Written by Dr Shane Cullinan, Lecturer in Pharmacy Practice Royal College of Surgeons Ireland
Very little has changed with regard to the treatment of primary hypothyroidism since the introduction of levothyroxine sixty years ago. It is safe, effective and relatively cheap. For all these reasons, both condition and treatment often drop to the bottom of priority lists in terms of patient and medication review, which, much of the time, is reasonable and justified. However, when a drug acquires this ‘reputation’, there is a danger that important details become slowly diluted until in some instances they are forgotten about altogether. The fact is, there are some quite unique and critical points to levothyroxine treatment, which, if ignored, can result in suboptimal therapy and patient harm. Indeed research shows a third of patients are inadequately treated. 1 Considering the burden of hypothyroidism with respect to associated comorbidities such as diabetes and cardiovascular disease, decreased quality of life and economic impact of same, a third of patients inadequately treated is significant. This article aims to highlight the salient points associated with hypothyroidism and levothyroxine therapy.
The thyroid produces two major hormones; Thyroxine (T4) and triiodothyronine (T3) in approximately a 4:1 ratio with most T4 subsequently being converted to T3 in the blood. Release of these hormones is triggered by Thyroid Stimulating Hormone (TSH) from the pituitary gland, which itself is triggered by Thyrotropin Releasing Hormone (TRH) from the hypothalamus. Initial diagnosis of hypothyroidism is usually on the basis of an elevated TSH level combined with a low free thyroxine level (FT4).
Accurate prevalence figures for hypothyroidism in Ireland are difficult to come by and largely unknown. Partly due to the fact that there is likely a large proportion of undiagnosed cases given the general and vague symptoms associated with the condition, which in some case can be mild, or even absent or silent and not trigger much concern (fatigue, weight gain, cold intolerance, dry skin hyperlipidaemia). Globally it is generally accepted that up to 5% of the population are affected, with as many again undiagnosed. Worldwide, iodine deficiency is the most common cause of hypothyroidism (iodine being essential for thyroid hormone production in the thyroid gland). However, in areas of iodine sufficiency, 95% of cases are autoimmune in nature (Hashimoto’s thyroiditis). Secondary and tertiary disease (insufficient production of thyroid stimulating hormone/thyroid releasing hormone from the pituitary/hypothalamus) are less common.
The mainstay of treatment for hypothyroidism is thyroid hormone replacement with levothyroxine (synthetic T4) and treatment tends to be lifelong. Levothyroxine is the second most commonly prescribed medication in the US and is considered an ‘essential medicine for basic healthcare’ by the WHO. 1 Synthetic T3 also exists in the form of liothyronine which has a much shorter halflife. However it is unlicensed in Ireland and although it may potentially play a role in specialist situations such as myxoedema coma (severe hypothyroidism and medical emergency) or as a trial in combination with levothyroxine when symptoms have not ceased, 2 NICE guidance does not recommend a routine role for liothyronine. 3
Initiation of therapy
For otherwise healthy patients under 50, levothyroxine is initiated at a dose of 50-100µg (taken on an empty stomach, half an hour before breakfast) and titrated until TSH falls to within desired range and symptomatic improvement is achieved. Most maintenance doses fall between 75-150µg/day with a maximum of 200µg.
Due to the long half-life of levothyroxine (6-7 days), TSH should not be measured until 4-6 weeks after initiation, as it can take this long for levels to return to normal. Similarly, dose titration should be done in 4 week intervals and 50 µg increments.
In patients over the age of 50 and/ or those with cardiac disease, an initial dose of 25-50µg/ day is recommended (or 50 µg on alternate days in the case of cardiac disease) with 25 µg titration increments every 4 weeks. Overtreatment with levothyroxine can induce or exacerbate cardiovascular disorders, including atrial and ventricular arrhythmias, atherosclerotic vascular disease, dyslipidaemia, and heart failure. In fact, low circulating thyroid hormone levels may be providing a protective effect for the heart, hence caution is advised when aiming to increase levels.
Factors affecting dose requirements
Levothyroxine is a narrow therapeutic index (NTI) drug, however dose control often doesn’t receive the same attention compared to other NTI-drugs such as digoxin and warfarin. An understanding of the factors affecting plasma concentrations of the drug and/or endogenous thyroid hormone are required in order to find and maintain the optimal dose for a patient and avoid therapeutic failure or adverse drugs reactions.
Maintenance doses in excess of 150 µg are not commonly required, therefore other factors such as medication adherence, malabsorption, concomitant medications and comorbidities should be examined in patients not achieving adequate control in the 75-150 µg range.
Several commonly taken medications, including over the counter products can impair the absorption of levothyroxine including iron and calcium supplements, aluminium hydroxide (found in many antacids), and some proton pump inhibitors. A gap of 4-5 hours should be observed between taking these medications and levothyroxine.
Inadequate treatment of existing hypothyroidism during pregnancy can be detrimental given the importance of these hormones to the baby’s development. Levothyroxine is generally continued therefore, however thyroid hormone requirements increase during pregnancy due to increased oestrogen levels. This means levothyroxine doses will often have to be increased during pregnancy. TSH levels should be monitored closely during each trimester and doses titrated accordingly.
When symptoms of hypothyroidism are not subsiding despite an increasing dose of levothyroxine and TSH levels returning to normal, consideration should be given to other potential causes such as hypoadrenalism and anaemia which often accompany hypothyroidism and result in similar symptoms.
Amiodarone can be a particularly problematic drug when it comes to interpreting thyroid function and dosing of levothyroxine as it can induce both hypo- and hyperthyroidism. The molecular structure of the drug contains two atoms of iodine. A standard 200mg/day regime of amiodarone can result in 20-40 times the recommended daily dose of iodine. Given that iodine is a principle substrate for the synthesis of thyroid hormones, this in turn can lead to elevated levels of thyroid hormone. This is rare however as the body normally initialises a protective mechanism against this called the Wolff-Chaikoff effect whereby excessive iodine levels inhibit thyroid hormone synthesis. However, when the body fails to ‘escape’ from the Wolff- Chaikoff effect, a phenomenon more commonly seen in patients with pre-existing autoimmune thyroiditis, this in turn leads to amiodarone induced thyroiditis (AIH). Furthermore, amiodarone exhibits some intrinsic properties which compound this such as inhibition of conversion of T4 to T3 in peripheral tissues. Importantly, the half-life of amiodarone can be up to 100 days, meaning that it can have adverse effects on thyroid function even months after cessation which must be taken into account when monitoring a patient on levothyroxine and titrating doses. 4
Treatment of subclinical hypothyroidism, defined as elevated TSH, normal FT4 and very mild or no symptoms, has long been a matter of debate. The benefits are not well proven, though thought to perhaps prevent progression to overt hypothyroidism, and these must be weighed against the potential risks including cardiovascular side effects. Indeed, some evidence suggests subclinical hypothyroidism, in the absence of overt symptoms, is actually associated with longevity in older patients. NICE guidance recommends treating with a TSH of 10 mlU/litre or higher on 2 separate occasions 3 months apart (with symptoms in those aged over 65). 3 Given the lack of data, several sources recommend basing the decision on whether to treat or not on individual circumstances.
Although a simple and effective treatment for hypothyroidism, levothyroxine therapy is not without its complications and warrants attention, particularly at the beginning of therapy.
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