THERAPY IN PRACTICE

Drugs 2012; 72(1); 17-33 0012.6667/12/(X)01.0017/S66.5S/0 2012 Adis Data information BV. Aii rights reserved.

Overt and Subclinical Hypothyroidism

Who to Treat and How
Deepak Khandelwal and Nikhil Tandon
Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

Contents
Abstract 1. Introduction 2. Epidemiology and Aetioiogy 2.1 Prevaience ot Overt and Subclinicai Hypothyroidism 2.2 Natural History of Subciinicai Hypothyroidism 2.3 Causes 3. Ciinicai Features and Diagnosis 4. Who to Treat 4.1 Overt Hypothyroidism 4.2 Subciinicai Hypothyroidism with Thyroid-Stimuiating Hormone (TSH) >10miU/L 4.3 Subciinicai Hypothyroidism with TSH <10mlU/L 5. Pharmacologicai Considerations 5.1 Levothyroxine Sodium (L-thyroxine, LT4) 5.2 Liothyronine Sodium (L-triiodothyronine, LT3) 5.3 Combination LT4/LT3 Therapy 5.4 Desiccated Thyroid 6. initiating LT4 Therapy 7. Monitoring 8. Persistently Eievated TSH Despite Thyroid Hormone Replacement 9. Treatment in Speciai Circumstances 9.1 Primary Hypothyroidism in Speciai Circumstances 9.1.1 Pregnancy 9.1.2 Coronary Artery Disease 9.1.3 Elderly 9.1.4 Congenitai Hypothyroidism 9.1.5 Chiidren 9.1.6 Adrenai Insufficiency 9.1.7 Differentiated Thyroid Cancer 9.2 Centrai Hypothyroidism 9.3 Myxoedema Coma 10. Adverse Effects 11. Conclusions 17 18 19 19 19 19 19 20 20 21 22 22 23 23 23 24 24 25 26 26 26 26 27 27 28 28 29 29 29 30 30 31

Abstract

Hypothyroidism denotes deficient production of thyroid hormone by the thyroid gland and can be primary (abnormality in thyroid gland itself) or secondary/central (as a result of hypothalamic or pituitary disease). The term 'subchnical hypothyroidism' is used to define that grade of primary hypothyroidism in which there is an elevated thyroid-stimulating hormone (TSH)

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concentration in the presence of normal serum free thyroxine (T4) and triiodothyronine (T3) concentrations. Subclinical hypothyroidism may progress to overt hypothyroidism in. approximately 2-5% cases annually. All patients with overt hypothyroidism and subclinical hypothyroidism with TSH >10mIU/L should be treated. There is consensus on the need to treat subclinical hypothyroidism of any magnitude in pregnant women and women who are contemplating pregnancy, to decrease the risk of pregnancy complications and impaired cognitive development of the offspring. However, controversy remains regarding treatment of non-pregnant adult patients with subclinical hypothyroidism and serum TSH values <10mIU/L. In this subgroup, treatment should be considered in symptomatic patients, patients with infertility, and patients with goitre or positive anti-thyroid peroxidase (TPO) antibodies. Limited evidence suggests that treatment of subclinical hypothyroidism in patients with serum TSH of up to 10 mlU/L should probably be avoided in those aged >85 years. Other pituitary hormones should be evaluated in patients with central hypothyroidism, especially assessment of the hypothalamic-pituitary-adrenal axis, since hypocortisolism, if present, needs to be rectified prior to initiating thyroid hormone replacement. Levothyroxine (LT4) monotherapy remains the current standard for management of primary, as well as central, hypothyroidism. Treatment can be started with the full calculated dose for most young patients. However, treatment should be initiated at a low dose in elderly patients, patients with coronary artery disease and patients with long-standing severe hypothyroidism. In primary hypothyroidism, treatment is monitored with serum TSH, with a target of 0.5-2.0mlU/L. In patients with central hypothyroidism, treatment is tailored according to free or total T4 levels, which should be maintained in the upper half of the normal range for age. In patients with persistently elevated TSH despite an apparently adequate replacement dose of LT4, poor compliance, malabsorption and the presence of drug interactions should be checked. Over-replacement is common in clinical practice and is associated with increased risk of atrial fibrillation and osteoporosis, and hence should be avoided.

inadequate thyrotropin-releasing hormone (TRH) release from the hypothalamus (tertiary hypoHypothyroidism is a condition in which the thyroidism). In clinical practice it is not always thyroid gland is unable to make adequate amounts possible to discriminate between secondary and of thyroid hormone to meet the requirements of tertiary hypothyroidism, which are consequently peripheral tissues. In primary hypothyroidism, often referred to as 'central hypothyroidism'.t'^ characterized by failure of the thyroid gland itself. Primary hypothyroidism is the aetiology in apa fall in serum concentrations of thyroid hormone proximately 99% of cases of hypothyroidism.f^l causes an increased secretion and elevation of serum The term subchnical hypothyroidism is used to thyroid-stimulating hormone (TSH) concentradefine that grade of primary hypothyroidism in tions. Decreased thyroidal secretion of thyroid which there is an elevated TSH concentration in hormone can also be caused by insufficient sti- the presence of normal serum free thyroxine (T4) mulation of a structurally normal gland due and triiodothyronine (T3) concentrations.'^^ Subto diminished TSH release from the pituitary clinical hypothyroidism may progress to overt (secondary hypothyroidism) or consequent to hypothyroidism in approximately 2-5% of cases
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1. Introduction

Overt and Subclinical Hypothyroidism

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annually.'"] The term myxoedema is now usually reserved for cases of overt hypothyroidism that are severe or complicated, or both.'^' In this review, we predominantly discuss and inform regarding issues pertaining to primary hypothyroidism in young healthy adults. Whenever necessary, distinctive aspects of the pathogenesis, clinical profile and management of primary hypothyroidism in other special populations and of central hypothyroidism is discussed separately. 2. Epidemiology and Aetioiogy 2.1 Prevalence of Overt and Subclinical Hypothyroidism Primary hypothyroidism, which is widely prevalent worldwide, is more common in women than men and increases in incidence with age, especially after the onset of middle age. The prevalence of spontaneous overt hypothyroidism is between 1 % and 2% and ten times more common in women than in men, while approximately 8% of women and 3% of men have subcUnical hypothyroidism.'^1 Community studies of elderly people have found a higher prevalence of hypothyroidism: approximately 10% of the subjects aged >60 years had serum TSH values above the normal

2.2 Natural History of Subclinical Hypothyroidism In a follow-up study of the Whickham Survey,f'*l a population-based study in northern England," women who had both high serum TSH and anti-thyroid antibody concentrations developed overt hypothyroidism at an annual rate of 4.3%, compared with 2.6% and 2.1% in women who had only high serum TSH concentrations or only elevated anti-thyroid antibody concentrations, respectively. Subsequent studies have also reported that subjects with higher baseline serum TSH values and/or elevated anti-thyroid antibodies have a higher propensity to progress to overt h ' ^ ^ l 2.3 Causes The causes of hypothyroidism are summarized in table I. 3. Ciinicai Features and Diagnosis Symptoms are generally related to the duration and severity of hypothyroidism, and the rapidity with which hypothyroidism occurs. Presenting signs, symptoms and laboratory findings of hypothyroidism are summarized in table II. The clinical manifestations of hypothyroidism are characterized by

Table I. Causes of hypothyroidismii Primary hypothyroidism Loss of functional thyroid tissue Hashimoto's thyroiditis Surgical removal of the thyroid Radioiodine ablation, external irradiation of the thyroid Silent and postpartum thyroiditis Cytokine-induced thyroiditis Invasive fibrous thyroiditis Thyroid infiltration (amyloidosis, haemochromatosis, sarcoidosis, scleroderma, cystinosis, primary thyroid lymphoma) Thyroid dysgenesis Functional defects in thyroid hormone biosynthesis and release Iodine deficiency and iodine excess Thyroid hormone biosynthetic defect Drugs: antithyroid agents, lithium, amiodarone, tyrosine kinase inhibitors (e.g. sunitinib), ethionamide, sulphonamides, goitrogenic chemicals, thalidomide Peripheral (extrathyroidal) hypothyroidism Large haemangioma Thyroid hormone resistance Central hypothyroidism Pituitary or hypothalamic neoplasms Trauma (surgery, head injury) Radiation Ischaemic necrosis (postpartum pituitary infarction/Sheehan's syndrome, severe shock, diabetes meilitUs) Vascular (haemorrhage, aneurysm of internal carotid artery) Infections (abscess, tuberculosis, syphilis, toxoplasmosis) Infiltrative disorders (sarcoidosis, histiocytosis, haemochromatosis) Lymphocytic hypophysitis Drugs (bexarotene) Set point diseases (infants born to mothers with poorly controlled Graves' disease) Genetic mutations Idiopathic

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Table II. Presenting symptoms, signs and laboratory findings of hypothyroidism'^"''^' Symptoms Exhaustion Somnolence Slow cognition Emotional lability Intolerance to cold Constipation Depression Weight gain Myalgia Muscle cramps Calf stiffness Growth failure Pubertal delay Sexual dysfunction Menorrhagia Menstrual irregularity Impaired fertility Paresthesia Hearing impairment Hoarseness of voice Signs Coarsening of facial features Puffiness below the eyes Dry, thin and pale skin Coarseness or loss of hair Macroglossia Goitre Hypothermia Bradycardia Diastolic hypertension Slow relaxation of tendon reflexes Pleural effusion Pericardial effusion Ascites Non-pitting oedema of lower leg Ataxia Galactorrhoea Sleep-disordered breathing Laboratory/radiological findings Hyponatraemia Hypercholesterolaemia Anaemia Elevated serum creatine kinase Hyperprolactinaemia Hyperhomocysteihaemia Elevated serum carcino-embryonic antigen level Epiphyseal dysgenesis Delayed bone age Pituitary gland enlargement

either slowing of body functions or consequent to accumulation of glucosaminoglycans in the tissues. No single symptom/sign is a very sensitive or specific indicator of the presence of hypothyroidism. However, presence of multiple symptoms, particularly if recent in onset, increases the likelihood of hypothyroidism.t'^1 There are certain symptoms or signs (e.g. presence of a goitre or short stature in children) that should always prompt a thyroid function test to rule out possible hypothyroidism.I'^l As mentioned in section 1, primary hypothyroidism is the aetiology in more than 99% cases of hypothyroidism, thereby making serum TSH measurement the best single test for the exclusion or detection of hypothyroidism in most clinical settings. Raised serum TSH concentrations identify primary hypothyroidism irrespective of the cause or severity. If the TSH level is high, further measurement of the serum free T4 should be carried out. A low serum free T4 in conjunction with an elevated serum TSH level establishes a diagnosis of overt hypothyroidism, while in subclinical hypothyroidism the serum free T4 concentration is, by definition, normal. However, serum TSH measurement will not reliably identify patients with central hypothyroidism, in whom serum TSH concentrations may be low, mildly
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elevated or inappropriately normal in the presence of low serum T4 values. In patients suspected of having central hypothyroidism, measurement of free T4 is the test of choice. Measuring total T4 is also acceptable, provided there are no alterations in binding proteins. Once the diagnosis of primary hypothyroidism is made, additional imaging or serological testing is unnecessary if the thyroid gland is normal on examination.[''*1 Measurement of anti-thyroid peroxidase (TPO) antibodies is a valuable adjunct in the evaluation of patients with subclinical hypothyroidism because it predicts a higher risk of developing overt hypothyroidism. In patients with central hypothyroidism, measurement of other pituitary hormones and imaging of the sellar-suprasellar area is required. Laboratory evaluation of a patient with suspected hypothyroidism is summarized in figure 1. 4. Who to Treat 4.1 Overt Hypothyroidism Patients with overt hypothyroidism, whether symptomatic or not, should be treated. Hypothyroidism in the majority of patients is permanent and requires lifelong treatment. Hence, it is good practice
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to confirm the results with a second sample.''^^ Individuals with some conditions, e.g. recovery phase of thyroiditis or drug-induced hypothyroidism may need temporary thyroxine replacement to ensure euthyroidism until recovery is complete. 4,2 Subclinical Hypothyroidism with Thyroid-Stimulating Hormone (TSH) >10mlU/L In the last few years, there have been several publications regarding subclinical hypothyroidism and its clinical relevance that have provoked debate about its screening and treatment. Because of the difficulties in interpreting data from many different sources, in 2002 the American Association of Clinical Endocrinologists (AACE), The US Endocrine Society and the American Thyroid Association (ATA) convened a panel to propose evidence-based guidelines on diagnosis, screening and

treatment of subclinical hypothyroidism. The panel found good evidence that subclinical hypothyroidism is associated with progression to overt hypothyroidism, and fair evidence that serum TSH levels >10mIU/L are associated with elevations in total and low-density lipoprotein cholesterol levels. However, there was insufficient evidence regarding an association between subclinical hypothyroidism and adverse cardiac events, cardiac dysfunction, neuropsychiatrie symptoms or systemic symptoms of hypothyroidism.t'^ The Panel recommended that patients with an elevated serum TSH level have the test repeated, along with a serum free T4 (FT4) measurement, within 2-12 weeks. When repeat studies confirm subclinical hypothyroidism, further evaluation is required, including clinical assessment of signs and symptoms of hypothyroidism, ascertainment of previous treatment for hyperthyroidism (e.g.

Signs and symptoms suggestive of hypothyroidism

Serum TSH

Low

Normal

High

Serum Fr4 Low suspicion of hypothyroidism Strong suspicion of hypotfiyroidism

Serum FT4

Low

Normal

No further test

Low

Normal

Central hypothyroidism

Evaluate for causes of suppressed TSH

Serum FT4

Overt primary hypothyroidism

Subclinical hypothyroidism

Low MRI sella Evaluation of other pituitary hormones

Normal Check anti-TPO antibody

Central hypothyroidism

Euthyroid

Fig. 1. Aigorithm for evaluation of a patient with suspected hypothyroidism. FT4=free thyroxine concentration; TPO=thyroid peroxidase; TSH = thyroid-stimulating hormone.

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Khandelwal & Tandon

radiotherapy, partial thyroidectomy), presence of thyromegaly and family history of thyroid disease. In addition, these patients should be screened for hyperlipidaemia. The Consensus Expert Panel recommended that treatment was reasonable for patients with TSH levels >10mIU/L, as these patients also have a higher rate of progression to overt hypothyroidism.''*! Most other guidelines and expert views also recommend treatment of subclinical hypothyroid patients with TSH levels

I Primary hypothyroidism |

ISubclinical] I Treat | |TSH>10mlU/L| |TSH:1QmlU/L|

4.3 Subclinicai Hypothyroidism with TSH <10miU/L

Pregnancy Planning pregnancy Infertility Symptomatic Antl-TPO antibody positive Goitre

Treatment of individuals with subclinical hypothyroidism and TSH values <10 mlU/L remains a controversial issue. Some authors recommend treating all these patients,'^"! some recommend an individualized approach,'-^'' and some strongly recommend against routine treatment for subclinical hypothyroidism with TSH <10mIU/L.'22' The Consensus Expert Panel recommended treatment for subclinical hypothyroidism with TSH <10mIU/L in pregnant women or women contemplating pregnancy, on the basis of a possible association between high TSH and subsequent neuropsychological complications in offspring. They also recommended a trial of thyroxine in individuals with TSH <10mIU/L but symptoms consistent with hypothyroidism, with a decision regarding continuance of therapy based on symptomatic improvement. The Panel recommended against routine treatment of patients with subclinical hypothyroidism with serum TSH <10 mlU/L, as available data do not confirm clear-cut benefit in this patient subgroup.''^^ However, the three societies that had sponsored the Consensus Panel considered this recommendation inappropriate, as it was based on a "lack of evidence for benefit" rather than "evidence for a lack of benefit." In a separate consensus statement, these societies recommended that most subclinical hypothyroid patients with serum TSH levels <10 mlU/L should be considered for treatment, with the key determinant being the clinical judgement of the provider.''^'
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Follow with TSH 6-12 monthly Fig. 2. Suggested algorithm for management of patients with primary hypothyroidism. TPO=thyroid peroxidase; TSH=thyroidstimuiating hormone.

In a review, Biondi and Cooper'^' further consolidated the available evidence and recommended thyroxine therapy in the case of pregnancy, presence of goitre or positive anti-TPO antibodies, and in patients with ovulatory dysfunction, infertility and high background cardiovascular risk. Current data suggest that middle-aged individuals are likely to benefit more from treatment than the elderly. In fact, in people aged >85 years, evidence suggests that subclinical hypothyroidism is associated with longevity.'^^^ Asymptomatic patients who are planned for follow-up without treatment should have a repeat thyroid function test every 6-12 months. Our suggested protocol for treatment of patients with primary hypothyroidism is depicted in figure 2.
5. Pliarmacoiogicai Considerations

The primary secretory product of the thyroid gland is 3,5,3',5'-tetraiodothyronine (T4), approximately 100 ng of which is secreted per day in normal adults. 3,5,3'-triiodothyronine (T3) is the principle active metabolite of the thyroid gland
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and 30 ^g of this is produced daily in healthy adults, 80% arising from the 5'-deiodination of T4 in peripheral tissues and 20% secreted directly from the thyroid.P"^' Thyroid hormone preparations available for treatment of hypothyroidism are levothyroxine sodium (L-thyroxine [LT4]), liothyronine sodium (L-triiodothyronine [LT3]) and desiccated thyroid.
5.1 Levothyroxine Sodium (L-thyroxine, LT4)

LT4 is synthetically produced but identical to T4 secreted by the thyroid. LT4 is the preferred drug because its administration closely mimics glandular secretion and its conversion to T3 is appropriately regulated by tissues, maintaining its steady and adequate supply.^''! Its long half-life of 7 days allows single daily dose administration . and results in only small fluctuations in serum concentrations between the daily doses. Omission of a single day's dose has little clinical relevance and the patient may safely take an omitted tablet the following day. Moreover, titration of dose is easy, because of availability of multiple tablet strengths. LT4 is primarily absorbed in the jejunum, and absorption is greater in the fasting (80%) than in the fed state (60%).P^l Non-specific absorption of LT4 by dietary fibre has been shown to decrease the bioavailability of LT4, necessitating a higher dose in patients with a high intake of dietary fibre. Serum T4 concentrations peak 2-4 hours after an oral dose and remain above normal for approximately 6 hours in patients receiving daily replacement therapy.'^^1 The LT4 content of tablets is standardized by high-pressure liquid chromatography and, the US FDA currently requires all LT4 preparations to contain 95-105% of the stated amount.^^' Generic and brand-name LT4 preparations are mostly bioequivalent, but altered bioavailability has been reported due to changes in the formulation of preparations. Hence, it is not advisable to alter the brand during long-term '^^'
5.2 Liothyronine Sodium (L-triiodothyronine, LT3)

is available in tablet strengths of 5 |ag, 25 ng and 50 |ig. It requires multiple daily administration in view of its short half-life of ~1 day. Another disadvantage is that serum T3 concentration rises to supranormal values of up to 250-600% in the absorption phase, during which many patients report adverse effects, especially palpitations.f^^' In a recent randomized, double-blind crossover trial, it was shown that substitution of LT3 for LT4 at equivalent doses (relative to the pituitary) reduced body weight and caused favourable changes in lipid profile without appreciable adverse effects. However, this study involved a very limited number of subjects and, also, both LT4 and LT3 were used thrice-daily in this study, which limits its clinical utility.^^"1LT3 may be useful prior to treatment of thyroid cancer with radioactive iodine ('^'I), as patients can be withdrawn from LT3 for shorter periods of time than LT4. It may be used when a rapid effect is desired (e.g. perioperatively or in myxedema coma). Furthermore, its use can be considered in rare cases of LT4 maldigestion or malabsorption as well as in patients with documentation of inhibition of T4 to T3 conversion.'-"' Otherwise, it is not intended as sole maintenance therapy in treatment of hypothyroidism.
5.3 Combination LT4/LT3 Therapy

LT3 is a synthetic form of natural T3 hormone with the same actions as the natural product and
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Combination LT4 and LT3 treatment has been tried in an effort to more closely mimic the thyroid secretion pattern of T4 and T3. However, there is no currently available preparation containing LT4 and LT3 in a combination that adequately reproduces the relative quantities of these hormones produced by the human thyroid. Furthermore, no preparation produces a sustained release of thyroid hormones in a pattern similar to that of the human thyroid.'^^' Having been disregarded as a therapeutic approach to the treatment of hypothyroidism since the 1970s, interest in combination LT4/LT3 therapy was re-ignited by a randomized, double-blind crossover trial of 31 patients published by Bunevicius et al.'^^l in 1999. This study found that the combination of LT4/LT3 improved several indices of quality of life, mood and psychometric performance compared
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with LT4 alone. However, a majority of patients in the study had been treated previously for thyroid cancer and were receiving relatively high doses of LT4, which could have confounded the results of the study. However, subsequent randomized controlled studies have failed to show a beneficial effect of combined LT4/LT3 therapy on measures of well-being, health and mental functioning, with some even reporting harmful effects.'^'*! A meta-analysis of 11 randomized controlled trials involving 1216 participants of LT4/LT3 combination versus LT4 monotherapy for treatment of clinical hypothyroidism found no difference in any clinical or biochemical parameter compared with LT4 monotherapy.'^^' The Executive Committee of the British Thyroid Association stated in 2007'^^' that combined LT4/LT3 cannot be recommended because of a lack of benefit and a small number of undesirable and harmful effects seen with combination treatment. 5.4 Desiccated Thyroid Desiccated thyroid contains both T4 and T3 extracted from the thyroid gland of animals. It contains excessive amounts of T3 relative to T4, is not a pure preparation of thyroid hormones and has issues related to stability.'^*! While it was the mainstay of therapy in hypothyroidism until the 1970s, there is currently no evidence supporting its use in the treatment of hypothyroidism. 6. initiating LT4 Therapy The goal of treatment is to restore the individual to a euthyroid state, with resolution of signs and symptoms. The rapidity with which the euthyroid state should be attained is dictated by several factors, notably, the age of patient, the duration and severity of hypothyroidism and the presence of other co-morbid conditions, specifically cardiac disease. LT4 is recommended to be taken as a single daily dose on an empty stomach at least 30 minutes before breakfast.'^''^ A recent randomized, double-blind crossover trial has suggested that LT4 taken at bedtime is also a good alternative.'^^] However, in this study, patients ate their dinner around 5.30pm, with no further
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snacks before bedtime, allowing a gap of 4-5 hours between the last meal and LT4. This may not be practicable in other cultures or for individuals who have a habit of late dinner or a bedtime snack. LT4 should be taken at least 4-6 hours apart from drugs that are known to interfere with its absorption (table 111).'^^^ Most patients who are aged <60 years and otherwise healthy can immediately begin a complete replacement dose of 1.6-1.8 ng/kg ideal body weight.''^' However, treatment should not be initiated with full replacement dose in elderly patients, patients with coronary artery disease and patients with long-standing severe hypothyroidism. In these patients, treatment should be started with a low dose (25-50 ng/day), and titrated slowly (discussed below).''^i Individual

Table III. Conditions requiring adjustment of the levothyroxine maintenance doset^^^^^' Increased LT4 requirement Increased need for LT4 (pregnancy, drugs [estrogen, selective estrogen receptor modulators], weight gain, nephrotic syndrome) Decreased intestinai absorption of LT4 (maiabsorption/medical conditions [coeliac disease, short bowel syndrome, IBD, Helicobacter pylori infectior\, atrophie gastritis of the body of stomach] dietary fibre supplements, soy supplements, coffee, drugs [sucraifate, ferrous suifate, bile acid squestrants, aiuminium hydroxide, caicium products, raloxifene, sevelamer, lanthanum carbonate, proton pump inhibitors, chromium picoiinate]) Drugs that increase metaboiism of LT4 (rifampicin, phenytoin, phnobarbital, carbamazepine) Conditions that may block deiodinase synthesis (cirrhosis, seienium deficiency) Precise mechanism unknown (sertraiine, lovastatin) IBD = inflammatory bowel disease; LT4 = levothyroxine. Decreased LT4 requirement Decreased need for LT4 (ioss of lean body mass, androgen therapy in women) Decreased clearance of LT4 (ageing; age >65 y)

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LT4 requirements are greatly dependent on the individual's lean body mass, rather than actual total body weight.'"^"^ The LT4 dose is generally higher in patients with previous thyroidectomy than in those with autoimmune thyroiditis, in which there may be some residual functioning thyroid tissue. In the absence of any functioning thyroid tissue, the complete daily replacement dose in women and men ranges from 100|xg to 150|ag and between 125 ^g and 200 |xg, respectively.''^' Pre-treatment serum TSH predicts, to a certain extent, the daily maintenance dose of LT4 in patients with primary hypothyroidism. Patients with subclinical hypothyroidism, because of the minimal extent of the thyroid hormone deficiency, may be controlled with total daily dosages of LT4 as low as 25-50 |xg.

to re-set after introducing or modifying LT4 therapy. Serum TSH should be maintained in the lower half of normal range (0.5-2.0 mlU/L).'^''-''^) In the event that serurn TSH is either elevat.ed or suppressed, there will be a need for a modest increase or decrease in dose, respectively. The dose should ideally not be increased or decreased by more than 12.5 or 25 \ig, and serum TSH again measured after 2 months to assess adequacy of the dose. Because of the long half-life of LT4, small dosage adjustments may even be performed by adding or withdrawing a tablet once or twice a week. A minor deviation from the targeted TSH value should not immediately prompt dose adjustment; instead, a repeat TSH measurement can be performed after 2-3 months before deciding on a dose change. Once the patient attains a biochemical euthyroid state, serum TSH should next be measured after 6 months. This is required be7. Monitoring cause, at initiation of therapy, due to the hypoAfter initiation of thyroid hormone therapy, thyroid state, the administered LT4 may be still symptoms and signs of hypothyroidism should be be metabolized slowly and appear adequate for assessed at each follow-up visit. LT4 effectively the patient's requirements. Once euthyroidism is relieves the manifestations of thyroid hormone restored, thyroxine metabolism may increase and deficiency in most patients; this can be expected the same dose be rendered sub-optimal. Once a several weeks to months after initiation of ther-. stable LT4 dose is achieved, monitoring needs to apy. Resolution of symptoms and signs usually be carried out annually. While this strategy works lags behind biochemical normalization. The ear- for most patients with hypothyroidism, patients liest clinical response to thyroxine replacement is with post-ablative hypothyroidism may continue usually diuresis and weight loss due to mobiliza- to have a decline in thyroid reserve over the years, tion of interstitial fiuid as glycosaminoglycans necessitating semi-annual or even annual dose are degraded. Weight loss is predominantly due changes until the effect of the '^'I plateaus. Someto fluid loss, and even in obese patients is unlikely times, a similar evolution of declining thyroid to exceed 5 kg, especially if pre-treatment TSH reserve over a period of time may also be observed values were modestly elevated.''^' A decrease in in patients with Graves' disease who have had a fat with thyroxine therapy, if any, is usually mini- sub-total thyroidectomy. Some experts also estimate serum T4 (total or mal and occurs late in the course of treatment. Reduction in puffiness and an increase in pulse free) to monitor therapy. If this is being done, rate and pulse pressure are also early responses care should be taken that the blood sample after treatment.''"! Features such as appetite, con- should be collected prior to receiving the day's stipation, hoarseness of voice, cold intolerance and dose of LT4. Invariably, if the serum TSH levels fatigue recover later, while symptoms and signs are in the mid to low normal range, serum T4 related to the skin, appendages and nervous sys- levels will be in the mid to high normal range. For obvious reasons, the main role of serum T4 is tem are the last to resolve.''^ After initiating therapy, -the dose should be when monitoring thyroxine replacement in a pamonitored by assessing serum TSH (with or with- tient with central hypothyroidism. Conditions out serum T4) after at least 2 months, the mini- requiring adjustment of the LT4 maintenance mum time required for the pituitary-thyroid axis dose are listed in table III.
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Khandelwal & Tandon

8. Persistentiy Eievated TSH Despite Thyroid Hormone Repiacement An important cause of persistently elevated TSH despite adequate replacement dose of LT4 is non-compliance of the patient. In fact, these patients can have an elevated TSH with highnormal or elevated FT4, as they may not take LT4 for days and then take several pills a few days before their testing. No change in the LT4 dose is needed in this situation; rather, emphasis should be placed on compliance with therapy and the thyroid function test repeated in 3-4 weeks. It sometimes helps to ask the patient to take a week's supply of medicine in a separate pill-box, which will allow easy ascertainment of missed doses. Any extra pills left in the container can actually all be taken on the last day of the week, to ensure that the patient receives his or her weekly dose. Because of the long half-hfe of 7 days, some authors propose that LT4 can be given once weekly in poorly compliant patients. A crossover trial of 12 patients showed that a single weekly dose achieved fairly good therapeutic results.'''^1 Weekly dosing or end-of-week catch-up dosing, while sub-optimal, remains an acceptable alternative for habitual non-compliers. Weekly dosing should not be given in patients who have coronary artery disease. Other causes of persistently elevated TSH despite an apparently adequate dose of LT4, include malabsorption and interference by drugs (table III). It is worth excluding coeliac disease in such cases, as it may coexist in patients with hypothyroidism because of its autoimmune nature. Interference to the laboratory assay as a result of heterophil antibodies in a patient's serum also can lead to artificial elevation in TSH. 9. Treatment in Speciai Circumstances 9.1 Primary Hypothyroidism In Speciai Circumstances
9.1.1 Pregnancy

nancy and fetal development. Untreated overt hypothyroidism during pregnancy is found to be associated with increased risk of maternal hypertension, pre-eclampsia, postpartum haemorrhage, anaemia, fetal death, low birth weight and neonatal respiratory distress.!'*''-'*^] In a landmark observational study, Haddow et al'^'^i also found that women with overt or subchnical hypothyroidism deliver babies with an average intelligence quotient (IQ) score 7 points below the mean IQ of children born to healthy women and thyroxinetreated women. If hypothyroidism has been diagnosed before pregnancy, the preconception LT4 dose should be modified to reach a TSH level not higher than 2.5mIU/L before planned pregnancy.''*^' During pregnancy, the LT4 requirement is increased by 25-50% in most hypothyroid women, which becomes evident early in the first trimester.f"*^' The increased requirement is probably due to a combination of factors: rapid rise in thyroxine-binding globuhn (TBG) levels resulting from the physiological rise in estrogen, increased distribution volume of thyroid hormones, and increased placental transport and metabolism of .maternal T4. The LT4 dose should be increased by 30-50% by 4-6 weeks gestation. As there is a large individual variability in dose requirements, dose adjustment requires testing serum TSH and total T4 (FT4 according to some authors) at regular intervals, such as every 4-6 weeks. It is recommended that serum TSH be maintained at trimester-specific normal ranges (<2.5mIU/L in first trimester and <3 mlU/L in second and third trimester).I"*^' Adjustments are made by increasing LT4 by 25-50 ng/day. Although it is clear that excess thyroid hormone can lead to fetal loss, the fetal risk from maternal over-treatment in such patients is generally low. The dose of LT4 should be reduced to the pre-pregnancy dose immediately after delivery, and serum TSH should be reassessed 6 weeks postpartum.'^'^1 In addition, patients should be cautioned against simultaneous use of iron and calcium supplements (commonly recommended during pregnancy) with LT4: a clinically significant reduction in LT4 efficacy can occur, probably caused by binding of LT4
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Patient Aiready on Repiacement Becoming Pregnant

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with iron or calcium. A time gap of 4-6 hours between LT4 and these supplements should be maintained.
Hypothyroidism Detected for the First Time during Pregnancy

9.7.2 Coronary Artery Disease

When hypothyroidism is detected for the first time during pregnancy, the test should be repeated. Unless the result is expected within 24 hours, treatment must be started before confirmation to avoid loss of time. LT4 dosage should be titrated to rapidly reach, and thereafter maintain, serum TSH concentrations to trimester-specific normal TSH ranges. Factors determining the appropriate dose for initiation of therapy are time of gestation, and the aetiology and severity of the disease. In view of increased requirements, the full replacement dose of LT4 in pregnancy is 2.0-2.4 [ig/kg bodyweight/day. Therapy may be initiated by giving, for the first few days, a LT4 dose corresponding to two to three times the estimated final replacement daily dose, to rapidly normalize the extra-thyroidal thyroxine pool. Thyroid function tests should be re-measured within 30-40 ''^^ Subciinical Hypothyroidism and Pregnancy Subclinical hypothyroidism has been shown to be associated with an adverse outcome for both the mother and the offspring. LT4 treatment has been shown to improve obstetrical outcome but has not been proved to modify long-term neurological development in the offspring. However, given that the potential benefits outweigh the potential risks, LT4 replacement is recommended in all pregnant women with subclinical hypothyroidism.'"*^! It is not clearly defined whether LT4 treatment should be continued postpartum in women in whom diagnosis of subclinical hypothyroidism was made during pregnancy. In our opinion, treatment should be continued in these women if serum TSH is >10mIU/L or in the presence of hypothyroid symptoms, goitre or antiTPO antibodies, as advised for other adults with subclinical hypothyroidism. Also, women who are planning a subsequent pregnancy should continue on LT4 replacement. In all other women, LT4 replacement can be stopped after delivery, and they can be followed up with repeat thyroid function tests every 612 months.
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Initiation of LT4 replacement therapy in patients with coronary heart disease should be carried out cautiously to avoid exacerbating angina pectoris, or precipitating acute myocardial infarction, ventricular arrhythmias or congestive heart failure.'^1 Although treatment of hypothyroidism with LT4 will improve myocardial function and reduce peripheral vascular resistance, it will increase the need for oxygen in the myocardium. In patients with an already compromised myocardial blood supply due to coronary atherosclerosis, LT4 treatment may provoke anginal symptoms. In a study of 1503 hypothyroid subjects (average age 71 years), 2% developed new onset angina during LT4 therapy. In patients with preexisting angina, after LT4 treatment, symptoms improved in 38%, remained unchanged in 46% and worsened in 16%.'^'^ Patients with pre-existing angina should ideally undergo cardiac evaluation for correctable lesions of the coronary arteries and be treated appropriately prior to initiating LT4 therapy. LT4 in such individuals should be started at a dose of 25 ng/day or even less and it should be increased no faster than at 4-weekly intervals. If angina is precipitated while increasing the LT4 dose, it should be reduced to the highest dose tolerated by the patient and a further attempt made to increase the dose again only after another 4 weeks.
9.1.3 Elderly

In many cases, hypothyroidism in elderly patients is characterized by a paucity of specific signs and symptoms. The symptoms may be subtle and include hoarseness, deafness, confusion, dementia, ataxia, depression, dry skin or hair loss.'^^' A normal starting dosage of LT4 in an elderly subject is around 1 (ig/kg/day, which is maintained for 4-6 weeks.'^^1 If heart disease is suspected, a lower starting dose, as mentioned in section 9.1.2 is appropriate. Dosage adjustments are guided by the response in TSH and the clinical state, with emphasis on possible cardiac adverse effects. Limited evidence suggests that treatment of subclinical hypothyroidism with serum TSH of up to 10 mlU/L should probably be avoided in patients older than 85 years, because subclinical hypothyroidism in this subpopulation does not result
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Table IV. Ciinicai characteristics, screening and evaluation of congenitai hypothyroidism' I^^"^^' Causes Thyroid dysgenesis Thyroid dyshormonogenesis Hypothalamic-pltuitary abnormaiity Transient hypothyroidism (maternal antithyroid medication, maternai blocking antibodies, iodine deficiency or excess) Symptoms and signs Unexplained postmaturity, poor feeding, hypothermia, iethargy, proionged jaundice, abdominai distension, umbilicai fiernia, iarge tongue, hoarse cry, mottied dry skin, iarge posterior fontanei, deiayed skeietai maturation Screening methods Primary TSH with backup T4 measurement Primary T4 with backup TSH measurement Combined primary TSH pius T4 measurements (ideai method) if screening positive or hypothyroidism suspected later Detailed history and examination Repeat serum TSH and either totai T4 or FT4 Additional work up in confirmed cases (shouid not iead to deiay in treatment); thyroid radionuciide scintigraphy, thyroid sonography and serum thyrogiobuiin a Frequency; 1 ; 3000 to 1 ; 4000 iive births. FT4=free T4; T4=thyroxine; TSH=thyroid-stimulating hormone.

be used because thyroid suspensions prepared by individual pharmacists may result in unreliable dosing. The tablet should be crushed and suspended in a few millilitres of formula, breast milk or water. Care should be taken to avoid concomitant administration of soy, fibre or iron, as they may reduce absorption of LT4. Breastfeeding can continue. The dose should be repeated if the child vomits within an hour after taking LT4.[^^1 Recommended frequency of thyroid function monitoring in management of congenital hypothyroidism is shown in figure 3.
9.1.5 Children

in adverse effects and is instead found to be associated with prolonged life

9.1.4 Congenital Hypothyroidism

Clinical characteristics, screening and evaluation of congenital hypothyroidism is summarized in table IV. The overall goals of treatment in congenital hypothyroidism are to assure normal growth and development and cognitive outcome similar to genetic potential by restoring serum T4 concentration rapidly to the normal range followed by continued clinical and biochemical euthyroidism. The aim of treatment is to keep the serum T4 (total or free) concentration in the upper half of the normal range adjusted for age. Of note, most commercial laboratories do not provide age-adjusted normal ranges in their reports. In the first postnatal year, serum T4 should be 10-16 i^g/dL and serum FT4 should be 1.4-2.3 ng/dL. The serum TSH concentration should be <5 mIU/L.[^^l The American Academy of Pediatrics (AAP) and European Society for Paediatric Endocrinology (ESPE) recommend an initial LT4 dose of 10-15 )ig/kg/day, which usually amounts to 37.5 or 50 ng/day.t^'^-^^J Only LT4 tablets should
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Hypothyroidism in children and adolescents is generally acquired, although rarely congenital hypothyroidism may not get diagnosed until early childhood. In addition to the usual manifestations, hypothyroidism in children and adolescents has a profound impact on growth, maturation and pubertal development. Slowing of linear growth with relatively preserved weight gain is in fact one of most sensitive indicators of hypothyroidism in children.t^^l Bone age is even less than the height age. There is also delay in permanent dentition. Pubertal development is generally delayed, although in some children it may be normal for age, and rarely children with severe primary hypothyroidism have precocious puberty as a result of activation of follicle-stimulating hormone receptors by very high serum TSH levels.t*^ Epiphyseal stippling and slipped capital femoral
Frequency of measurement of serum totai or free T4 and thyroid-stimuiating hormone concentrations in congenital hypothyroidism At 2 and 4 weeks after the initiation of LT4 treatment Every 1-2 months during the first 6 postnatal months Every 3-4 months between 6 months and 3 years of age Every 6-12 months thereafter until growth is complete 4 weeks after any change in dose At more frequent intervals when compliance Is questioned or abnormal results are obtained Fig. 3. Recommendations of the American Academy of Pediatrics.'^^' LT4 = ieyothyroxine; T4=thyroxine.

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epiphysis are other radiological manifestations of hypothyroidism in children. The recommended dose of LT4 for each age group is as follows:'^'! 3-12 months: 6-10 |ig/kg/day 1-3 years: 4-6 fxg/kg/day 3-10 years: 3-5 ng/kg/day 10-16 years: 2-4 ng/kg/day. Treatment should be individualized because the absorption of LT4 and metabolism vary among individuals. Serum FT4 and TSH concentrations should be monitored periodically, preferably at 3- to 6-month intervals. Available data indicate that risk of progression from subclinical to overt hypothyroidism is less common in children and adolescents, and the recovery of thyroid function is more frequent.'^^' In one recent multicentre study from Italy, 88% of subclinical hypothyroid children normalized their TSH over a period of 2 years.'*^^ Also, persistent subclinical hypothyroidism in children is not associated with alteration in growth, maturation, body mass index and cognitive functions, even after several years.'*"*' In fact, there is a view that subclinical hypothyroidism in children may be just a normal variation, rather than a sign of a failing thyroid gland.'^^' In a matched case-control study of type 1 diabetic children, subclinical hypothyroidism was associated with significantly increased risk of symptomatic hypoglycaemia as compared with matched euthyroid controls, which became comparable after 6 months of LT4 replacement.^**'
9.1.6 Adrenal Insufficiency

Table V. American Thyroid Association and European Thyroid Association recommendations for thyroid-stimulating hormone (mlU/L) targets in patients with differentiated thyroid cancer'^^'^^' Patient category High and intermediate risk (initial therapy) Persistent disease High-risk disease free (follow-up) Low risk (initial therapy) 0.1-0.5 (for 5-1 Oy) 0.1-0.5 <0.1 (for 3-5 y) <0.1 Recommendation ATA ETA

Low-risk disease free (follow-up) 0.3-2.0 0.5-1.0 ATA=American Thyroid Association; ETA=European Thyroid Association.

growth. A meta-analysis has suggested an association between thyroid hormone suppression therapy and reduction of major adverse clinical events.'*'^ Clinical practice guidelines by the American Thyroid Association (ATA) and European Thyroid Association (ETA) regarding LT4 therapy in patients with differentiated thyroid cancer and targets for TSH are'summarized in table V. 9,2.Centrai iHypothyroidism The clinical manifestations of central hypothyroidism are generally similar to those of primary hypothyroidism. However, many typical symptoms of primary hypothyroidism (e.g. coarse skin, coarseness and loss of hair, thick tongue, hoarseness, peripheral oedema and paresthesias) are less common in patients with central hypothyroidism.''^' Furthermore, manifestations might be modified by symptoms of other coexisting pituitary hormone deficiencies. Skin is pale and cool, and loss of axillary, pubic and facial hair are usually more pronounced. Atrophie breasts and amenorrhea, rather than menorrhagia, are found in pre-menopausal women.'^' Also, symptoms and signs that arise directly from the hypothalamic or pituitary lesion, such as headache and visual field defects in cases of large tumours, may precede or accompany the manifestations of pituitary failure. Although thyrotropin-releasing hormone (TRH) and TSH administration are theoretically ideal for treatment of central hypothyroidism, they are not used because of high cost, limited applicability of these molecules and
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In the event there is co-existence of thyroid hormone deficiency and glucocorticoid deficiency, it is important to replace glucocorticoids before starting LT4. This is because LT4 therapy may lead to an increased metabolism and, thereby, an increased demand of cortisol, potentially increasing the likelihood of precipitating an adrenal crisis.
9.1.7 Differentiated Ttiyroid Cancer

Patients who have had a thyroidectomy for differentiated thyroid cancer, with or without additional treatment with '-"I, need to take LT4 not only for treatment of hypothyroidism but also to minimize potential TSH stimulation of tumour
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ease of treatment with LT4, which is the standard treatment even in central hypothyroidism.[^'' Serum TSH level is not helpful in cases of central hypothyroidism. Instead, the chnician should evaluate serum FT4, adjusting the LT4 dosage to keep the serum FT4 in the upper half of the normal range for age.^^^l Monitoring total T4 is also acceptable, provided there are no alterations in binding proteins. The possible presence of secondary adrenal insufficiency should be kept in mind and pituitaryadrenal function should be assessed, usually by an adrenocorticotropic hormone (ACTH) stimulation test. If present, secondary adrenal insufficiency should be treated before starting LT4 replacement. Treatment of other pituitary hormone deficiencies might affect dosing of LT4. Growth hormone deficiency may mask central hypothyroidism, and this might become evident only after replacement of growth hormone.'^^^ Concomitant estrogen replacement in women also significantly increases LT4 dose requirement due to an increase in TBG I^^i 9.3 Myxoedema Coma Myxoedema coma represents a decompensated state of severe untreated hypothyroidism. In general, it occurs in elderly individuals with long-standing hypothyroidism and usually during winter months. Major chnical hallmarks of myxoedema coma are altered mental status, defective thermorgulation and a precipitating event or illness, in addition to biochemical hypothyroidism.'^^-^^l Diagnosis requires a high index of suspicion, and failure to recognize and treat it in a timely manner can be fatal. Given a reasonable index of suspicion, treatment should begin immediately while awaiting laboratory results. The three-pronged approach to treatment comprises (i) supportive measures, with particular emphasis on haemodynamic support, including use of steroids; (ii) thyroid hormone replacement; and (iii) concomitant management of coexisting problems, most importantly infections. Controversy surrounds thyroid hormone replacement in myxoedema coma regarding type of preparation (LT4 or LT3 or both) and route (oral/nasogastric or intravenous). Due to the
2012 Adis Data Information BV. All rights reserved.

rarity of this emergency, very few randomized studies have looked at the treatment and outcome. Most experts recommend use of intravenous LT4 (loading doses varying from 200 to 500 |ag followed by maintenance doses of 50-100 |ig daily), until oral intake and bowel motility are adequate, after which patients can be switched to oral replacement. Advice regarding use of concomitant intravenous LT3 is inconsistent, with some experts recommending that it has no utility,'^'' others advising that it should be used only in comatose patients,t''*i and a few suggesting that it should be administered in all patients with myxoedema coma.I'''' Arguments in favour of the intravenous route are risk of aspiration and the uncertainty of absorption with the nasogastric route. However, in one previous'^^l and one recent^^'^ study, outcomes did not differ between patients who received LT4 via a nasogastric tube and those who received it intravenously. The use of larger doses of LT4 (>500 ng/day) is associated with higher mortality and therefore is not recommended.'^^' 10. Adverse Effects LT4 is a drug recognized to have a narrow toxic to therapeutic ratio with significant clinical consequences of excessive treatment. Chronic under- or over-replacement is common in clinical practice and data indicate that over-treatment occurs in about 20% of LT4-treated patients.'^^"^^! Adverse effects of over-replacement include the risk of bone loss, especially in postmenopausal !^''-^''] and increased risk of atrial fibrillaA syndrome of hyperadrenergic state soon after LT4 treatment has been described, which could be attributable to anaemia in some cases.'^'' Transient scalp hair loss can also take place during the first few weeks of LT4 replacement.'^^ Rare cases of allergic reactions have been reported, which were almost always secondary to dye or other inactive constituents.t'^^ Changing to a different brand or tablet with a different dye generally overcame the problem. Two other rare adverse effects reported in children in the early phase of LT4 replacement are acute transient psychosis and benign intracranial ^
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11. Conclusions Hypothyroidism is a common disorder, readily diagnosed with laboratory investigations. All patients with overt hypothyroidism and subclinical hypothyroidism with TSH >10mIU/L should be treated, as should all pregnant women with any degree of subclinical hypothyroidism. However, treatment of non-pregnant patients with subclinical hypothyroidism and serum TSH values up to lOmlU/L remains controversial, with most expert groups recommending LT4 therapy only in the presence of symptoms, goitre, positive anti-TPO antibodies or infertility. LT4 remains the current standard for treatment and combined LT4/LT3 is not recommended. Adequacy of treatment is monitored using serum TSH in primary and serum FT4 in secondary hypothyroidism. Special considerations are needed in pregnant women, children, elderly patients and patients with cardiac disease. Under- or over-treatment is common in clinical practice and should be avoided. Acknowledgements
No sources of funding were used to conduct this study or prepare this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this article.

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