Subclinical hypothyroidism

Subclinical hypothyroidism (SCH) is diagnosed when peripheral thyroid hormone levels are within the normal range, but thyroid-stimulating hormone (TSH) is mildly elevated.

About 62% of TSH levels between 4 and 10 mIU/L normalise without intervention within five years¹ .

Biochemical measurement

There is biological variation in TSH levels which may rise in response to stress and transient disease. TSH secretion also has a diurnal variation with a peak late at night/early hours of morning.This biological variation in TSH values means that one abnormal TSH level should be followed by a repeat blood test to confirm the diagnosis.

Measurement of serum TSH is generally considered the best screening test for thyroid disease. Increased values indicate hypothyroidism. The test is both sensitive and specific. Serum TSH concentrations have a logarithmic relationship with serum thyroxine, so that a doubling in thyroxine produces a hundredfold change in TSH.

TSH is thus a much more sensitive test. The population reference laboratory normal ranges for thyroxine are set wide compared to the normal individual range, so that a fall in thyroxine levels at the lower end of the range may elevate the TSH above normal. However, its sensitivity causes a dilemma, as some patients are found to have elevated TSH levels, but have normal free thyroxine hormone levels, and may also be asymptomatic. Most of the circulating T3 is generated by peripheral conversion from T4, mainly by the liver, through enzymatic removal of an iodine atom from T4. Very little T3 is produced by the thyroid gland itself.

Reference ranges are usually defined as those into which 95% of the population will fall. They are altered slightly by ethnicity, age and iodine intake, and more substantially by pregnancy. There is, however, some debate regarding the upper limits of the TSH reference range. The high background prevalence of autoimmune thyroid disease as well as the age, iodine status, smoking prevalence and ethnicity of the 'normal' population may have raised the 'normal' upper limit. In people without these factors the normal upper limit may be lower.

Epidemiology

Subclinical hypothyroidism is a common condition. Prevalence increases with age and is more common in women. Approximately 8% of women (10% of women over 55 years of age) and 3% of men have subclinical hypothyroidism² .

In studies restricted to older persons, the reported prevalence of subclinical hypothyroidism is between 1.5-12.5%³ . Treatment with thyroid hormones is increasing and more than 10-15% of people aged over 80 years are prescribed levothyroxine replacement therapy.

Aetiology

Causes are the same as those of overt thyroid disease:

• Chronic autoimmune thyroiditis - Hashimoto's disease. This is by far the most common cause, accounting for over 90% of cases.

• Treatment of hyperthyroidism - most commonly after radioactive iodine treatment.

• Hypothyroidism can occur in 5-25% of patients treated with surgery or antithyroid drugs.

• Less common causes are medications - eg, lithium or amiodarone.

• Other causes include head and neck surgery or radiotherapy.

Clinical features

The term subclinical is at times inaccurate, as some patients have symptoms. In the elderly a diagnosis of hypothyroidism may be delayed by wrongly attributing the symptoms of, for example, fatigue and constipation to ageing.

Clinical manifestations can be explained by assuming that a T4 level of 6-7 mcg/dL, although inside the normal range, may represent a significant decrease from a previous normal of 10 mcg/dL, and is low for this particular patient.

Some studies have suggested that if symptoms are present then treatment with thyroxine will resolve them.

Common clinical features of hypothyroidism include:

• Depression and fatigue.

• Hyperlipidaemia and hyperhomocysteinaemia.

• Goitre.

• Coarse hair.

• Cold intolerance.

• Constipation and weight gain.

• Hoarseness.

• Hearing loss.

• Menorrhagia.

• Slow return phase in knee reflexes.

• Bradycardia.

• Coronary artery disease or cardiac risk factors.

Investigations

In The UK, screening is not felt to be warranted although case-finding in women at the menopause or if visiting a doctor with nonspecific symptoms may be justified.

The practical approach may be to measure thyroid function in those patients who have persistent, nonspecific complaints - women in particular, and the elderly⁴ .

Borderline results and asymptomatic patients need to be repeated at a consistent time of day, with consistent fasting status.

Differential diagnosis

There are a few other causes of a raised TSH in the presence of normal thyroxine levels:

• Recovery from acute (non-thyroidal) illness.

• Assay variability.

• Heterophile antibodies interfering with the TSH assay (heterophile antibodies are weak antibodies with multispecific activities, which can cause significant interference immunoassays).

• Central hypothyroidism: in these patients there is hypothalamic or pituitary failure, usually leading to normal or only mildly raised TSH in the presence of low serum T4 and T3, with overt hypothyroidism (but no goitre). It is rare - around 1 in 100,000, and usually associated with other pituitary axis abnormalities. Causes include pituitary microadenoma and pituitary infarction.

Associated diseases

TSH elevation is important as a risk factor for cardiovascular disease.

Patients with full hypothyroidism have serum levels of triglycerides, total cholesterol and low-density lipoprotein (LDL) cholesterol that are elevated. The same changes exist in subclinical hypothyroidism, but are less marked and less consistent.

Management

A 2019 review and meta-analysis concluded that almost all adults with subclinical hypothyroidism would not benefit from treatment with thyroid hormones¹ . However the National Institute for Health and Care Excellence (NICE) committee found that most of the evidence related to older adults. The committee agreed that as most studies used 65 years as a cut-off it was appropriate to define older adults as over 65 and make separate recommendations for this group.

The NICE committee also noted that a TSH level above 10 mlU/L is more often associated with symptoms. They therefore agreed that levothyroxine should be considered for all adults with a TSH level of 10 mlU/L or more because this may improve symptoms and may have long-term benefits including on cardiovascular outcomes. For people with a TSH level lower than 10 mIU/L, the committee agreed based on their experience that treatment was less likely to have a benefit but that the balance of risks to benefits was most favourable for adults under the age of 65. The committee noted that for people over 65 there was less likely to be an improvement in symptoms and the potential for harms from suppressing TSH (such as atrial fibrillation) is greater.

Therefore the 2019 NICE Guidelines suggest that levothyroxine treatment should be considered for adults with subclinical hypothyroidism who have a TSH of 10 mlU/litre or higher on two separate occasions three months apart⁵ . A six-month trial of levothyroxine should also be considered for adults under 65 with SCH who have a TSH above the reference range but lower than 10 mlU/L on two separate occasions three months apart, and symptoms of hypothyroidism.

If symptoms do not improve after starting levothyroxine, re-measure TSH and if the level remains raised, adjust the dose. If symptoms persist when serum TSH is within the reference range, consider stopping levothyroxine and follow the recommendations on monitoring untreated SCH and monitoring after stopping treatment.

Patients with a history of radio-iodine treatment or positive thyroid antibody test should be treated, as this subgroup will nearly always progress to overt hypothyroidism.

For people with untreated SCH consider measuring TSH and FT4 once a year if they have features suggesting underlying thyroid disease, or once every two to three years if they have no features suggesting underlying thyroid disease.

Medication

If the decision is made to treat:

• Levothyroxine is the drug of choice as it has a long half-life (seven days) and is partially converted to T3 in the body, resulting in a constant physiological level of both T3 and T4 with a single daily dose.

• Dosing: <65 years old start at 50 micrograms od.

• Elderly: >65 years old at 12.5 to 25 micrograms od.

• Monitor at 6- to 8-week intervals initially. Once the correct dose has been established, monitoring can be 6- to 12-monthly.

• Aim to lower TSH to mid-normal: 1-3 mlU/L.

• Contra-indications to treatment are osteoporosis and fracture risk.

• Goals for treatment are symptomatic improvement, or TSH normalising.

Prognosis²

About 62% of TSH levels between 4 and 10 mIU/L normalise without intervention within five years. About 2-5% of people with SCH develop overt hypothyroidism (OH) - progression to OH is particularly more likely with higher serum TSH levels (especially greater than 10 mU/L), with positive thyroid autoantibodies (to thyroid peroxidase), and in women⁶ .

Observational data suggest that SCH is associated with an increased risk of coronary heart disease, heart failure, and cardiovascular mortality, particularly in those with TSH levels >10 mIU/L¹ . Such associations were not found for most adults with TSH levels of 5-10 mIU/L.

The annual rate of progression from subclinical to overt hypothyroidism has been estimated as about 4% in women with raised TSH and positive anti-thyroid antibodies, 2-4% in those with raised TSH alone, and 1-3% in those with anti-thyroid antibodies alone.

Pregnancy

During the first trimester thyroxine is supplied exclusively by the mother. Fetal production begins at 10-12 weeks of gestation. Thyroxine is important for fetal neural development throughout pregnancy, but particularly so in the first trimester. Maternal hypothyroidism has been associated with learning difficulties in euthyroid children, and with increased fetal loss.

Maternal hypothyroidism in the third trimester may increase the chances of caesarean section and of low birth weight. Thyroxine requirement increases during pregnancy so close monitoring is needed to maintain a normal serum TSH.

Pregnant women with goitre, high anti-thyroid antibody titre, family history of thyroid disease or symptoms suggestive of hypothyroidism, should be screened early in pregnancy, or preferably prior to conception, and treated⁷ .

All women with SCH who are planning a pregnancy should be referred to an endocrinology specialist² .

• Check TFTs before conception if possible.

• If TFTs are not within the euthyroid range, advise delaying conception, until stabilised on levothyroxine treatment - discuss with an endocrinologist if there is any uncertainty about initiation of treatment or what dose to prescribe while waiting for review.

• Check that the woman understands that her dose of levothyroxine must be adjusted as early as possible in pregnancy to reduce the chance of obstetric and neonatal complications.

• Advise the woman to seek medical advice immediately if pregnancy is suspected or a menstrual period is missed.

If the woman is pregnant:

• Check TFTs immediately once pregnancy is confirmed.

• Discuss urgently with an endocrinologist regarding initiation of, or changes to, dosage of levothyroxine and TFT monitoring while waiting for review - trimester-specific TFT reference ranges may vary locally.

Dr Mary Lowth is an author or the original author of this leaflet.