Overt and Subclinical Hypothyroidism

8/13/2019 Overt and Subclinical Hypothyroidism

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THER PY IN PR CTICE Drugs 2012; 72 1) ; 17-330012.6667/12/ X)01.0017/S66.5S/0

2012 Adis Data information BV. Aii rights r e se rved .

Overt and Subclinical ypothyroidismWho to Treat and How

eepak Khandelwal an d Nikhil Tandon

Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

Contents

Abstract 171. Introduction 182. Epidemiology and Aetioiogy 19

2.1 Prevaience ot Overt and Subclinicai Hypothyroidism 192.2 Natural History of Subciinicai Hypothyroidism 192.3 Causes 19

3. Ciinicai Features and Diagnosis 194. Who to Treat 20

4.1 Overt Hypothyroidism 204.2 Subciinicai Hypothyroidism with Thyroid-Stimuiating Hormone TSH) >10miU/L 21

4.3 Subciinicai Hypothyroidism with TSH


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18 Khandelwal Tando

concentration in the presence of normal serum free thyroxine (T4) a

triiodothyronine (T3) concentrations. Subclinical hypothyroidism may pgress to overt hypothyroidism in. approxima tely 2-5 cases annually. patients with overt hypothyroidism and subclinical hypothyroidism wTSH >10mIU/L should be treated. There is consensus on the need to trsubclinical hypothyroidism of any magnitude in pregn ant wom en and w omwho are contemplating pregnancy, to decrease the risk of pregnancy coplications and impaired cognitive development of the offspring. Howevcontroversy remains regarding treatm ent of non-pregn ant a dult patients wsubclinical hypothyroidism and serum TSH values 85 years. Other pituitary hormones should be evuated in patients with central hypothyroidism, especially assessment of thypothalam ic-pituitary-adrenal axis, since hypocortisolism, if present, neeto be rectified prior to initiating thyroid hormone replacement.

Levothyroxine (LT4) monotherapy remains the current standard fmanagement of primary, as well as central, hypothyroidism. Treatment cbe started with the full calculated dose for most young patients. Howevtreatme nt should be initiated at a low dose in elderly patien ts, patients w

coronary artery disease and patients with long-standing severe hypothroidism. In primary hypothyroidism, treatment is monitored with seruTSH, with a target of 0.5-2.0mlU/L. In patients with central hypothyroism, treatment is tailored according to free or total T4 levels, which shouldmaintained in the upper half of the normal range for age. In patients wpersistently elevated TSH despite an apparently adequate replacement doof LT4, poor compliance, malabsorption and the presence of drug intertions should be checked. O ver-replacement is comm on in clinical practice ais associated with increased risk of atrial fibrillation and osteoporosis, ahence should be avoided.

. I n t roduc t ion inadequate thyrotropin-releasing horm one (Trelease from the hypothalamus (tertiary h

Hy poth yroid ism is a con dition in which the thyroid ism ). In clinical practice it is no t thyroid gland is unable to make adequate am ounts possible to discrim inate between secondaryof thyroid hormo ne to meet the requirements of tertiary hypothy roidism, which are conseqperip heral tissues. In prim ary hypothy roidism , often referred to as 'centra l hypo thyroidicharacterized by failure of the thyroid g land itself Primary hypothyroidism is the aetiology ina fall in serum con centra tions of thyroid ho rm one proxim ately 99 of cases of hypothyroidcauses an increased secretion and elevation of serum Th e term subc hnica l hy po thy roi dis m is u

thyroid-stimulating horm one (TSH) conce ntra- define that grade of primary hypothyro idtions. Dec reased thyro idal secretion of thyro id which there is an elevated TS H con cen traho rm on e can also be caused by insufficient sti the presence of norm al serum free thyroxin


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Overt and Subclinical Hypothyroidism 19

nnually.' ] The term myxoedema is now usually

eserved for cases of overt hypothyroidism thatre severe or complicated, or both.'^'

In this review, we predominantly discuss andnform regarding issues pertaining to primary hy-othyroidism in young healthy adults. Wheneverecessary, distinctive aspects of the pathogenesis,linical profile and management of primary hy-othyroidism in other special populations and ofentral hypothyroidism is discussed separately.

2 Epidemiology a nd Aetioiogy

2.1 Prevalence of O vert an d SubclinicalHypothyroidism

Primary hypothyroidism, which is widely pre-alent worldwide, is more common in womenhan men and increases in incidence with age,specially after the onset of middle age. The pre-alence of spontaneous overt hypothyroidism isetween 1 and 2% and ten times more commonn women than in men, while approximately 8%f women and 3% of men have subcUnical hy-othyroidism.'^1 Community studies of elderlyeople have found a higher prevalence of hy-oth yroid ism: app roxim ately 10% of the subjectsged >60 years had serum TSH values above theormal

2.2 Natural History of Subclinical

HypothyroidismIn a follow-up study of the Whickham Sur-

vey,f'*l a population-based study in northernEngland, women who had both high serum TSHand anti-thyroid antibody concentrations devel-oped overt hypothyroidism at an annual rate of4.3%, com pared with 2.6% and 2 .1% in womenwho had only high serum TSH concentrations oronly elevated anti-thyroid antibody concentra-tions, respectively. Subsequent studies have alsoreported that subjects with higher baseline serumTSH values and/or elevated anti-thyroid anti-bodies have a higher propensity to progress toovert h ' ^ ^ l

2.3 Causes

The causes of hypothyroidism are sum marizedin table I.

3 Ciinicai Features and Diagnosis

Symptoms are generally related to the durationand severity of hypothyroidism, and the rapiditywith which hypothyroidism occurs. Presenting signs,symptoms and laboratory findings of hypothyroid-ism are summarized in table II. The clinical mani-festations of hypothyroidism are characterized by

able I Causes of hypothyroidismii

rimary hypothyroidism Central hypothyroidismoss of functional thyroid tissueHashimoto s thyroiditisSurgical removal of the thyroidRadioiodine ablation, external irradiation of the thyroidSilent and postpartum thyroiditisCytokine-induced thyroiditisInvasive fibrous thyroiditisThyroid infiltration (amyloidosis, haemochromatosis,sarcoidosis, scleroderma, cystinosis, primary thyroid lymphoma)Thyroid dysgenesis

unctional defects in thyroid hormone biosynthesis and releaseIodine deficiency and iodine excess

Thyroid hormone biosynthetic defectDrugs: antithyroid agents, lithium, amiodaron e, tyrosine kinase inhibitors (e.g.sunitinib), ethionamide, sulphonamides, goitrogenic chemicals, thalidomide

Pituitary or hypothalamic neoplasmsTrauma (surgery, head injury)RadiationIschaemic necrosis (postpartum pituitaryinfarction/Sheehan s syndrome, sev ere shock,diabetes meilitUs)Vascular (haemorrhage, aneurysm of internal carotidartery)Infections (abscess, tuberculosis, syphilis,toxoplasmosis)Infiltrative disorders (sarcoidosis, histiocytosis,haemochromatosis)Lymphocytic hypophysitisDrugs (bexarotene)Set point diseases (infants born to mothers w ith poorly


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20

Table II Presenting symptoms,

Symptoms

signs and laboratory findings of hypothyroidism'^ ''^'

Signs

handelwal Tan

Laboratory/radiological findings

ExhaustionSomnolenceSlow cognitionEm otional labilityIntolerance to coldConstipationDepressionWeight gainMyalgiaMuscle crampsCalf stiffness

Growth failurePubertal delaySexual dys functionMenorrhagiaMenstrual irregularityImpaired fertilityParesthesiaHearing impairmentHoarseness of voice

Coarsening of facial featuresPuffiness below the eyesDry, thin and pale skinCoarseness or loss of hairMacroglossiaGoitreHypothermiaBradycardiaDiastolic hypertensionSlow relaxation of tendon reflexesPleural effusion

Pericardial effusionAscitesNon-pitting oedema of lower legAtaxiaGalactorrhoeaSleep-disordered breathing

HyponatraemiaHypercholesterolaemiaAnaemiaElevated serum creatine kinaseHyperprolactinaemiaHyperhomocysteihaemiaElevated serum carcino-embryonic antigen Epiphyseal dysgenesisDelayed bone agePituitary gland enlargement

either slowing of body functions or consequent

to accumulation of glucosaminoglycans in thetissues. No single symptom/sign is a very sensitiveor specific indicator of the presence of hypothy-roidism. However, presence of multiple symp-toms, particularly if recent in onset, increases thelikelihood of hypothyroidism.t'^1 There are certainsymptoms or signs (e.g. presence of a goitre orshort stature in children) that should alwaysprompt a thyroid function test to rule out possiblehypothyroidism.I'^l

As me ntione d in section 1, prim ary hyp othy -roidism is the aetiology in mo re tha n 99 cases ofhypothyroidism, thereby making serum TSHme asure me nt the best single test for the exclusionor detection of hypothyroidism in most clinicalsettings. Raised serum TSH concentrations iden-tify primary hypothyroidism irrespective of thecause or severity. If the TSH level is high, furthermeasurement of the serum free T4 should becarried out. A low serum free T4 in conjunctionwith an elevated serum TSH level establishes a

diagnosis of overt hypothyroidism, while in sub-clinical hypothyroidism the serum free T4 con-

t ti i b d fi iti l H

elevated o r inappropriately norm al in the pres

of low serum T4 values. In patients suspectehaving central hypothyroidism, measuremenfree T4 is the test of choice. Measuring total Talso acceptable, provided there are no alterain binding proteins.

Once the diagnosis of prima ry hypothy roiis made, additional imaging or serological teis unnecessary if the thyroid gland is normaexamination.[' '*1 Measurement of anti-thyperoxidase (TPO ) antibodies is a valuable adin the evaluation of patients with subclinhypothyroidism because it predicts a higher of developing overt hypothyroidism. In patwith central hypothyroidism, measuremenother pituitary hormones and imaging ofsellar-suprasellar are a is required. La bor aevaluation of a patient with suspected hyporoidism is summarized in figure 1.

4 Who to Treat

4.1 Overt Hypothyroidism

P i i h h h idi h


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vert and Subclinical H ypothyroidism 21

o confirm the results with a second sample. ^^ In-ividuals with some conditions, e.g. recovery phasef thyroiditis or drug-induced hypothyroidism mayeed temporary thyroxine replacement to ensureuthyroidism until recovery is complete.

4,2 Subclinical Hypothyroidism withThyroid-Stimulating Hormone TSH) >10mlU/L

In the last few years, there have been severalublications regarding subclinical hypothyroid-

sm and its clinical relevance that have provokedebate about its screening and treatment. Becausef the difficulties in interpreting data from manyifferent sources, in 2002 the American Associa-on of Clinical Endocrinologists (AACE), The USndocrine Society and the American Thyroid As-ociation (ATA) convened a panel to propose evi-ence-based guidelines on diagnosis, screening an d

treatment of subclinical hypothyroidism. The panelfound good evidence that subclinical hypothy-roidism is associated with progression to overt hy-pothyroidism, and fair evidence that serum TSHlevels >10mIU/L are associated with elevations intotal and low-density lipoprotein cholesterol levels.However, there was insufficient evidence regardingan association between subclinical hypothyroidismand adverse cardiac events, cardiac dysfunction,neuropsychiatrie symptoms or systemic symptomsof hypothyroidism .t

The Panel recommended that patients with anelevated serum TSH level have the test repeated,along with a serum free T4 (FT4) measurement,within 2-12 weeks. When repeat studies confirmsubclinical hypothyroidism, further evaluation isrequired, including clinical assessment of signsand symptoms of hypothyroidism, ascertainmentof previous treatment for hyperthyroidism (e.g.

Signs and symptoms suggestive of hypothyroidism

Serum TSH

Low Normal

Serum Fr4

High

Low suspicion ofhypothyroidism

Strong suspicionof hypotfiyroidism

Low Normal

Central hypothyroidism

No further test

Evaluate for causesof suppressed TSH

Serum FT4

Low Normal

Serum FT4Overt primary

hypothyroidismSubclinical

hypothyroidism

MRI sellaEvaluation of otherpituitary hormones

Low Normal

Check anti-TPOantibody


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22 Khandelwal Tando

radiotherapy, partial thyroidectomy), presence of

thyromegaly and family history of thyroid disease.In addition, these patients should be screened forhyperlipidaemia. The Consensus Expert Panel rec-ommended that treatment was reasonable forpatients with TSH levels >10mIU/L, as thesepatients also have a higher rate of progression toovert hypothyroidism.''* Most other guidelinesand expert views also recommend treatment ofsubclinical hypothyroid patients with TSH levels

Primary hypothyroidism |

4.3 Sub clinicai Hyp othyroidism with TSH


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Overt and Subclinical H ypothyroidism

nd 30 g of this is prod uce d daily in he althy

dults, 80% arising from the 5'-deiodination ofT4 in periphera l tissues and 20% secreted d irectlyrom the thyroid.P"^' Thyroid hormone prepara-ions available for treatment of hypothyroidismre levothyroxine sodium (L-thyroxine [LT4]),iothyronine sodium (L-triiodothyronine [LT3])

and desiccated thyroid.

5.1 Levoth yrox ine Sodium L-thyrox ine, LT4)

LT4 is synthetically produced but identical to

T4 secreted by the thyroid. LT4 is the preferreddrug because its administration closely mimicsglandular secretion and its conversion to T3 isappropriately regulated by tissues, maintainingts steady and a deq uate supply.^'' Its long half-life

of 7 days allows single daily dose administrationand results in only small fluctua tions in serumconcentrations between the daily doses. Omissionof a single day's dose has little clinical relevanceand the patient may safely take an omitted tablet

he following day. Moreover, titration of dose iseasy, because of availability of multiple tabletstrengths. LT4 is primarily absorbed in the jeju-num, and absorption is greater in the fasting80%) than in the fed state (60%).P^l Non-specific

absorption of LT4 by dietary fibre has beenshown to decrease the bioavailability of LT4,necessitating a h igher dose in patients with a highntake of dietary fibre. Serum T4 concentrations

peak 2-4 hours after an oral dose and remainabove normal for approximately 6 hours inpatients receiving daily replacement therapy.'^^1The LT4 content of tablets is standardized byhigh-pressure liquid chromatography and, theUS FDA currently requires all LT4 preparationso contain 95-105% of the stated amount.^^'

Generic and brand-name LT4 preparat ions aremostly bioequivalent, but altered bioavailabilityhas been reported due to changes in the formula-tion of preparations. Hence, it is not advisable toalter the bran d 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 m ultiple daily ad m inistratio n inview of its short half-life of ~ day. Another dis-advantage is that serum T3 concentration risesto supranormal values of up to 250-600% in theabsorption phase, during which many patientsrep ort ad verse effects, especially palpitations.f^^'In a recent randomized, double-blind crossovertrial, it was shown that substitution of LT3 forLT4 at equivalent doses (relative to the pituitary)reduced body weight and caused favourablechanges in lipid profile without appreciable ad-verse effects. However, this study involved a verylimited number of subjects and, also, both LT4and LT3 were used thrice-daily in this study,which limits its clinical utility. ^"1LT3 may be usefulprior to treatment of thyroid cancer with radio-active iodine ('^'I), as patients can be withdrawnfrom LT3 for shorter periods of time than LT4. Itmay be used when a rapid effect is desired (e.g.perioperatively or in myxedema coma). Further-more, its use can be considered in rare cases of

LT4 maldigestion or malabsorption as well as inpatients with documentation of inhibition of T4to T3 conversion.'-"' O therwise, it is not intendedas sole maintenance therapy in treatment of hypo-thyroidism.

5.3 C om b in at io n LT4/LT3 Therapy

Combination LT4 and LT3 treatment hasbeen tried in an effort to more closely mimic the

thyroid secretion pattern of T4 and T 3. How ever,there is no currently available preparation con-taining LT4 and LT3 in a combination that ade-quately reproduces the relative quantities of thesehormones produced by the human thyroid. Fur-thermore, no preparation produces a sustainedrelease of thyroid hormones in a pattern similarto that of the human thyroid.'^^' Having been dis-regarded as a therapeutic approach to the treat-ment of hypothyroidism since the 1970s, interestin combination LT4/LT3 therapy was re-ignitedby a randomized, double-blind crossover trial of31 patients published by Bunevicius et al.'^^l in


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24 Khandelwal Tando

with LT4 alone. However, a majority of patientsin the study had been treated previously forthyroid cancer and were receiving relatively highdoses of LT4, which could have confounded theresults of the study. However, subsequent ran-domized controlled studies have failed to show abeneficial effect of combined LT4/LT3 therapyon measures of well-being, health and mentalfunctioning, with some even reporting harm-ful effects.'^'* A me ta-an alys is of 11 ran dom izedcontrolled trials involving 1216 participants of

LT4/LT3 combination versus LT4 monotherapyfor treatment of clinical hypothyroidism foundno difference in any clinical or biochemical para-meter compared with LT4 monotherapy.'^^' TheExecutive Committee of the British Thyroid As-sociation stated in 2007' ^' tha t combined LT 4/LT 3cannot be recommended because of a lack of ben-efit and a small num ber of undesirable and harmfuleffects seen with combination treatment.

5.4 Desiccated ThyroidDesiccated thyroid contains both T4 and T3

extracted from the thyroid gland of animals. Itcontains excessive amounts of T3 relative to T4,is not a pure preparation of thyroid hormonesand ha s issues relate d to stability.'^* W hile it wasthe mainstay of therapy in hypothyroidism untilthe 1970s, there is currently no evidence support-ing its use in the treatment of hypothyroidism.

6 initiating LT Therapy

The goal of treatme nt is to restore the individualto a euthyroid state, with resolution of signs andsymp toms. The rapidity with which the euthyroidstate should be attained is dictated by severalfactors, notably, the age of patient, the durationand severity of hypothyroidism and the presenceof other co-morbid conditions, specifically car-diac disease. LT4 is recommended to be taken as

a single daily dose on an empty stomach at least30 minutes before breakfast.'^''^ A recent ran-domized double blind crossover trial has sug

snacks before bedtime, allowing a gap ofhours between the last meal and LT4. This not be practicable in other cultures or fordividuals who have a habit of late dinner bedtime snack. LT4 should be taken at leasthours apart from drugs that are known to ifere with its absorption (table 111).'^^^

Most patients who are aged


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vert and Subclinical Hj^pothyroidism 25

T4 requirements are greatly dependent on the

ndividual 's lean body mass, rather than actualotal body weight.'"^"^ The LT4 dose is generallyigher in patients with previous thyroidectomyhan in those with autoimmune thyroiditis, inhich there may be some residual functioning

hyroid tissue. In the absence of any functioninghyroid tissue, the complete daily replacement dosen women and men ranges from 100|xg to 150|agn d betwe en 125 ^g a nd 200 |xg, respe ctively.''^'re-treatment serum TSH predicts, to a certainxtent, the daily maintenance dose of LT4 inatients with primary hypothyroidism. Patients

with subclinical hypothyroidism, because of theminimal extent of the thyroid hormone defi-iency, may be controlled with total daily dosagesf LT4 as low as 25-50 |xg.

7 Monitoring

After initiation of thyroid hormone therapy,ymptom s and signs of hypothyroidism should bessessed at each follow-up visit. LT4 effectivelyelieves the manifestations of thyroid hormoneeficiency in most patients; this can be expectedeveral weeks to months after initiation of ther-.py. Resolution of symptoms and signs usuallyags behind biochemical normalization. The ear-iest clinical response to thyroxine replacement issually diuresis and weight loss due to mobiliza-ion of interstitial fiuid as glycosaminoglycansre degraded. Weight loss is predominantly due

o fluid loss, and even in obese patients is unlikelyo exceed 5 kg, especially if pre-treatment TSHalues were modestly elevated.' '^' A decrease inat with thyroxine therapy, if any, is usually mini-

mal and occurs late in the course of treatment.Reduction in puffiness and an increase in pulseate and pulse pressure are also early responsesfter treatm ent.' '" Fea tures such as appetite, con-tipation, hoarseness of voice, cold intolerance andatigue recover later, while symptoms and signselated to the skin, appendages and nervous sys-em are the last to resolve.''^

After initiating ther apy , -the dose sho uld be

to re-set after introducing or modifying LT4 ther-

apy. Serum TSH should be maintained in thelower half of normal range (0.5-2.0 mlU/L).'^''-''^)In the event that serurn TSH is either elevat.ed orsuppressed, there will be a need for a modest in-crease or decrease in dose, respectively. The doseshould ideally not be increased or decreased bymore than 12.5 or 25 \ig and serum TSH againme asured after 2 m onth s to assess ade qua cy ofthe dose. Because of the long half-life of LT4,small dosage adjustments may even be performedby adding or withdrawing a tablet once or twice aweek. A minor deviation from the targeted TSHvalue should not immediately prom pt dose adjust-ment; instead, a repeat TSH measurement can beperformed after 2-3 months before deciding ona dose change. Once the patient attains a bio-chemical euthyroid state, serum TSH should nextbe measured after 6 months. This is required be-cause, at initiation of therapy, due to the hypo-thyroid state, the administered LT4 may be stillbe metabolized slowly and appear adequate for

the patient 's requirements. Once euthyroidism isrestored, thyroxine metabolism m ay increase andthe same dose be rendered sub-optimal. Once astable LT4 dose is achieved, monitoring needs tobe carried out annually. While this strategy worksfor most patients with hypothyroidism, patientswith post-ablative hypothyroidism may continueto have a decline in thyroid reserve over the yea rs,necessitating semi-annual or even annual dosechange s until the effect of the '^ 'I plate aus . Some-

times, a similar evolution of declining thyroidreserve over a period of time m ay also be ob servedin patients with Graves' disease who have had asub-total thyroidectomy.

Some experts also estimate serum T4 (total orfree) to monitor therapy. If this is being done,care should be taken that the blood sampleshould be collected prior to receiving the day'sdose of LT4. Invariably, if the serum TSH levelsare in the mid to low normal range, serum T4levels will be in the mid to high nor m al ra nge. Fo robvious reasons, the main role of serum T4 iswhen monitoring thyroxine replacement in a pa-


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8 Persistentiy Eievated TS Despite

Thyroid Hormone RepiacementAn important cause of persistently elevated

TS H despite adequa te replacement dose of LT4 isnon-compliance of the patient. In fact, thesepatients can have an elevated TSH with high-normal or elevated FT4, as they may not takeLT4 for days and then take several pills a fewdays before their testing. No change in the LT4dose is needed in this situation; rather, emphasisshould be placed on com pliance with therapy andthe thyroid function test repeated in 3-4 weeks.It sometimes helps to ask the patient to take aweek's supply of medicine in a separate pill-box,which will allow easy ascertainment of misseddoses. Any extra pills left in the container canactually all be taken on the last day of the week,to ensure that the patient receives his or her weeklydose. Because of the long half-hfe of 7 days, someauthors propose that LT4 can be given onceweekly in poo rly co mp liant patients. A crossover

trial of 12 patie nts show ed tha t a single weeklydose achieved fairly good therapeutic results.'' '^1Weekly dosing or end-of-week catch-up dosing,while sub-optimal, remains an acceptable alter-native for habitual non-com pliers. Weekly dosingshould not be given in patients who have cor-onary artery disease.

Other causes of persistently elevated TSH de-spite an apparently adequate dose of LT4, includemalabsorption and interference by drugs (table

III). It is worth excluding coeliac disease in suchcases, as it may coexist in patients with hypo-thyroidism because of its autoimmune nature.Interference to the laboratory assay as a result ofheterophil antibodies in a patient's serum also canlead to artificial elevation in TSH.

9 Treatment in Spe ciai Circumstanc es

9.1 Primary Hypothyroidism In SpeciaiCircumstances9 1 1 Pregnancy

Patient Aiready on R epiacement Becoming

nancy and fetal development. Untreated

hypothyroidism during pregnancy is found associated with increased risk of maternal htension, pre-eclampsia, postpartum haemorranaemia, fetal death, low birth weight and na ta l r es pir ato ry distress. '*''-'*^] In a la ndobservational study, Haddow et al'^'^i also fthat women with overt or subchnical hyproidism deliver babies with an average intelligquotient (IQ) score 7 points below the mean children born to healthy women and thyrotreated women. If hypothyroidism has beeagnosed before pregnancy, the preconcepLT4 dose should be modified to reach a level not higher than 2.5mIU/L before plapregnancy.''*^'

During pregnancy, the LT4 requirement icreased by 25-50% in most hypothyroid wowhich becomes evident early in the first trster.f * The increased requirement is probab lyto a combination of factors: rapid rise in thyine-binding globuhn (TBG) levels resulting the physiological rise in estrogen, increasedtribution volume of thyroid hormones, andcreased placental transport and metabolism

.maternal T4. The LT4 dose should be increby 30-50% by 4-6 weeks gestation. As therelarge individual variability in dose requiremdose adjustment requires testing serum TSHtotal T4 (FT4 according to some authors) atular intervals, such as every 4-6 weeks. It isommended that serum TSH be maintaine

trimester-specific normal ranges (


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with iron or calcium. A time gap of 4-6 hours

etween LT4 and these supplements should bemaintained.

Hypothyroidism De tecte d for the First Time duringPregnancyWhen hypothyroidism is detected for the first

ime during pregnancy, the test should be repeated.Unless the result is expected within 24 hours,reatment must be started before confirmation tovoid loss of time. LT4 dosage should be titratedo rapidly reach, and thereafter maintain, serum

TSH concentrations to trimester-specific normalTSH ranges. Factors determining the appropriate

ose for initiation of therapy are time of gesta-ion, and the aetiology and severity of the disease.n view of increased requirements, the full replace-

me nt dose of LT 4 in pregna ncy is 2.0-2.4 [ig/kgodyweight/day. Therapy may be initiated by giv-ng, for the first few days, a LT4 dose corre-pond ing to two to three times the estimated finaleplacement daily dose, to rapidly normalize the

xtra-thyroidal thyroxine pool. Thyroid functionests shou ld be re-m easure d within 30- 40 '' ^

Subciinical Hypothyroidism and PregnancySubclinical hypothyroidism has been shown to

be associated with an adverse outcome for bothhe mother and the offspring. LT4 treatment has

been shown to improve obstetrical outcome buthas not been proved to modify long-term neuro-ogical development in the offspring. However,

given that the potential benefits outweigh the

potential risks, LT4 replacement is recomm endedn all pregnant women with subclinical hypo-hyroidism.'"*^ It is no t clearly defined whe the r

LT4 treatment should be continued postpartumn women in whom diagnosis of subclinical hypo-hyroidism was made during pregnancy. In our

opinion, treatment should be continued in thesewomen if serum TSH is >10mIU/L or in the pre-ence of hypothyroid symptoms, goitre or anti-

TPO antibodies, as advised for other adults withsubclinical hypothyroidism. Also, women who areplanning a subsequent pregnancy should continueon LT4 replacement. In all other women, LT4

9 7 Coronary Artery Disease

Initiation of LT4 replacement therapy in patientswith coronary heart disease should be carried outcautiously to avoid exacerbating angina pectoris,or precipitating acute myocardial infarction,ventricular arrhythmias or congestive heart fai-lure.'^1 Alth oug h tre atm ent of hyp othy roidismwith LT4 will improve myocardial function andreduce peripheral vascular resistance, it will in-crease the need for oxygen in the myocardium.In patients with an already compromised myo-

cardial blood supply due to coronary athero-sclerosis, LT4 treatment may provoke anginalsymp toms. In a study of 1503 hypothyro id subjects(average age 71 years), 2% developed new onsetangina during LT4 therapy. In patients with pre-existing angina, after LT4 treatment, symptomsimproved in 38%, remained unchange d in 46% andworsened in 16%.'^' Patients with pre-existing an-gina should ideally undergo cardiac evaluation forcorrectable lesions of the coronary arteries and betreated appropriately prior to initiating LT4 ther-apy. LT4 in such individuals should be started at adose of 25 ng/day or even less and it should be in-creased no faster than at 4-weekly intervals. If an-gina is precipitated while increasing the LT4 dose,it should be reduced to the highest dose toleratedby the patient and a further attempt made to in-crease the dose again only after another 4 weeks.

9 1 3 lderly

In many cases, hypothyroidism in elderly patients

is characterized by a paucity of specific signs andsymptoms. The symptoms may be subtle and in-clude hoarseness, deafness, confusion, dementia,ataxia, depression, dry skin or hair loss.'^^' A n orm alstarting dosage of LT4 in an elderly subjectis aro un d 1 (ig/kg/day, which is m aintain ed for4 -6 weeks. ^1 If heart disease is suspected, a lowerstarting dose, as mentioned in section 9.1.2 isappropriate. Dosage adjustments are guided bythe response in TSH and the clinical state, withemphasis on possible cardiac adverse effects.Limited evidence suggests that treatment of sub-clinical hypothyroidism with serum TSH of up to


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28 Khandelwal Tand

Table IV Ciinicai characteristics, screening and evaluation of

congenitai hypothyroidism' I^^ ^^'CausesThyroid dysgenesisThyroid dyshormonogenesisHypothalamic-pltuitary abnormaiityTransient hypothyroidism (maternal antithyroid medication, maternaiblocking antibodies, iodine deficiency or excess)

Symptoms and signsUnexplained postmaturity, poor feeding, hypothermia, iethargy,proionged jaundice, abdominai distension, umbilicai fiernia, iargetongue, hoarse cry, m ottied dry skin, iarge posterior fontanei,deiayed skeietai maturation

Screening methodsPrimary TSH with backup T4 measurementPrimary T4 with backup TSH measurementCombined primary TSH pius T4 measurements (ideai method)

if screening positive or hypothyroidism suspected laterDetailed history and examinationRepeat serum TSH and either totai T4 or FT4Additional work up in confirmed cases (shouid not iead to deiay intreatment); thyroid radionuciide scintigraphy, thyroid sonographyand serum thyrogiobuiin

a Frequency; ; 3000 to ; 4000 iive births.

FT4=free T4; T4=thyroxine; TSH=thyroid-stimulating hormone.

in adverse effects and is instead found to beassociated with prolonged life

9 4 Congenital ypothyroidism

Clinical characteristics, screening and evalua-tion of congenital hypothyroidism is summ arizedin table IV. The overall goals of treatment incongenital hypothyroidism are to assure normalgrowth and development and cognitive outcomesimilar to genetic potential by restoring serum T4concentration rapidly to the normal range fol-lowed by continued clinical and biochemical eu-thyroidism. The aim of treatment is to keep theserum T4 (total or free) concentration in the up-per half of the normal range adjusted for age. Ofnote, most commercial laboratories do not pro-vide age-adjusted normal ranges in their reports.In the first postnatal year, serum T4 should be10-16 i^g/dL an d serum FT 4 sh ould be 1.4 2.3

ng/dL. The serum TSH concentration should be


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piphysis are other radiological manifestations of

ypothyroidism in children.The recommended dose of LT4 for each age

roup is as follows:'^'3-12 m onth s: 6-10 |ig/kg/day1-3 years : 4 -6 fxg/kg/day3-10 years: 3-5 ng/kg/day10-16 years: 2-4 ng/kg/d ay.Treatment should be individualized because

he absorption of LT4 and m etabolism vary am ongndividuals. Serum FT4 and TSH concentrations

hould be monitored periodically, preferably at- to 6-month intervals. Available data indicatehat risk of progression from subclinical to overtypothyroidism is less common in children anddolescents, and the recovery of thyroid functions more frequent.'^^' In one recent multicentretudy from Italy, 88% of subclinical hypo thyro idhildren normalized their TSH over a period of

years.'*^^ Also, persistent subclinical hypothy-oidism in children is not associated with altera-ion in growth, maturation, body mass index andognitive functions, even after several years.'*"*' Inact, there is a view that subclinical hypothy-oidism in children may b e just a norm al variation,ather than a sign of a failing thyroid gland.'^^' In

match ed case -control stud y of type 1 diabetichildren, subclinical hyp othyroidism was associated

with significantly increased risk of symptomaticypoglycaemia as compared with matched eu-hyroid controls, which became compa rable after months of LT4 replacement.^**'

9 1 6 Adren al Insufficiency

In the event there is co-existence of thyroidormone deficiency and glucocorticoid deficiency,t is important to replace glucocorticoids beforetarting LT 4. This is because LT 4 therapy may leado an increased metabolism and, thereby, an in-reased demand of cortisol, potentially increasinghe likelihood of precipitating an adrenal crisis.

9 1 7 D ifferentiated tiyroid Cancer

Patients who have had a thyroidectomy forifferentiated thyroid cancer, with or without

Table V American Thyroid Association and E uropean Thyroid As-

sociation recommendations for thyroid-stimulating hormone (mlU/L)targets in patients with differentiated thyroid cancer ^ ^

Patient category Recommendation

ATA ETA

High and intermediate risk (initialtherapy)

Persistent disease

High-risk disease free (follow-up)

Low risk (initial therapy)

Low-risk disease free (follow-up)

0.1-0.5


14/18

30 Khandelwal Tand

ease of treatmen t with LT 4, which is the s tanda rd

treatment even in central hypothyroidism.[^' 'Serum TS H level is not helpful in cases of centra lhypothyroidism. Instead, the chnician shouldevaluate serum FT 4, adjusting the LT4 dosage tokeep the serum FT4 in the upper half of the nor-mal range for age.^^^l Monitoring total T4 is alsoacceptable, provided there are no alterations inbinding proteins.

The possible presence of secondary adrenalinsufficiency should be kept in mind and pituitary-

adrenal function should be assessed, usually byan adrenocorticotropic hormone (ACTH) stimula-tion test. If present, secondary adrenal insufficiencyshould be treated before starting LT4 replace-ment. Treatment of other pituitary hormone de-ficiencies might affect dosing of LT4. Growthhormone deficiency may mask central hypothy-roidism, an d this might beco me evident only afterreplacement of growth hormone.'^^^ Concomitantestrogen replacement in women also significantlyincreases LT 4 dose requireme nt due to an increasein TB G I i

rarity of this emergency, very few random

studies have looked at the treatment and outM ost experts recommend use of intravenous(loading doses va rying from 200 to 500 |alowed by m aintenan ce doses of 50-100 |ig duntil oral intake and bowel motility are adeqafter which patients can be switched to oraplacement. Advice regarding use of concomintravenou s LT3 is inconsistent, with som e exrecommending that it has no utility,'^' ' othervising that it should be used only in compatients,t''*i and a few suggesting that it shouadministered in all patients with myxoecom a.I ' ' '' Argu men ts in favour of the intraveroute are risk of aspiration and the uncertof absorption with the nasogastric rHowever, in one previous'^^l and one recenstudy, outcomes did not differ between patwho received LT4 via a nasogastric tubethose who received it intravenously. The ularger do ses of L T4 (>500 ng/day) is assocwith higher mortality and therefore isrecommended.'^^'

9.3 Myxoedema Com a

Myxoedema coma represents a decompensatedstate of severe untreated hypothyroidism. In general,it occurs in elderly individuals with long-s tandinghypothyroidism and usually during winter months.Major chnical hallmarks of myxoedema coma arealtered men tal status, defective therm orgulationand a precipitating event or illness, in addition tobiochemical hypothyroidism.'^^-^^l Diagnosis re-quires a high index of suspicion, and failure torecognize and treat it in a timely manner can befatal. Given a reason able index of suspicion, treat-ment should begin immediately while awaitinglaboratory results. The three-pronged approachto treatment comprises (i) supportive measures,with particular emphasis on haemodynamic sup-port, including use of steroids; (ii) thyroid hor-

mone replacement; and (iii) concomitant man-agement of coexisting problems, most importantlyinfections Controversy surrounds thyroid hor-

10 Adverse Effects

LT4 is a drug recognized to have a natoxic to therapeutic ratio with significant cal consequences of excessive treatment. Chunder- or over-replacement is common in clpractice and data indicate that over-treatoccu rs in ab ou t 20% of LT 4-tre ated patients.'Adverse effects of over-replacement includrisk of bone loss, especially in postmenop

^''-^''] and increased risk of atrial fibA syndrome of hyperadrenergic

soon after LT4 treatment has been descrwhich could be attributable to anaemia in cases.'^' ' Transient scalp hair loss can also place during the first few weeks of LT4 repment.'^^ Rare cases of allergic reactions havereported, which were almost always seconda

dye or other inactive constituents.t'^^ Ch ang ia different brand or tablet with a differentgenerally overcame the problem Two other


15/18


11 Conclusions

Hypothyroidism is a common disorder, read-ly diagnosed with laboratory investigations. Allatients with overt hypothyroidism and sub-linical hypothyroidism with TSH >10mIU/Lhould be treated, as should all pregnant women

with any degree of subclinical hypothyroidism.However, treatment of non-pregnant patientswith subclinical hypothyroidism and serum TSH

alues up to lOmlU/L remains controversial, withmost expert groups recommending LT4 therapy

nly in the presence of symptoms, goitre, positiventi-TPO antibodies or infertility. LT4 remains theurrent standard for treatment and combined

LT4/LT3 is not recommended. Adequacy of treat-ment is monitored using serum TSH in primary

nd serum FT4 in secondary hypothyroidism.Special considerations are needed in pregnantwomen, children, elderly patients and patientswith cardiac disease. Un der- or over-treatm ent is

ommon in clinical practice and should be avoided.

Acknowledgements

No sources of funding were used to conduct this study orrepare this manuscript. The authors have no conflicts of in-erest that are directly relevant to the content of this article.

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Overt and Subclinical Hypothyroidism