04

Assay or adherence problem

Biotin, binding effects, missed doses and inconsistent administration can create discordant thyroid results that should be resolved before escalating treatment.

Management

01Primary diagnosisConfirm and begin replacementFirst stepRaised TSH with free T4 below the local reference interval.+
  1. 1Assess severity, pregnancy possibility, cardiovascular disease, previous thyroid intervention, medicines and features of adrenal or pituitary disease before prescribing.
  2. 2Start levothyroxine using NICE age and cardiac-risk principles, explain consistent administration and separate it from relevant food, iron and calcium exposure.
  3. 3Review TSH about every three months until stable, adjusting gradually and avoiding suppression; check free T4 as well if symptoms remain unexplained.
02Central diagnosisProtect the adrenal axis firstLow free T4 with an inappropriately low or normal TSH and pituitary context.+
  1. 1Assess haemodynamics, glucose, sodium, cortisol and other pituitary symptoms; emergency features or pituitary apoplexy require same-day endocrine-critical-care management.

Complications

01

Myxoedema coma

Profound untreated hypothyroidism can decompensate into hypothermia, hypoventilation, bradycardia, shock, hyponatraemia and altered consciousness after a physiological stress.

02

Cardiometabolic disease

Low thyroid hormone can worsen atherogenic lipids, diastolic blood pressure and cardiac function, particularly in established vascular disease.

03

Fertility and pregnancy harm

Untreated disease can disrupt ovulation and pregnancy physiology, increasing maternal and fetal risk when replacement is inadequate.

04

Adrenal crisis from treatment sequence

In central disease, thyroid replacement before cortisol protection can increase metabolic demand and expose unrecognised ACTH deficiency.

Monitoring and follow-up

  • In primary hypothyroidism, measure TSH approximately every three months until stable and then annually, adjusting frequency for symptoms, adherence or interacting medicines.
  • Expect TSH to take longer to normalise after very severe or prolonged deficiency; titrate from trend and clinical state rather than making rapid repeated changes.
  • In central disease, document free T4 in relation to tablet timing and use an endocrinology-agreed target alongside symptoms; TSH is not the dose marker.
  • After any material dose or product change, allow an appropriate steady-state interval before routine biochemical reassessment unless the clinical situation is urgent.
  • Monitor pulse, weight, tremor, atrial arrhythmia and bone-risk context to identify over-replacement, particularly in older adults.
  • Review promptly when pregnancy is confirmed, before conception, or after substantial weight change, bariatric surgery or initiation of an interacting medicine.

Special situations

TSH can be biologically misleading

Central hypothyroidism may produce a measured TSH that is normal or mildly raised but inadequate in amount or biological activity for the low free T4.

Cortisol comes before thyroxine

Thyroid hormone increases metabolic demand and cortisol clearance. In an ACTH-deficient patient, beginning replacement without glucocorticoid protection can expose or precipitate adrenal crisis.

Administration is part of the prescription

A consistent fasting or bedtime routine, compatible with the product information, often resolves apparent resistance more safely than simply escalating the tablet strength.

Symptoms lag and overlap

Hair, skin, cognition and energy may recover slowly, while common symptoms have many causes. Normalising one biochemical marker cannot prove every complaint was thyroid-mediated.

Combination therapy is exceptional

Current UK specialist consensus restricts any carefully supervised liothyronine trial to selected patients after diagnosis and levothyroxine optimisation, with explicit stopping criteria and shared uncertainty.

Common pitfalls

  1. 01

    Calling central hypothyroidism subclinical because the TSH is not raised.

  2. 02

    Starting levothyroxine in pituitary disease before considering ACTH deficiency.

  3. 03

    Increasing replacement every few days before TSH has reached a new steady state.

  4. 04

    Treating thyroid peroxidase antibody titre as a serial marker of disease control.

  5. 05

    Attributing all fatigue or weight gain to hypothyroidism after the biochemical target is achieved.

  6. 06

    Using a suppressed TSH to reduce levothyroxine in central disease without examining free T4 and clinical context.

  7. 07

    Applying routine adult initiation to pregnancy, severe decompensation or significant coronary disease.

Practice

Two practice questions

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Question 1 of 2
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Endocrinology and metabolismOriginal SBA

Order of replacement in hypopituitarism

A patient with a pituitary mass has low free T4, low-normal TSH, postural hypotension and hyponatraemia. Which management principle is most important before routine thyroid replacement?

Choose one answer, then submit
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Sources and review status5 sources · checked 27 Aug 2026 · clinical review pending+
Sources

Sources and review status

National guidance is shown before implementation-dependent detail. Typical adult dose examples remain subject to patient factors, contraindications and the live BNF or specialist protocol. Source check completed 27 Aug 2026; clinical approval remains outstanding.

  • NICE NG145 hypothyroidism managementFirst-line replacement, initiation, biochemical follow-up and treatments not routinely recommended.
  • BNF hypothyroidism treatment summaryCurrent prescribing principles and special situations.
  • BNF levothyroxine sodium monographDose, administration, interactions and monitoring cautions.
  • Society for Endocrinology adrenal crisis guidanceEmergency glucocorticoid sequence when cortisol deficiency is suspected.
  • British Thyroid Association professional guidanceUK specialist statements including use of liothyronine in selected cases.

Editorial contact: Doctor’s Passport editorial team. Source-check date is separate from clinical approval. Report a content problem · Content changes

Authoring stateComplete draftClinical stateAwaiting reviewJurisdictionUnited Kingdom

Key points

  • Primary hypothyroidism produces raised TSH with low free T4; central hypothyroidism produces low free T4 with TSH that is low, normal or biologically inadequate.
  • Autoimmune thyroiditis, thyroidectomy and radioiodine are frequent primary causes; pituitary tumours, surgery, radiotherapy, apoplexy and infiltrative disease underlie many central cases.
  • Symptoms such as tiredness, weight gain, constipation, dry skin, cold intolerance and cognitive slowing are common but nonspecific, so diagnosis requires credible biochemistry.
  • Levothyroxine is NICE first-line treatment for primary hypothyroidism; routine liothyronine and natural thyroid extract are not recommended.
  • Adults under 65 without cardiovascular disease can usually start near full replacement, while older people and those with cardiac disease need lower initiation and careful titration.
  • Never use TSH to exclude or titrate central hypothyroidism; specialist follow-up uses free T4, clinical response and the status of other pituitary axes.
  • Before treating central hypothyroidism, assess adrenal function and give glucocorticoid cover first if adrenal insufficiency is possible, because levothyroxine can precipitate crisis.
  • Iron, calcium, food, antacids and several gastrointestinal conditions can reduce levothyroxine absorption; structured administration review is more useful than repeated unexplained dose increases.
  • 05
    Full blood count, ferritin, B12, folate and coeliac screen
    Why
    Find common autoimmune, nutritional or absorption comorbidity when symptoms persist.
    Interpretation and limitations
    Anaemia or positive coeliac serology can explain fatigue and unstable replacement; confirm and treat the cause instead of assuming thyroid hormone failure.
  • 06
    Creatine kinase, sodium, lipids and ECG
    Why
    Assess selected complications and cardiovascular context in marked disease.
    Interpretation and limitations
    Hyponatraemia and raised CK or cholesterol can accompany hypothyroidism but are nonspecific. Bradycardia, low voltage or conduction change increases caution during replacement.
    • 2
    Give glucocorticoid treatment before thyroid hormone if adrenal insufficiency is suspected, taking cortisol first only when this causes no dangerous delay.
  • 3Under endocrinology, investigate all pituitary axes and anatomy, then titrate levothyroxine to clinical response and an appropriate free-T4 target rather than TSH.
    • 03Unstable controlAudit administration before escalating doseEscalationTSH remains high or fluctuates despite prescribed levothyroxine.+
    1. 1Confirm the actual product, dose, missed tablets, pharmacy switches and whether tablets are swallowed with breakfast, coffee or interacting medicines.
    2. 2Separate levothyroxine from calcium, iron and antacids according to product advice, and investigate coeliac disease or other malabsorption when clinically supported.
    3. 3Repeat after an adequate steady-state interval, seeking specialist advice for very high requirements, persistent discordance, pregnancy or suspected assay interference.
    04Persistent symptomsReassess before alternative hormoneAlternativeSymptoms continue after TSH normalises on a stable levothyroxine regimen.+
    1. 1Verify the original overt diagnosis, adherence, free T4, and absence of over-replacement, then seek non-thyroid explanations through focused history and examination.
    2. 2Treat relevant anaemia, sleep disorder, depression, menopause, cardiopulmonary disease or nutritional deficiency rather than using thyroid hormone as nonspecific therapy.
    3. 3If substantial symptoms persist after optimisation, refer to an endocrinologist; any liothyronine trial should follow current BTA/Society guidance, shared decision-making and specialist monitoring.
    Key medicines and prescribing safety3 treatments · regimens, roles and cautions+
    NICE first-line thyroid hormone replacement for confirmed primary hypothyroidism.

    Levothyroxine for primary hypothyroidism

    Adults under 65 without cardiovascular disease: consider 1.6 micrograms/kg once daily, rounded to the nearest 25 micrograms; age 65 or over, or cardiovascular disease: consider 25 to 50 micrograms once daily with titration.

    Use the current BNF and product information. Start cautiously with ischaemic heart disease, avoid biochemical suppression, review absorption interactions, and arrange urgent specialist adjustment in pregnancy.

    Restores thyroid hormone after adrenal safety and the wider pituitary diagnosis are addressed.

    Levothyroxine for central hypothyroidism

    Individualised once-daily replacement prescribed and titrated by endocrinology using free T4, symptoms, age and cardiac risk rather than a TSH target.

    Never start before glucocorticoid coverage when cortisol deficiency is possible. TSH may remain low and must not drive dose reduction; pregnancy and panhypopituitarism need specialist plans.

    Provides life-saving glucocorticoid cover before thyroid replacement in suspected adrenal crisis.

    Hydrocortisone when adrenal crisis is suspected

    Give 100 mg intravenously or intramuscularly immediately, then follow the current Society for Endocrinology adrenal-crisis regimen with fluids and ongoing dosing.

    Take cortisol beforehand only if this does not delay treatment. Monitor fluid, glucose and electrolytes; confirm the longer-term diagnosis after stabilisation with endocrinology.

    Pregnancy, planned conception, childhood and severe decompensation need rapid specialist pathways rather than ordinary adult titration.