Hypothyroidism

Hypothyroidism is a clinical state resulting from deficient circulating thyroid hormone. It is most commonly caused by Hashimoto thyroiditis in iodine sufficient populations.

Other causes include:

• iatrogenic causes (following thyroidectomy, radioactive iodine treatment, or external beam radiotherapy involving the neck)
• iodine deficiency (remaining an important cause in specific regions globally)
• certain medications
• less commonly, central (pituitary or hypothalamic) causes

The clinical presentation is typically insidious, given the generally slow, gradual onset of symptoms.

Severity ranges from subclinical (biochemical abnormality without overt clinical symptoms) through to severe, life threatening myxoedema coma in the most extreme, longstanding, untreated presentations.

Pathophysiology and classification

• Primary hypothyroidism reflects intrinsic thyroid gland dysfunction. Causes are autoimmune destruction in Hashimoto thyroiditis, surgical or radioactive iodine ablation, iodine deficiency, or certain medication effects including amiodarone and lithium.
• It accounts for the great majority of hypothyroidism. It is characterised biochemically by elevated thyroid stimulating hormone with reduced free thyroxine, the normal compensatory pituitary response to reduced circulating thyroid hormone.
• Central hypothyroidism reflects inadequate thyroid stimulating hormone production from pituitary or hypothalamic dysfunction. Thyroid stimulating hormone is inappropriately normal or low despite reduced free thyroxine.
• This distinction from primary disease has direct implications for the diagnostic workup, which must investigate for broader pituitary dysfunction.
• It also affects treatment monitoring. Thyroid stimulating hormone cannot be the primary monitoring parameter, so monitoring is based on free thyroxine level and clinical response.
• Subclinical hypothyroidism is defined as an elevated thyroid stimulating hormone with normal free thyroxine. It is a milder, often asymptomatic or minimally symptomatic biochemical state.
• Management requires individualised consideration of the degree of thyroid stimulating hormone elevation, patient age, symptoms, and clinical context including pregnancy.

• The typical, generally insidious symptom constellation comprises fatigue, cold intolerance, weight gain, constipation, dry skin, hair thinning and, in women, menstrual irregularity (typically menorrhagia). Cognitive slowing and, in more severe or longstanding disease, depression also occur.
• Examination findings include bradycardia, dry, coarse skin and hair, and non pitting oedema (myxoedema, reflecting glycosaminoglycan accumulation in the skin and other tissues).
• Delayed relaxation phase of deep tendon reflexes is a classically described, though not universally elicited, finding.
• Where the cause is Hashimoto thyroiditis, there may be a firm, often nodular goitre.
• Severe, longstanding, untreated hypothyroidism can progress to myxoedema coma, a rare but life threatening medical emergency requiring immediate, aggressive treatment.
• Myxoedema coma is characterised by severe hypothermia, altered consciousness, bradycardia and hypotension, together with hypoglycaemia and hyponatraemia.
• It is typically precipitated by an intercurrent illness or physiological stressor in a patient with severe, previously undiagnosed or inadequately treated hypothyroidism.
• Subclinical hypothyroidism is frequently entirely asymptomatic, or produces only mild, non specific symptoms. These are difficult to attribute to the thyroid abnormality alone, given their prevalence in the general population independent of thyroid status.

• Thyroid stimulating hormone is the essential initial screening test. Elevation supports primary hypothyroidism, or subclinical disease where free thyroxine remains within the normal range.
• Free thyroxine measurement confirms and quantifies the severity of overt disease where thyroid stimulating hormone is elevated.
• Thyroid peroxidase antibody testing supports identification of Hashimoto thyroiditis as the cause where relevant.
• Further investigation directed at an alternative cause is pursued according to clinical context and initial biochemical findings. This includes medication review and assessment of iodine intake.
• Where the biochemical pattern suggests central hypothyroidism, broader pituitary function assessment and pituitary imaging are pursued.
• Full blood count (given the recognised association with macrocytic anaemia) and lipid profile (given the characteristic elevation of cholesterol in hypothyroidism) are useful.
• Other targeted investigation, where clinically relevant to presenting features or examination findings, supports assessment of the metabolic consequences and associated findings of confirmed hypothyroidism.

• Levothyroxine replacement is standard treatment. The starting dose is individualised to patient age, weight and cardiac status.
• The typical dose is 1.6 micrograms per kg once daily in a younger, otherwise healthy adult.
• A substantially lower starting dose (such as 25 to 50 micrograms once daily, titrated gradually) is used in older patients or those with significant cardiac disease. Overly rapid correction of longstanding hypothyroidism in this population risks precipitating angina or arrhythmia.
• Thyroid stimulating hormone is rechecked approximately six to eight weeks after any dose change, and the levothyroxine dose is titrated to this result. The aim is a thyroid stimulating hormone within the normal reference range.
• The target is sometimes adjusted toward the lower end of normal in younger patients seeking optimal symptomatic control. A suppressed thyroid stimulating hormone is avoided because of iatrogenic subclinical hyperthyroidism, including atrial fibrillation risk and reduced bone density with longer term over replacement.
• Central hypothyroidism is monitored using free thyroxine level and clinical response rather than thyroid stimulating hormone, because the underlying pituitary dysfunction makes thyroid stimulating hormone unreliable.
• Coexisting adrenal insufficiency must be excluded and, where present, treated before thyroid hormone replacement starts. Thyroid hormone increases metabolic clearance of cortisol, so starting it in unrecognised, untreated adrenal insufficiency risks precipitating an adrenal crisis.
• Subclinical hypothyroidism management is individualised. Treatment is generally recommended for thyroid stimulating hormone persistently above 10 mIU per litre, given evidence of benefit at this level.
• For milder elevation (thyroid stimulating hormone between the upper limit of normal and 10 mIU per litre), treatment is considered individually. Factors are symptoms, positive thyroid peroxidase antibodies (predicting higher likelihood of progression to overt disease), and clinical context.
• Pregnancy warrants a lower threshold for treatment, given the recognised adverse effects of even mild maternal hypothyroidism on fetal neurodevelopment.
• Myxoedema coma requires emergency treatment with intravenous levothyroxine (and, in some protocols, additional triiodothyronine given its more rapid onset of action).
• Intravenous hydrocortisone is given empirically to cover possible coexisting adrenal insufficiency, which cannot be reliably excluded in the acute emergency before formal testing results are available.
• Further management is careful, gradual rewarming and full supportive intensive care addressing the associated hypotension, hypoglycaemia and hyponatraemia. Mortality is substantial even with prompt, appropriate treatment.
• Regular thyroid function monitoring, with dose adjustment over time, underpins long term management of this generally straightforward, though lifelong, condition.
• Levothyroxine requirement changes with weight change, pregnancy, and certain concurrent medications affecting its absorption or metabolism.