Pharmacotherapy Thyroid disorders

RVS Chaitanya Koppala

Thyroglobulin and thyroid peroxidase (TPO) aresynthesised by follicular cells.

Hydrogen peroxide (H2O2) is synthesised at the luminalmembrane.

Dietary inorganic iodide is trapped

Iodine is then transferred onto the tyrosine residues(MIT) and di-iodotyrosine (DIT).

Subsequently, the formation of T4 occurs as a resultof the coupling of two DIT residues and

T3 by coupling a DIT and an MIT residue. The hormones arethen stored within the gland until their release into thecirculation.

Finally, thyroglobulin is resorbed into the follicular cell,hydrolysed and its amino acids and remaining iodine re-used

Hypothyroidism

• Hypothyroidism is the clinical state resulting from decreased production of thyroid hormones or very rarely from tissue resistance.

Epidemiology

• Accurate assessment of the prevalence and incidence of hypothyroidism is difficult due to variation in definitions and population samples.

• The prevalence of previously undiagnosed, spontaneous, overt hypothyroidism has been estimated to be between 2 and 4 per 1000 of the total population worldwide

• However, if all cases of previously diagnosed hypothyroidism and the effects of previous thyroid surgery and radioiodine treatment are included, this prevalence rises to approximately 10 per 1000.

• In the UK, primary hypothyroidism is common with a prevalence of 14/1000 women (but <1/1000 men).

AetiologyPrimary hypothyroidism accounts for more than

95% of adult cases (failure of the thyroid gland itself as a result of autoimmune destruction), or the effects of treatment of thyrotoxicosis.

Hypothyroidism may be drug induced. Amiodaroneand lithium cause hypothyroidism in around 10% of patients treated.

Secondary disease is due to hypopituitarism.

Tertiary disease due to failure of the hypothalamus.

Peripheral hypothyroidism is due to tissue insensitivity to the action of thyroid hormones.

Iodine absorption from topical iodine-containing antiseptics has been shown to cause hypothyroidism in neonates.

This is potentially very dangerous at a critical time of neurological development in the newborn infant.

Transient hypothyroidism may be seen in 25% of iodine-exposed infants.

Clinical manifestations

Hypothyroidism can affect multiple body systems, Symptoms arefrequently vague especially in the early stages.

hypothyroidism will assume that it is responsible for symptoms of fatigueand weight gain.

The most useful clinical signs are myotonic (slow-relaxing) tendonreflexes, bradycardia, hair loss and cool, dry skin.

Effusions may occur into pericardial, pleural, peritoneal or joint spaces.

Mild anaemia is quite common and responds to thyroxine replacement.

Pernicious anaemia is a frequent concomitant finding in hypothyroidism.

Other, organ-specific autoimmune diseases such as Addison's disease maybe associated.

Signs and symptoms of hypothyroidism

Myxoedema coma

Myxoedema coma is a rare but potentially fatal complication ofsevere, untreated hypothyroidism.

Coma can be precipitated by hypothermia, stress, infection, traumaand certain drugs, notably β-blockers and respiratory depressants,including anaesthetic agents, narcotics, phenothiazines andhypnotics.

The condition is a medical emergency and should be treated rapidlyand aggressively.

The term ‘myxoedema’ used to be synonymous with hypothyroidism.It is now reserved for advanced disease in which there is swelling ofthe skin and subcutaneous tissues

InvestigationsUsually clinical assessment, combined with a single estimation of thyroid

hormones and TSH, is sufficient to make the diagnosis.

In primary disease, the levels of free T4 and T3 are low and the TSH levelrises markedly.

Some laboratories offer only TSH as a first-line test of thyroid functionthough this can result in delayed diagnosis of secondary Or tertiaryhypothyroidism(low free T4 along with low TSH levels)

Elevation of the TSH level occurs early in the course of thyroid failure.

A chest radiograph may detect the presence of effusions, and anelectrocardiogram (ECG) is useful, especially in patients with angina orcoronary heart disease, in whom replacement therapy needs to beintroduced gradually.

Treatment

The aims of treatment (?).

All patients with symptomatic hypothyroidism require replacement therapy. T4 is usually the treatment of choice except in myxoedema coma where T3 may be used in the first instance.

Before commencing T4 replacement, the diagnosis of glucocorticoid deficiency must be excluded to prevent precipitation of a hypoadrenal crisis.

If in doubt, hydrocortisone replacement should be given concomitantly until cortisol deficiency is excluded.

The initial dose of T4 will depend on the patient's age, severity and duration of disease and the coexistence of cardiac disease. T4 (50–100 μcg daily).

The most convenient time is usually in the morning. After 6 weeks on the same dose.

Thyroid function tests should be checked.

The TSH concentration is the best indicator of the thyroid state, and this should be used for further dosage adjustment.

The majority of patients will be controlled with doses of 100–200 μcgdaily, with few patients requiring more than 200 μcg.

In adults, the median dose required to suppress TSH to normal is 125 μcg daily.

In the majority of patients, once the appropriate dose has been established, it remains constant.

During pregnancy, an increase in the dose of thyroxine by 25–50% is needed to maintain normal TSH levels.

Prevention

At present, nothing can be done to prevent autoimmune thyroid failure from developing

Careful follow-up of patients who have undergone radioiodine treatment, subtotal thyroidectomy or completed a course of treatment for thyrotoxicosis is essential along with monitoring of those prescribed amiodarone and lithium.

An increase in TSH with normal concentrations of T3 and T4 will indicate the onset of hypothyroidism before the patient becomes symptomatic.

Prevalence of thyroid disturbance

Hyperthyroidism/thyrotoxicosis

Hyperthyroidism is defined as the production by the thyroid gland of excessive amounts of thyroid hormones.

Thyrotoxicosis refers to the clinical syndrome associated with prolonged exposure to elevated levels of thyroid hormone.

This distinction is important when evaluating thyroid function tests

Epidemiology

Hyperthyroidism is a common condition.

It has been estimated that there are 4.7/1000 women with active disease.

When previously treated cases were included, the population prevalence rose to 20/1000 in women.

As for hypothyroidism, it is much less common in men who have a lifetime prevalence of around 2/1000

Aetiology

Hyperthyroidism is a disorder of various aetiologies.

In clinical terms, thyrotoxicosis is the result of persistently elevated levels of thyroid hormones.

Clinical manifestations

Thyrotoxicosis is characterised by increases in metabolic rate and activity of many systems due to excessive circulating quantities of thyroid hormones.

The signs and symptoms reflect increased adrenergic activity, especially in the cardiovascular and neurological systems

The clinical features of thyrotoxicosis in the elderly may not be so obvious.

Signs and symptoms of cardiovascular disturbance tend to predominate, atrial fibrillation is frequent and the patient may develop congestive cardiac failure

Signs and symptoms

Investigations

In those with suspected thyrotoxicosis,

If the diagnosis is in doubt, treatment should be withheld because unless severe, thyrotoxicosis can usually be safely observed whilst awaiting the results of investigations.

Plasma free T4 (and/or T3) levels are elevated. The TSH level is suppressed to subnormal levels in all causes of thyrotoxicosis, except the exceptionally rare cases of TSH secreting pituitary adenomas.

Radioactive iodine uptake scans will differentiate those patients with thyroiditis.

Measurement of TRABs will identify Graves' disease patients.

If the diagnosis is still equivocal, the clinical findings should be reassessed and particular attention paid to the patient's drug history.

Treatment

A number of factors need to be considered when choosing the most appropriate form of therapy for an individual patient.

Three forms of therapy are available, including anti-thyroid drugs, surgery and radioactive iodine.

There is no general agreement as to the specific indications for each form of therapy, and none of them is ideal.

Neither surgery nor radioactive iodine should be given until the patient has been rendered euthyroid due to the risk of inducing a thyroid crisis.

In children, surgery may be difficult and the complication rate is higher.

Also, radioiodine has been avoided due to concern about the potential development of thyroid malignancy,

Treatment

In pregnancy, radioiodine is not used due to the likelihood of producing a hypothyroid neonate.

Thyroid surgery during pregnancy should be deferred until the second trimester if possible and most patients can be controlled with drugs.

Thionamide doses should be kept as low as possible, especially in the last 2 months of pregnancy, as excessive treatment may produce goitre in the fetus.

Aplasia cutis is said to occur after carbimazole therapy, so Propylthiouracil(PTU) is usually used in pregnancy.

Immediate treatment of thyrotoxicosis

Patients need to have their symptoms addressed and their thyrotoxicosis controlled.

β-Blockers in standard antihypertensive doses are effective within a matter of hours and should be offered to all non-asthmatics with severe thyrotoxicosis.

Carbimazole (40 mg once a day) or PTU (150 mg twice daily) will render most patients euthyroid within 6 weeks.

Adjunctive treatment of cardiac disease and anxiety/ sleeplessness may be required.

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