Case 17.1 – Primary Hypothyroidism

Clinical features depend on the duration and severity of the hypothyroidism. In the patient in whom complete thyroid failure has developed insidiously over months or years many of the clinical features listed below are likely to be present. Care must be taken to identify patients with transient hypothyroidism, in whom life-long thyroxine therapy is inappropriate (after subtotal thyroidectomy or ¹³¹I treatment of Graves' disease, in the post-thyrotoxic phase of subacute thyroiditis and in post-partum thyroiditis).

SYMPTOMS (Italics = common features, *rare)

• Weight gain
• Cold intolerance
• Fatigue, somnolence
• Hoarseness
• Constipation
• Carpal tunnel syndrome
• Aches and pains
• Muscle stiffness
• Deafness
• Depression
• Psychosis (myxoedema madness)*
• Dry skin
• Dry hair
• Alopecia
• Menorrhagia
• Infertility
• Galactorrhoea*
• Impotence*

SIGNS

• Weight gain
• Hoarse voice
• Goitre
• Ileus
• Ascites
• Bradycardia
• Hypertension
• Pericardial and pleural effusions
• Macrocytosis
• Anaemia
• Iron deficiency (pre-menopausal women) Normochromic
• Delayed relaxation of tendon reflexes
• Cerebellar ataxia
• Myotonia
• Myxoedema
• Purplish lips
• Malar flush
• Carotenaemia
• Vitiligo
• Erythema abigne (Granny's tartan)
• Periorbital oedema/myxoedema
• Loss of lateral eyebrows

A consequence of prolonged hypothyroidism is the infiltration of many body tissues by the mucopolysaccharides, hyaluronic acid and chondroitin sulphate, resulting in a low-pitched voice, poor hearing, slurred speech due to a large tongue, and compression of the median nerve at the wrist (carpal tunnel syndrome).

Infiltration of the dermis gives rise to non-pitting oedema (i.e. myxoedema) which is most marked in the skin of the hands, feet and eyelids. The resultant periorbital puffiness is often striking and, when combined with facial pallor due to vasoconstriction and anaemia, or a lemon-yellow tint to the skin due to carotenaemia, purplish lips and malar flush, the clinical diagnosis is simple.

Most cases of hypothyroidism are not so obvious, however, and unless the diagnosis is positively entertained in the middle-aged woman complaining of tiredness, weight gain, depression or carpal tunnel syndrome, an opportunity for early treatment will be missed.

Normal anatomy of the thyroid gland

• The thyroid gland consists of two bulky lateral lobes connected by a relatively thin isthmus, usually located below and anterior to the larynx
• The weight of the normal adult thyroid is approximately 15 to 25 gm
• The thyroid has a rich intraglandular capillary network that is supplied by the superior and inferior thyroidal arteries
• Nerve fibres from the cervical sympathetic ganglia indirectly influence thyroid secretion by acting on the blood vessels
• The thyroid is divided by thin fibrous septae into lobules composed of about 20 to 40 evenly dispersed follicles
• Normal follicles range from 50 to 500 μm in size, are lined by cuboidal to low columnar epithelium, and are filled with periodic acid Schiff (PAS)-positive thyroglobulin

Decreased levels of T₃ and T₄ stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-stimulating hormone (TSH) from the anterior pituitary.

In Addison's case:

• Her T₄ is low (9 pmol/L, below the normal range of 10-25)
• Her T₃ is normal (5.5 pmol/L, within normal range 3.5-7.5)
• Her TSH is elevated (12 mU/L, above normal range of 0.3-3.5)
• This pattern indicates primary hypothyroidism - the thyroid gland itself is failing to produce sufficient T₄
• The pituitary responds appropriately by increasing TSH production in an attempt to stimulate the failing thyroid gland
• The hypothalamic-pituitary axis is functioning normally, but the thyroid gland is not responding adequately to TSH stimulation

One of the most common problems in medical practice is how to manage patients with abnormal thyroid function test results who have no obvious signs or symptoms of thyroid disease. For practical purposes these can be divided into three categories:

1. Subclinical thyrotoxicosis

• The serum TSH is undetectable and the serum T₃ and T₄ lie in the upper parts of their respective reference ranges
• This combination is most often found in older patients with multinodular goitre
• These patients are at increased risk of atrial fibrillation and osteoporosis
• Consensus view is that such patients have mild thyrotoxicosis and require therapy, usually with ¹³¹I
• Otherwise, annual review is essential as the conversion rate to overt thyrotoxicosis with elevated T₄ and/or T₃ concentrations is 5% each year

2. Subclinical hypothyroidism

• The serum TSH is raised and the serum T₃ and T₄ concentrations are usually in the lower part of their respective reference ranges
• It may persist for many years, although there is a risk of progression to overt thyroid failure
• Risk is particularly increased if antibodies to thyroid peroxidase are present in the serum or if the TSH rises above 10 mU/l

3. Non-thyroidal illness ('sick euthyroidism')

• In patients with systemic illness (e.g. myocardial infarction, pneumonia) there is decreased peripheral conversion of T₄ to T₃ and alterations of binding proteins and their affinity for thyroid hormones
• In addition, serum TSH concentrations may be subnormal as a result of the illness itself or the use of drugs such as dopamine or corticosteroids
• The most common combination is a low serum TSH, raised T₄ and normal or low T₃, but many patterns of thyroid function tests can be seen, dependent upon the type of assay used
• During convalescence, serum TSH concentrations may increase to levels found in primary hypothyroidism
• Biochemical assessment of thyroid function should not be undertaken in patients with non-thyroidal illness, unless there is good evidence of concomitant thyroid disease, e.g. goitre, exophthalmos
• If an abnormal result is found, treatment should only be given with specialist advice and the tests should be repeated after recovery

CAUSES OF HYPOTHYROIDISM	Anti-PO antibodies1	Goitre2
Autoimmune
Hashimoto's thyroiditis	++	±
Spontaneous atrophic hypothyroidism	−	−
Graves' disease with TSH receptor-blocking antibodies	+	±
Iatrogenic
Radioactive iodine ablation	+	±
Thyroidectomy	+	−
Drugs
Carbimazole, methimazole, propylthiouracil	+	±
Amiodarone	+	±
Lithium	−	±
Transient thyroiditis
Subacute (de Quervain's) thyroiditis	+	±
Post-partum thyroiditis	+	±
Iodine deficiency
e.g. In mountainous regions	−	++
Congenital
Dyshormonogenesis	−	++
Thyroid aplasia	−	−
Infiltrative
Amyloidosis, Riedel's thyroiditis, sarcoidosis etc.	+	++
Secondary hypothyroidism
TSH deficiency

Treatment approach for adults with suspected primary hypothyroidism:

This scheme ignores congenital causes of hypothyroidism such as thyroid aplasia and dyshormonogenesis, which are usually diagnosed in childhood.

Initial assessment:

• Confirm diagnosis with ↑TSH and ↓T₄
• Check for features of secondary hypothyroidism (TSH <20 mU/l)
• Assess for possible sick euthyroidism - repeat when acute illness has resolved if suspected

Determine the cause:

• Features of transient thyroiditis?
  • Neck pain
  • <12 months post-partum
  • Recent symptoms of thyrotoxicosis
  • <6 months since ¹³¹I or thyroidectomy
• Relevant drugs? (Amiodarone, Lithium)
• Thyroid ablation? (\>6 months since ¹³¹I or thyroidectomy)
• Positive anti-thyroid peroxidase antibodies? (suggests Hashimoto's thyroiditis)
• Goitre? (If yes with positive antibodies = Hashimoto's, if no with positive antibodies = spontaneous atrophic hypothyroidism)
• Consider rare causes if indicated

Treatment:

• Temporary T₄ replacement if transient thyroiditis:
  • After 4 months with normal TSH, reduce to 50μg/d for 6 weeks and repeat TSH
  • If normal, stop T₄ for 6 weeks and repeat
• T₄ replacement for as long as other drug is required if drug-induced
• Permanent T₄ replacement for confirmed primary hypothyroidism (autoimmune, post-ablation, etc.)

Levothyroxine (T₄) replacement therapy:

• Start with 50-100 μg daily (lower dose in elderly or those with cardiac disease - start 25μg)
• Titrate dose based on TSH levels (aim for TSH in normal range)
• Check TSH 6-8 weeks after starting or changing dose
• Once stable, annual TSH monitoring
• Take on empty stomach, at least 30 minutes before food
• Lifelong therapy for most causes

Follow-up:

• Regular monitoring of TSH
• Assess for resolution of symptoms
• Screen for other autoimmune conditions if autoimmune cause
• Adjust dose if pregnancy occurs (increased requirement)