MINISTRY OF HEALTH OF REPUBLIC OF MOLDOVA [600107]

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MINISTRY OF HEALTH OF REPUBLIC OF MOLDOVA

STATE UNIVERSITY OF MEDICINE AND PHARMACOLOGY
"NICOLAE TESTEMITANU"

FACULTY OF MEDICINE II

ENDOCRINOLOGY DEPARTMENT

DIPLOMA THESIS

SUBCLINICAL THYROID DISORDERS

Prepared by : Badarnah Amjad
Group: 1643
Supervised by : Dr.Lorina Vudu ,
PhD, associate professor

Chisianu – 2015

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TABLE OF CONTENTS

ABSTRACT……… ….……………… ..………… …….……………..…… ……….4
INTRODUCTION…………………… …………… …….…………….……………5
CHAPTER I THYROID FUNCTION….………….………….. .………………….6
1.1 Thyroid anatomy and lo cation…………………………… …… …………6
1.2 Function o f the thyroid gl and…………………………… .………… ……. 6
1.3 Regulation o f thyroid ho rmones………………… ..………… ……………7
1.4 Nomenclature………………………………… .…..……… ..…….………..8
1.5 Physiologi cal effects of overt hyperthyroidism…………… ..………… ..…9
1.6 Morbidity associated with overt hyperthyroidism…………… ……. ……10
1.7 Thyroid hormone deficiency: overt hypothyroidism ……… ….………11
1.8 Prevalence …………………………………………………… ………… .12
1.9 Etiology …………………………………………………… ..………. ….13
1.10 Cli nical expression of overt thyroid dysfunction ………… ……. ……14

CHAPTER II BIOCHEMICAL DIAG NOSIS OF THYROID
DYSFUNCTION…………………………… ………………… …..…… .………. 17
2.1 Definition of subclinical thyroid dysfunction ……………… ..………..17
2.2 Prevalence of subclinical thyroid dysfuncti on……………… …..…….18
2.3 Etiology of subclinical thyroid dysfunction ………………… …..….…18
2.4 Statistical nature of defining a reference range ……………… …….. …..19
2.5 Diagnosis of subclinical thyroid dysfunction in primary care ..………20
2.6 Current management strategie s……………………………… ……….. .21

CHAPTER III SUBCLINICAL HYPOTHYROIDISM……………………..…23
3.1 Differential diagnosis of raised serum TSH …………… .…… …….. …26
3.2 Etiology of subclinical hypothyroidism ……………… .…… …….. …..26
3.3 Prevalence of subclinical hypothyroidism ……………… .………. .…..26

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3.4 Consequences of subclinical hypothyroidism ……… .……..…………27
3.5 Progression to overt hypothyroidism (natural history of subclinical
hypothyroidism) …………………………………………… ………………….. …….27
3.6 Cardiovascular events and mortality ……………… ..….………… ……28
3.7 Heart failure ……………………………………………… ………………. 29
3.8 Others …………………………………………………… ….…………… ..29
3.9 Special population groups affecting treatment considerations …….. …30
3.10 Treatment…………………… ……………………… …………………… …….. ..32

CHAPTER IV SUBCLINICAL HYPERTHYROIDISM……….. ……………………. 36
4.1 Differential diagnosis of suppressed serum TSH ………………………37
4.2 Etiology of subclinical hyperthyroidism ……………………………….38
4.3 Prevalence of subclinical hyperthyroidism …………………………….38
4.4 Consequences of subclinical hyperthyroidism …………………………38
4.5 Progression to overt hyperthyroidism (natural history of subclinical
hyperthyroidism) ……………………………………………………… ……… …..38
4.6 Cardiovascular effects …………………………………………… .……39
4.7 Bone metabolism …………………… ……………………………… .…40
4.8 Cognitive impairment ………………………………………… ..………41
4.9 Special population groups affecting treatment considerations ……….41
4.10 Treatment …………………… ………………………………… …..…..42

CONCLUSIONS ………………………. …………………………………………46

REFERENCES ……………………..………… ………….……… ..……………..48

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ABSTRACT

Subclinical hyperthyroidism appears to be a common disorder. It may be caused
by exogenous or endogenous factors: excessive TSH suppressive therapy with L –
thyroxine (L -T4) for benign thyroid nodular dis ease, differentiated thyroid cancer, or
hormone over -replacement in patients with hypothyroidism are the most frequent
causes.
Consistent evidence indicates that ‘subclinical’ hyperthyroidism reduces the
quality of life, affecting both the psycho and soma tic components of well-being, and
produces relevant signs and symptoms of excessive thyroid hormone action, often
mimicking adrenergic overactivity.
Subclinical hyperthyroidism exerts many significant effects on the cardiovascular
system; it is usually ass ociated with a higher heart rate and a higher risk of
supraventricular arrhythmias, and with an increased left ventricular mass, often
accompanied by an impaired diastolic function and sometimes by a reduced systolic
performance on effort and decreased exe rcise tolerance.
It is well known that these abnormalities usually precede the onset of a more
severe cardiovascular disease, thus potentially contributing to the increased
cardiovascular morbidity and mortality observed in these patients. In addition, it is
becoming increasingly apparent that subclinical hyperthyroidism may accelerate the
development of osteoporosis and hence increased bone vulnerability to trauma,
particularly in postmenopausal women with a pre -existing predisposition.
Subclinical hyper thyroidism and its related clinical manifestations are reversible
and may be prevented by timely treatment.

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INTRODUCTION
Subclinical thyroid disorders are not uncommon in primary care. Many patients
with subclinical thyroid disorders are discovered incidentally during health screening
conducted by family physicians. Stable patients followed up by restructured hospitals
often undergo transition of care to the family physician for long -term management.
These examples highlight some of the ways in which family physicians may find
themselves managing subclinical thyroid disorders.
This article aims to review the latest evidence and recommendations for the
management of subclinical thyroid disorders, includ ing the important decision of
treatment initiation from the perspective of a family physician.
Aims of the study
To determine the consequences of Subcinical Hyperthyroidism on systems and
clarify the necessity of treatment
Objectives
 To know the Epidemiology of SCH
 To Monitor the Progression to overt disease
 The Pathophysiological effects on the skeleton and cardiovascular risk
 Determine whether to Treat or not
Actuality
 The rate of progression to overt hyperthyroidism is significant.
 Subclinical hyperthyroidism associated with increase risk of atrial fibrillation and
reduction in bone mineralization especially in postmenopausal women.
 The Change on quality of life parameters in subclinical hyperthyroid patients
(cognit ion and mood rate)

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CHAPTER I THYROID FUNCT ION
1.1 Thyroid anatomy and lo cation
The thyroid is a bi-lobed gland situated at the upper end of the trachea. The
lateral lobes are approximately 4 cm in length and 2 cm in thickness, and are connected
by a thin band of tissue called the isthmus. Each lobe receives a rich and rapid (4-
6ml/min/g of tissue) supply of blood from two sources; the superior thyroid artery
(abranch of the external carotid artery) and the interior thyroid artery (a branch of the
subclavian artery). Thyroid tissue comprises numero us follicles, each of which has a
central colloid filled cavity lined with follicular cells.

Fig. 1.1: Thyroid gland

1.2 Function o f the thyroid gl and
The function of the thyroid gland is the synthesis, storage and secretion of
the thyroid hormo nes, tertraiodothyronin e, (otherwise known as thyroxine [T4])

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and triiodothyronine (T3). These thyroid hormones are responsible for control
and regulation of basal metabolic rate (BMR, the minimu m amount of energy
expended to maintain vital processes) and have an essential role in the
metabolism of carbohydrates, fats and proteins and in the development and
maintenance of both mental and physical function. These hormones are involved in
almost every organ system of the body, therefore dysfunctions of the thyroid gland
exhibit a broad spectrum of clinical effects.

1.3 Regulation o f thyroid ho rmones
Since the hypothalamus and anterior pituitary gland coordina te the
endocrine system, synthesis and secretion of the thyroid hormones is ultimately
under their control. With the anterior pituitary gland acting as a sensor of
circulating thyroid hormone concentration, this coordi nation is directed through
the hormone thyrotrophin (otherwise known as thyroid stimulating hormone [TSH])
via a negative feed-back regula tory mechanism. Thyrotrophin is 7ynthesized and
secreted by the anterior pituitary gland in response to a decline in circulating
thyroid hormone concentration, accompanied by secretion of thyrotrophin releasing
hormone by the hypothalamus. Thyrotrophin continues to stimulate thyroid gland
activity until sufficient concentrations of circulating thyroid hormone are detected by
the anterior pituitary gland. Restoration of normal concentrations of thyroid hormones
leads to down regulation of thyrotrophin production and subsequent reduction in thyroid
gland activity. The inverse log-linear relationship between serum thyrotrophin and
free thyroxine means that a small decrease in free thyroxine concentration is associated
with exponential increases in serum thyrotrophin concentration. Thyrotrophin acts upon
the thyroid gland to encourage an increased uptake of iodide ions thereby intensifying
protein synthesis and cellular metaboli sm. These activities are accompanied by an
increase in the overall size, vasculature, intracellular volume and colloid storage

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capacity of the gland, allowing additional synthesis and storage of thyroid hormones.
Meanwhile, thyroid hormones are secreted into the general circulation. In the blood,
thyroid hormones are transported almost entirely bound to the plasma proteins;
thyroxine binding globulin (TBG), pre-albumin and albumin.
How ever, a small proportion remains unbound and it is this free fraction of
thyroid hormone (free thyroxine [FT4] and free triiod othyronine [FT3]) that is
biologically active and available to act on the tissues to promo te energy production,
growth and developme nt.
Since FT4 is converted to the more active FT3 in the tissues, both of the thyroid
hormones have the same metabolic and physiologi cal effects.

Fig.1.2 : Hypothalamic -Pituitary -Thyroid Axis

1.4 Nomenclature
Thyroid gland dysfunction is commo nly described as under- or over-active
based upon the concentrations of thyroid hormone being produced. The term overt

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thyroid dysfunction is the generic term used to describe conditions that arise as a result
of consistently altered thyroid function with excess or insufficient concentrations of
thyroid hormone. More specifically, the condition resulting from thyroid hormone
excess accompanied by suppressed serum thyrotrophin concentration is known as overt
hyperthyroidism and insufficient thyroid hormone in combination with surplus serum
thyrotrophin concentration is described as overt hypothyroidism. 3

1.5 Physiologi cal effects of overt hyperthyroidism
Excessive concentrations of the thyroid hormones lead to an increase in
basal metabolic rate with an associated increase in oxygen consumption and heat
production (thermogenesis). This general increase in cellular metabolic activity also
results in an increased rate of carbohydrate metabolism, leading to greater
absorption of glucose and enhanced glycolysis (conversion of glucose to lactic acid),
glycogen olysis (catabolism of glycogen stores to produce glucose) and
gluconeogeneisis (catabolism of non–carboh ydrate sources) if carbohydrate is in
short supply. Metabolism of fat is similarly stimulated by increased concentrations of
thyroid hormones resulting in an increase in synthesis, mobilisation and degradation of
lipids. When the gland is functioning normally, these effects are necessary to
maintain basal metabolic rate and as such are relatively short lived. In altered thyroid
function, however, these effects persist and can lead to significant morbidi ty and
mortality.4
1.6 Morbidity associated with overt hyperthyroidism
A persistent excess of thyroid hormone confers high basal metabolic rate
and increased metaboli sm leading to heat intolerance and weight loss. With respect to
enhancemen t of the protein metaboli sm, protein degrada tion dominates which, if
persistent, leads to a decrease in muscle mass and muscle weakness. Other
common musculoskeletal complaints are muscle cramping, stiffness, parae sthesia

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(sensation of pins and needles), joint swelling, and carpal tunnel syndrome.
Likewise, excess thyroid hormones enhan ce bone metabolism with bone resorption
being affected to a greater extent than synthesis. This results in net loss of bone and
reduced bone mineral density, accompanied by increased urinary excretion of
calcium and phosphate. These effects can lead to hypercalcaemia and an increased risk
of osteoporosis and fracture. The cardiovascular system is also a major target of thyroid
hormone action. The indirect effects of raised metabolic rate due to increased
demand for oxygen and heat dissipation to peripheral vessels are increased
cardiac output and blood flow. Thyroid hormones also directly act on the heart to
increase cardiac contractility and heart rate. Sinus tachycardia is the most common
cardiac disturbance of overt hyperthyroidism. Atrial fibrillation (AF), a risk factor for
embolism, is however a more clinically significant cardia c condition associated
with overt hyperthyroidism. AF occurs in up to 15% of patients with overt
hyperthyroidism compared with just 4% of the general population and incidence
increases with age. 2
Thyroid hormones also influence vascular smooth muscle cells to promo te
relaxation and reduce systemic vascular resistance. This in turn impro ves diastolic
relaxation leading to more efficient use of energy and nutrients by the
cardiomyocytes. The increase in peripheral metabolism leads to an increased demand on
cardia c output. The mechanism by which increased cardiac output is achieved is
thought to be activated by a decrease in vascular resistance and an increase in blood
volume. Cardia c prelo ad augments stroke volume in response to increased venous
return and overall cardiac output is amplified in response to a raised stroke volume
and increased heart rate. 2
An association between overt hyperthyroidism and anxiety, depression and
changes in mood and cognitive functions has been widely reported, however, the
exact mechanisms for these relationships remain largely unknown. Additionally,

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perceived quality of life and health status has been shown to be significantly
impaired in individuals with overt hyperthyroidism.
The symptoms of excess thyroid hormone reflect hypersensitivity and
include intolerance to heat, breathlessness, palpitation, diarrh oea due to
intestinal hypermotility, excessive perspiration, tremor, weak muscles, weight loss,
irritability, short attention span and fatigue. Physical signs include rapid pulse, fine
tremor and atrial fibrillation. In the longer term, thyroid hormo ne excess is associated
with significant morbidi ty in the form of osteopor osis, heart failure and AF. Overt
hyperthyroidism is also associated with an increased mortality risk particularly from
cardio vascular and cerebrovascular causes.
1.7 Thyroid hormone deficiency: overt hypothyroidism
The pathophysiological effects of thyroid hormone deficiency are diametrically
opposed to those described for overt hyperthyroidism . Diminished metabolic rate and
thermogenesis a re associated with reduced heat production, decreased oxygen demand
and blood flow to the tissues. Since overall energy production and expenditure is
reduced, degradation of carbohydrate and fat is diminished, leading to storage of
glycogen with weight gai n and a rise in the concentration of plasma lipids which confer
an increased risk for atherosclerosis. Cholesterol levels are further affected due to a
reduction in action of thyroid hormones on production of low density lipoprotein
cholesterol receptors b y the liver and a reduction in the removal of low density
lipoprotein cholesterol from the circulation. 8
The accompanying effects of overt hypothyroidism manifest as intolerance to
cold, constipation, weight gain, hoarse voice, puffy eyes, dry skin, muscl e cramps, poor
memory and delayed reflex relaxation time. Hypertension may manifest due to the direct
effect of thyroid hormone increasing vascular resistance to prevent heat loss, increased
arterial stiffness and/or alterations to endothelial function. Fu rthermore, atherosclerotic

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narrowing of the arteries potentiated by serum lipid anomalies may contribute to
hypertension associated with overt hypothyroidism.
Skeletal muscle is also a known target organ for thyroid hormones with a wide
range of alteration s in neuromuscular and neuropsychiatry function being well
established in overt hypothyroidism. Alterations in muscle structure and function can
manifest as painful paraesthesia (partial numbness, tingling, buzzing and vibration, pins
and needles sensation s) and cramping of the hands and feet. The deficiency in thyroid
hormones affects metabolism of the myocytes, causing a reduction in speed of muscle
contraction and relaxation. Cell wall integrity is also adversely affected leading to
muscle necrosis. 13
Proximal weakness and slow reflexes are therefore well established findings in
individuals with overt hypothyroidism. Like overt hyperthyroidism, hypothyroidism has
also been shown to impact on aspects of cognitive function and mood, and patients
frequently have neuropsychiatric complaints. Most studies suggest an association
between hypothyroidism and depression. Overt hypothyroidism has also been associated
with impaired quality of life. However this relationship is complicated, and it is unclear
whether r educed quality of life associated with overt hypothyroidism is a cause or a
consequence of depression. Additionally, dementia has been widely linked to overt
hypothyroidism.
Despite increased bone quantity, overt hypothyroidism has also been associated
with increased fracture risk, both before and after diagnosis. In the longer term, overt
hypothyroidism is associated with adverse cardiac consequences and events such as
atherosclerosis, coronary heart disease, myocardial infarction; angina and increased
cardiovascular mortality risk. 12
1.8 Prevalence
Overt thyroid dysfunction is one of the most common chronic endocrine disorders
in the general population. In 2006, 3% of the UK population were prescribed thyroxine

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replacement therapy for treatment of ove rt hypothyroidism. Data derived from a cross –
sectional study of a representative sample of the UK population suggested a higher
prevalence of overt hypothyroidism in women than in men (1.4% versus 0.1%,
respectively) and with advancing age. This study repo rted an overall prevalence of overt
hyperthyroidism of 2.0% in women and around 0.2% in men. Outside of the UK,
prevalence rates have been shown to vary considerably in accordance with ethnicity, age
and frequency of anti -thyroid antibody status of the pop ulation studied. 22
An additional explanation for the discrepancies in prevalence data from around
the world is the difference in iodine sufficiency between geographical locations.
However prevalence data derived in areas of iodine deficiency and sufficien cy
consistently demonstrate a higher prevalence of both hyper – and hypothyroidism in older
age groups compared with those younger than 60 years of age. Less generalisable and
rigorous estimates of prevalence have been reported due to research methods being
highly selective with respect to the populations being studied. Additionally, in some
studies prevalence may be overestimated due to misclassification of thyroid function in
individuals receiving drugs that interfere with thyroid function tests or with co ncomitant
or acute illnesses that impact upon serum thyrotrophin independently of thyroid disease.
Despite the discrepancies between smaller studies, epidemiological data from large
cross -sectional and longitudinal screening studies demonstrates that overt thyroid
dysfunction is a common and clinically significant disorder. 34

1.9 Etiology
The predominant cause of spontaneous overt hypothyroidism is autoimmune
infiltration and destruction of the thyroid gland due to Hashimotos thyroiditis or primary
atrophic hypothyroidism. Alternatively, destructive treatment for overt hyperthyroidism
in the form of total or partial thyroidectomy and/or radioiodine therapy can often prompt
under activity of the thyroid gland and lead to reduced thyroid hormone synthesis. 32

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Similarly, overt hyperthyroidism can be of autoimmune or iatrogenic origin.
Graves‟ disease is an autoimmune disease of unknown cause. In Graves‟ disease, auto
antibodies of the immunoglobulin G subclass mimic thyrotrophin by binding to
thyrotrophin recept ors on the thyroid cell membranes and stimulate thyroid function.
Development of autonomously functioning follicular adenomas within the gland
also leads to overt hyperthyroidism. These benign thyroid nodules known as “hot
nodules” cause the thyroid gland to be come unresponsive to the normal secretary control
mechanisms and continually secrete thyroid hormone into the circulation.
This condition is known as either solitary toxic nodule or toxic multinodular
goitre depending upon the number of nodules. Intent ional or unintentional excessive
thyroid hormone replacement therapy can also be responsible for overt hyperthyroidism.
Since iodine is essential for thyroid hormone production, another major cause of
overt hypothyroidism worldwide is iodine deficiency. Insufficient dietary intake is the
main cause of iodine deficiency with dietary sources containing varying degrees
dependant upon the amount available in the soil and/or in animal feed. The
recommended daily intake of iodine is 150μg with population based iodine intake
programmes achieving adequate intake through iodisation of salt.
Excess dietary iodine intake or iodine -containing medication or drugs that mimic
iodine action can be responsib le for overt hypothyroidism (via iodine induced inhibition
of thyroid hormone production) or overt hyperthyroidism (through surplus production of
thyroid hormone). The drug amiodarone, which is frequently prescribed for cardiac
arrhythmias, is iodine rich and may be responsible for either hyperthyroidism or
hypothyroidism in up to 18% of patients with apparently normal thyroid function or pre –
existing disease. 34 Likewise, lithium therapy for psychotic disorders has been shown to
induce hypothyroidism or hy perthyroidism in 10% of patients, particularly in the
presence of thyroid auto antibodies.

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Altered concentrations of serum thyrotrophin and thyroid hormones are not
exclusive to overt thyroid dysfunction, however, and may also be identified in
hospitalized individuals, patients with transient thyroid dysfunction due to viral
infection, or during recovery from other non thyroidal illnesses.
Transient increases in serum thyrotrophin concentration due to non t hyroidal
illnesses continue for approximately seven-ten days. In contrast, persistent alterations in
serum thyrotrophin concentration will stabilise to a new baseline in six to eight weeks
and are indicative of more permanent alterations in thyroid function. 26

1.10 Clinical expression of overt thyroid dysfunction
Almost all cases of overt thyroid dysfunction encountered in general practice are
caused by primary disease of the thyroid. Biochemical measurement of thyroid function
is required to exclude or confirm diagnosis of overt thyroid dysfunction. T he majority of
studies suggest that consideration of physical symptoms in isolation is associated with
very poor diagnostic accuracy for overt thyroid dysfunction. 23
Whilst endocrinology text books describe classical signs and symptoms of overt
hypothyro idism and hyperthyroidism, in routine primary care practice many of these
manifestations are rarely apparent. The clinical presentation of individuals with overt
hypothyroidism and overt hyperthyroidism varies widely. Additionally, many of the
classical si gns and symptoms are non -specific and as such frequently present in
euthyroid individuals.
A number of validated instruments are available for evaluation of the signs and
symptoms of overt hypothyroidism and overt hyperthyroidism. Some of these tools are
intended to aid diagnosis and assessment of severity of thyroid dysfunction, whereas
others are designed for monitoring the response to treatment. In terms of diagnosis,
arguably the availability of relatively low cost assays leads to thyroid function tes ting
without the use of such instruments in the majority of cases.

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Nevertheless, several investigators support the use of multiple symptoms as a
diagnostic tool for identification of individuals i n whom subsequent testing would be
appro priate. Simple scorin g systems have been shown to increase the pretest probability
of overt thyroid dysfunction by 15 -19%. In general, however, high frequencies of false
positive results have been associated with these clinical scoring systems. A recent study
to assess the sig nificance of the clinical versus biochemical diagnosis of overt
hypothyroidism reported correct classification of only 21% according to the Billewicz
score. Almost half of the 388 individuals with primary hypothyroidism were classified
as euthyroid and the remaining 29% fell into the inconclusive category. In another recent
study in which the Billewicz questionnaire was administered to individuals with overt
hypothyroidism and age matched controls, the classical symptoms were described much
less frequently than in the earlier literature. 26
There is, however, evidence to suggest that the clinical picture of overt thyroid
dysfunction has changed over time. Classical signs and symptoms of thyroid dysfunction
are now observed much less frequently than in earli er studies. The most plausible
explanation for this is earlier diagnosis of overt thyroid dysfunction due to the wide
availability of more sensitive and cost -effective assays for measurement of serum
thyrotrophin and FT4 concentrations. Previously, the diagnosis may have been made
based upon the clinical manifestations of more severe or longstanding thyroid
dysfunction. Older scoring systems developed before the 1970s when assays for
measurement of serum thyrotrophin and FT4 were not available may now be le ss
sensitive and of limited use for identification of signs and symptoms of relatively early
thyroid dysfunction. The diagnosis of overt thyroid dysfunction can be particularly
challenging in older individuals, not least because the signs and symptoms of t his
dysfunction also accompany normal healthy ageing.

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Signs and symptoms in older people may also be masked by coexisting disease
and concomitant medication. Several authors have documented a decrease in the number
and severity of symptoms of overt thyroid dysfunction with increasing age.
There are also data supporting age related alterations in the clinical manifestation
of overt thyroid dysfunction with a different constellation of signs and symptoms being
expressed in older individuals compared with youn ger people.
One study evaluating 24 clinical signs reported a significantly lower mean number
of signs in 67 individuals aged 70 years or more with overt hypothyroidism (mean age
79.3 years, range 70 -98 years) compared with 54 younger individuals (mean ag e 40.8
years, range 23 -55 years) with overt hypothyroidism (6.6 ± 4 versus 9.3 ±4.7
respectively, p <0.01). 34
50 Furthermore, four signs were observed significantly less frequently in elderly
individuals compared with younger subjects; sensitivity to col d temperatures (34.9%
versus 64.8 %, p<0.002), paraesthesia (17.9% versus 61.1%, p<0.001), weight gain
(23.7% versus 58.5%, p<0.001) and muscle cramps (20.3% versus 54.7%, p<0.001).
Similarly, in a study comparing presence of 19 classic signs of hyperthyro idism in older
(≥70 years, mean age 80.2 years) and younger (≤50 years; mean age 37.4 years) patients
with overt hyperthyroidism, the mean number of signs observed was significantly lower
in older than younger individuals (6.0 ± 3.5 versus 10.8 ± 3.1 respe ctively, p<0.001). 51
Seven of the 19 signs (hyperactive reflexes, excessive sweating, heat intolerance,
tremor, nervousness, polydipsia, and increased appetite) were observed significantly less
frequently in older subjects than in younger individuals. How ever anorexia was
significantly more prevalent in older individuals than in younger individuals with overt
hyperthyroidism (32% versus 4%, p<0.001). This study also recruited a third group
which comprised 68 older (≥70 years, men age 81.3 years) euthyroid controls matched
to older individuals with overt hyperth yroidism by gender, age and co -morbidity.
Comparison between the older groups with and without overt hyperthyroidism identified

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three signs, namely apathy (Odds Ratio, OR 14.8, 95% CI 3.8 -57.5, p<0.001), weight
loss (OR 8.7, 95% CI 3.1 – 24.4, p<0.001) and tachycardia (OR 11.2, 95% CI 4.3 -29.4,
p<0.001) significantly associated with overt hyperthyroidism. 18
51 Another study described a gradual decrease in the total number and frequency
of signs and symptoms beyond the age of 50 years, 49 with little change in clinical
presentation observed, until the age of 50 years. It seems therefore, that diagnosis
becomes more difficult as age progresses.
More recently, a cross -sectional st udy of 3049 patients with overt
hyperthyroidism demonstrated that the majority of individuals aged 61 years or older
reported a maximum of two symptoms (54%) compared with 36% in those aged 16 -32
years, 32% in those aged 33 -44 years and 30% in 45 -60 year groups. 52 Equally, the
group aged 61 years or more was less likely to report five or more symptoms than the
younger age groups. These results support and further extend th e findings of earlier
smaller studies by demonstrating an association between advancing age and number of
symptoms that is independent of severity and aetiology of ove rt hyperthyroidism.

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CHAPTER II. BIOCHEMICAL DIAGNOSIS OF THYROID
DYSFUNCTION
2.1 Definition of subclinical thyroid dysfunction
Subclinical hypothyroidism and subclinical hyperthyroidism were identified as
clinical entities during development of the 2 nd and 3rd generation serum thyrotrophin
assays, and as such, the diagnoses are essentially biochemical. The term „subclinical
thyroid dysfunction‟ is used when abnormal concentrations of serum thyrotrophin and
normal concentrations of circulating thyroxin e (FT4) are observed. The distinction
between overt and subclinical thyroid dysfunction disease therefore is based purely upon
biochemical criteria with subclinical hyperthyroidism being defined by a reduction in
concentration of serum thyrotrophin accompa nied by concentrations of the thyroid
hormone FT4 within the standard reference range. In contrast, subclinical
hypothyroidism is characterised by a raised serum thyrotrophin concentration in
conjunction with a serum FT4 concentration which is within the standard reference
range. 41
Subclinical hypothyroidism is often subdivided according to the degree of
elevation in serum thyrotrophin concentration. A thyrotrophin concentration of between
4.5-10mIU/L (detected in around 75% of cases) is generally regarded as being indicative
of less severe thyroid failure than a thyrotrophin concentration greater than 10mIU/L.
Similarly, subclinical hyperthyroidism is often subdivided based the upon degree of
thyrotrophin suppression, with concentrations of less than 0.01m IU/L representative of
more severe thyroid dysfunction than concentrations of between 0.1 -0.4mIU/L. This
stratification of serum thyrotrophin concentration is frequently used to define subgroups
for analysis in research and is utilised in guideline documen ts of expert opinion in
relation to testing, management and treatment of subclinical thyroid dysfunction.
Subclinical thyroid dysfunction is considered by some to be essentially a biomedical
diagnosis characterised by abnormal serum thyrotrophin (TSH) in association with

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normal serum thyroid hormone. Others, however, have designated subclinical thyroid
dysfunction, a mild form of overt thyroid dysfunction and have demonstrated presence
of symptoms suggestive of overt thyroid dysfunction.

2.2 Prevalence of subclinical thyroid dysfunction
Worldwide prevalence figures for subclinical hypothyroidism and subclinical
hyperthyroidism are variable. The use of different assays for measurement of serum
thyrotrophin concentration, differing reference criteria for definition of subclinical
thyroid dysfunction and inclusion of some individuals receiving treatment for thyroid
dysfunction are the most likely reasons for the diverse prevalence estimates reported.
Older studies of UK -based populations report a prevalenc e of subclinical
hypothyroidism of around 5 -6% and subclinical hyperthyroidism of approximately 1-
2%. These studies also suggest that the prevalence of subclinical hypothyroidism and
subclinical hyperthyroidism is higher in older individuals and in women. Our own recent
local study in which approximately 5800 community dwelling individuals aged 65 years
or more were screened reported an overall prevalence of subclinical hypothyroidism of
2.9% and subcl inical hyperthyroidism of 2.1%. Like the overt forms of this dysfunction,
prevalence figures vary considerably with ethnicity, dietary iodine intake and frequency
of anti -thyroid antibodies of the populations studied. As is the case with overt thyroid
dysfunction, the prevalence of subclinical hypothyroidism i s greater in areas of iodine
sufficiency and subclinical hyperthyroidism is more common in areas that are iodine
deficient. 65 Data derived from populations located in iodine sufficient and iodine
deficient areas consistently demonstrate an increased preva lence of subclinical thyroid
dysfunction in females and older individuals.

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2.3 E tiology of subclinical thyroid dysfunction
Subclinical hyperthyroidism and subclinical hypothyroidism have similar causes
to the overt forms of these disorders. Subclinical hypothyroidism has two main causes in
the UK, namely autoimmunity and overzealous treatment for overt hyperthyroidism. The
aetiology of subclinical hyperthyroidism can be divided into two categories: exogenous
and endogenous. These terms are used to define the origins of the disease with
endogenous being indicative of spontaneous disease (endo denotes from within) and
exogenous disease defining disease of external origin (exo denoting external).
Exogenous subclinical hyperthyroidism can be intentionally induced, for example as in
patients with differentiated thyroid carcinoma (DTC) receiving thyrotrophin -suppressive
thyroxine therapy, or unintentionally due to over aggressive anti thyroid therapy. The
most common cause of exogenous subclinical hyperthyroidis m is therefore the use of
unintentional or intentional excessive suppressive doses of thyroid hormone. The
endogenous form is usually related to autonomous thyroid dysfunction. It remains to be
seen whether endogenous and exogenous subclinical hyperthyroid ism are comparable
conditions that exert equivalent effects.

2.4 Statistical nature of defining a reference range
Reference intervals are widely used medical decision making tools and aid the
clinician in differentiating between healthy and „unhealthy‟ patients. In general, these
are population, assay and statistical methodology dependent. The National Committee
for Clinical Laboratory Standards (NCCLS) suggest that calculation of reference criteria
is based upon measurement of at least 120 „normal‟ heal thy samples. The reference
range is calculated from the sample mean and two standard deviations of the data set.
The value corres ponding to the 2.5th percentile defines the lower limit of the reference
range and the value corresponding with the 97.5th percentile indicates the upper limit of
the reference range. The most sensitive indicator of thyroid dysfunction is serum

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thyrotrophin concentration, however there are no universal reference criteria or
reference material for definition of normal serum thyrotr ophin concentration, therefore
reference ranges vary from one endocrine laboratory to the next. Reference criteria for
serum thyrotrophin concentration are derived from screened samples of healthy
volunteers with no known or apparent thyroid dysfunction or medication known to affect
thyroid function.
However there has been much debate about this derivation method particularly in
relation to defining the upper limit of normal. Over the last 20 years the upper limit has
been reduced from 10mIU/L to around 4mI U/L and some authors suggest further
reductions are necessary. These suggestions are based upon data derived from exclusion
of individuals with thyroid auto antibodies, goitre or a strong family history of thyroid
disease from the reference population. In such thyroid disease and risk factor free
populations the upper limit decreases to between 2.5mIU/L to 3.0 mIU/L. Some argue
that the refined reference range is better than the standardised population –based
reference range particularly because elevated thyrotrophin values may predict future
hypothyroidism Additionally, current assays for detection of anti thyroid antibody are
not sufficiently sensitive to identify all individuals with low grade thyroid
autoimmunity. Furthermore, an increased risk of overt h ypothyroidism has been
demonstrated in antibody negative individuals. This decreased upper limit of normal
would however increase the sensitivity of the diagnosis and decrease specificity
resulting in a greater number of individuals being given a false pos itive diagnosis.
Furthermore, lowering the upper limit of the reference range would have a large impact
upon the prevalence figures for the older age groups and would lead to reclassification
of one in five euthyroid individuals tosubclinically hypothyroid . One recent study
demonstrated a modified serumthyrotrophin distribution in older individuals and
suggested that serum thyrotrophin progressively moves towards higher concentrations
with advancing age. Reanalysis of data from the NHANES study demonstrated that the

Page | 23
upper limit of normal at the 97.5th percentile was 3.56mIU/L for the 20 -29 age group,
4.5mIU/L in individuals aged 50 -59 years and 7.5mIU/L in individuals older than 80
years. Seventy percent of older patients with a serum thyrotrophin concentrat ion greater
than 4.5mI/L were therefore within their age -specific reference range. It is possiblethat
current statistically defined laboratory reference criteria for serum thyrotrophin
concentration are neither adequately sensitive nor specific for identif ication of abnormal
concentrations of serum thyrotrophin in older age groups and as such current prevalence
rates for subclinical hypothyroidism in the older individuals may be substantially over
estimated. However, in a further study, the geometric mean serum thyrotrophin
concentration and the 95% confidence intervals for older individuals (1.45mIU/L; 95%
CI 0.54 -3.9) did not differ significantly from that in middle aged individuals
(1.24mIU/L; 95% CI 0.29 -5.4). The investigators therefore concluded that o ne reference
range is appropriate for all age groups. The development of age -specific reference
ranges would cause additional problems, with screening of more individuals being
required in order to obtain a suitable reference sample. Equally, extrapolation of data
from such a selected population may also be inappropriate. 19
2.5 Diagnosis of subclinical thyroid dysfunction in primary care
The definitive diagnosis of subclinical thyroid dysfunction is based upon the
relationship between serum thyrotrophi n and serum free thyroxine. Expert opinion and
guidance recommends routine front line measurement of both serum thyrotrophin and
free thyroxine concentration for patients without a previous thyroid function test on
record and on all specimens where the req uest for thyroid function testing is not
accompanied by a ny additional clinical details.
Estimation of FT3 is generally recommended when serum thyrotrophin
concentration is below the lower threshold of the laboratory reference criteria and FT4 is
greater than the higher threshold; however protocols for measurement of FT3 are

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laboratory specific and vary accordingly.The annual cost of thyroid function testing in
the UK is approximately 30 million.
Estimates suggest that one in four people in the UK have a thyroid function test
annually with the majority of requests for thyroid function testing coming from primary
care. Measurement of serum thyrotrophin concentration is reported to be one of the most
frequently requested test by primary care physicians and repeat tests are frequent despite
normal initial findings. In view of the high prevalence of thyroid dysfunction in the
general population and the wide availability of cost -effective and sensitive assays for
measurement of thyroid dysfunction this level of testing may seem justified. There have
however been suggestions that the associated diagnostic yield is low. Meyerovitch et al
examined data from a large health care database inorder to determine the use of routine
tests of serum thyrotrophin concentratio n by primary care physicians over a period of
five years. Findings demonstrated an increased rate of testing with advancing age and an
average frequency of three repeat requests for measurement of serum thyrotrophin per
person during the five year period.
Furthermore, 95% of the initial tests were within the reference range and
remained so throughout the five year study period. More recently, a small retrospective
observational study and survey of general practitioners in the UK reported variability
across 19 primary care practices with respect to testing and treatment of subclinical
thyroid dysfunction. This study suggested that thyroid function testing is being requested
freque ntly and repeatedly for elderly individuals based upon presentation with a varie ty
of non specific symptoms. Equally, administration of thyroxine therapy was described in
elderly individuals presenting with and without symptoms after one thyroid function test
result. Similarly, a survey assessing the procedural options most frequently followed and
the difficulties encountered by GPs suggested that development of standardised
protocols is necessary to aid GP testing and management of subclinical thyroid
dysfunction. 51

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2.6 Current management strategies
In terms of frequency of thyroi d function testing, expert opinion from the UK
Association for Biochemistry (ACB), the Britis h Thyroid Association (BTA) and the
British Thyroid Foundation (BTF) suggest repeat testing to confirm subclinical
hyperthyroidism if initial serum thyrotrophin is below 0.1mIU/L and after exclusion of
interference from concomitant non thyroidal illness or medication. Monitoring on a 6 -12
monthly basis is also advocated. Repeated thyroid function testing should, however be
requested based upon the clinical presentat ion with earlier repeat testing being
conducted in elderly individuals and subjects with vascular disease. 36
Successful treatment of overt thyroid dysfunction requires normalisation of
thyroid hormone concentration in peripheral tissues. In overt hypothyr oidism this is
achieved through administration of thyroxine replacement therapy. Similarly, overt
hyperthyroidism is readily treated with anti thyroid therapy often in combination with
thyroidectomy or radioiodine therapy. Whilst treatment of abnormal thyr oid hormone
levels in overt thyroid dysfunction is generally accepted, the threshold and indications
for treatment of subclinical dysfunction is an unresolved issue due to a lack of evidence
pertaining to the clinical impact of these disorders and the bene fits associated with
treatment. This is particularly so in the elderly in whom the burden of other existing
chronic disease and polypharmacy is common. In terms of treatment of subclinical
hypothyroidism, expert opinion recommends treatment of individuals with a serum
thyrotrophin concentration >10mIU/L. Treatment for milder subclinical hypothyroidism
(4.5-10mIU/L) remains controversial with frequent monitoring being preferential.
Similarly, the benefits of treating subclinical hyperthyroidism particularly in older
individuals are uncertain. Recent recommendations from a panel of experts suggest
treatment of endogenous subclinical hyperthyroidism in the presence of serum
thyrotrophin concentration of <0.1 mIU/L, 71 particularly, in individuals aged 60 years
of age or more with clinical symptoms or at increased risk for heart disease and

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osteoporosis. The panel did not however recommend routine treatment in individuals
with serum thyrotrophin concentration of between 0.1 –0.45mIU/L regardless of
expression of s ymptoms. 61
Another controversial aspect of subclinical thyroid dysfunction is with regard to
routine screening. In view of the high prevalence of subclinical thyroid dysfunction in
the general population some advocate routine screening. Others argue howev er that
screening programmes cannot be justified because the associated clinical burden of
subclinical thyroid dysfunction is unknown and there is no robust evidence to
demonstrate that early diagnosis and treatment in the subclinical phase improves clinic al
outcomes. The American Thyroid Association (ATA) has recommended initial
screening of men and women at 35 years of age and every five years there after. In
contrast, the America Association of Clinical Endocrinology (AACE) supported only
screening of el derly women. A more recent joint statement from a conference between
the various US based pr ofessional organisations agreed that current data are insufficient
to advocate population based screening due to the uncertainty with regard to the benefits
of earl y treatment, although aggressive case finding in those aged 60 years or more is
promoted.

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CHAPTER III SUBCLINICAL HYPOTHYROIDISM
Subclinical hypothyroidism is defined bio -chemically as “a serum thyroid
stimulating hormone (TSH) level above the upper referen ce limit in combination with a
normal free thyroxine level, provided that the thyroid function has been stable for
weeks, the hypothalamic -pituitary -thyroid axis is normal, and there is absence of recent
or ongoing severe illness”. Some patients with subcl inical hypothyroidism may have
symptoms suggestive of hypothyroidism but symptoms are non -specific and may be
present in euthyroid persons. Most guidelines recommend rechecking serum TSH within
3–6 months to confirm persistence of elevated TSH. 58
Epidem iology
Subclinical hypothyroidism is a common biochemical finding in the general
population, although prevalence figures vary with the characteristics of the populations
studied, as well as the upper limit set for TSH measurements. Meticulous studies from
the United States and elsewhere have addressed the question of the reference range,
taking into account the influence of inclusion or exclusion of subjects with a personal or
family history of thyroid disease or those with positive antithyroid antibodies. Evidence
from one such study (NHANES III) of a large 'reference' population without evidence of
thyroid disease indicated that 95% of adults have a serum TSH concentration within the
range 0·45 –4·12 mU/l,determining that the widely applied upper limit of n ormal for
serum TSH of around 4·5 mU/l remains appropriate. In terms of pathophysiological
consequences, experts typically classify subjects with subclinical hypothyroidism into
two groups: those with mildly elevated TSH (4·5 –10 mU/l) and those with more m arked
TSH elevation (TSH >10 mU/l).
Overall, the population prevalence of subclinical hypothyroidism is around 5 –
10%, the diagnosis being more common in women and increasing with increasing age
and being higher in white than in black populations. The Whic kham survey in the north –
east of England reported TSH >6·0 mU/l in 7·5% of women and 2·8% of men. TSH did

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not vary with age in men but increased markedly in women aged more than 45 years.
The NHANES III study in the United States found subclinical hypothyr oidism (TSH
>4·6 mU/l) in 4·3%, while in a large study of subjects attending health fairs in Colorado,
9·5% had raised TSH, 75% of these cases being in the 'mild' (5·0 –10·0 mU/l) range and
25% of whom were taking thyroid hormones. Our own study of 1210 sub jects aged over
60 years who were recruited from primary care revealed a prevalence of subclinical
hypothyroidism of 11·6% in women and 2·9% in men. Significant titres of antithyroid
antibodies were found in 46% of those with serum TSH between 5 and 10 mU/ l and in
81% of those with a serum TSH greater than 10 mU/l, providing evidence for underlying
autoimmune thyroid disease in the majority. However, our more recent community
screening study of the elderly in the same geographical area revealed a lower popu lation
prevalence of subclinical hypothyroidism of 2·9%, perhaps reflecting more frequent
testing of thyroid function and earlier treatment of raised TSH in primary care in the
intervening years. 63
The commonest causes for subclinical hypothyroidism are a utoimmune thyroiditis
(Hashimoto's disease) and previous treatment for hyperthyroidism. Treatment of
hyperthyroidism with radioiodine results in hypothyroidism in at least 50% of patients
with Graves' disease (depending upon the dose administered), althoug h a lower
proportion in those with toxic nodular hyperthyroidism development of subclinical
hypothyroidism typically preceding overt thyroid failure. Partial thyroidectomy for
hyperthyroidism or nodular goitre is associated with a similar risk of developme nt of
hypothyroidism, which is again first identified by a rise in serum TSH. In the early
months after both radioiodine treatment and partial thyroidectomy, subclinical
hypothyroidism may be a transient phenomenon, not always indicative of progressive or
permanent thyroid failure. Graves' disease is itself associated with the eventual
development of hypothyroidism in 5 –20% (even in the absence of ablative thyroid
treatment).

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A further major category of patients with a biochemical diagnosis of subclinical
hypothyroidism is those already treated with thyroxine for hypothyroidism, a high serum
TSH indicating that the dose prescribed is inadequate or compliance poor. We found a
raised serum TSH in 25% of subjects in the community prescribed thyroxine, with a
close relationship evident between prescribed dose and TSH results, indicating that at
least in some patients (especially those prescribed doses of 75 mcg per day or less), the
cause for subclinical hypothyroidism was inadequate dose prescription. In those
prescribed higher doses, compliance is typically the major issue.
Other groups at particular risk of subclinical hypothyroidism include those with
other autoimmune diseases such as type I DIABETES mellitus and Addison's disease.
Conversely, we have shown that the presence of autoimmune thyroid disease is strongly
associated with other autoimmune diseases. Down's and Turner's syndromes are both
associated with the development of both subclinical and overt thyroid failure of
autoimmune aetiology. The risk of subclinical hypothyroidism during pregnancy is
considerable in women identified in the first trimester as having positive antithyroid
antibodies. This antibody status also represents a risk factor for the development of post –
partum thyroiditis, subclinical or overt hypothyroidism being a feature of postpartum
thyroiditis in about 75% of cases.[42] A further cause for subclinical hypothyroidism is
radiotherapy to the head and neck (which is itself associated with the development of
positive antithyroid antibodies). 'Non -thyroidal' illness may be associated with a
transient and modest increase in serum TSH, especially in the recovery phase from
illness, although in most instances, a raised TSH does reflect underlying thyroid disease.
Therapy with drugs such as lithium and amiodarone can induce subclinical
hypothyroidism, as can administration of iodine c ontaining compounds such as
radiographic contrast agents.
The natural history of subclinical hypothyroidism depends upon the underlying
cause and the population studied. One large follow -up study has shown that in those

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with modest elevation of serum TSH ( 5·5–10·0 mU/l), the TSH measurement returns
spontaneously to the reference range in more than 60% of cases during 5 years of
follow -up. Our own study of the over 60 s in the community revealed that the finding of
a raised serum TSH identified on screening disappeared in 5·5% after 12 months, while
the biochemical abnormality remained stable in 76·7% and relatively few (17·8%)
progressed to overt hypothyroidism (defined as raised TSH with serum free T4 below
the reference range). Twenty -year follow -up of the Whickham cohort in the north -east
of England revealed an annual rate of progression of subclinical to overt hypothyroidism
of 2·6% if thyroid antibodies were negative, but 4·3% if antibodies to thyroid peroxidase
were present.
3.1 Differential diagnos is of raised serum TSH
Before making a diagnosis of subclinical hypothyroidism, other conditions that
cause serum TSH to be raised should be excluded. Thyroid stimulating hormone levels
may be raised as a result of acute nonthyroidal illness. Patients wi th nonfunctioning
pituitary adenomas, with central hypothyroidism, may have mildly elevated serum TSH
levels due to secretion of TSH, which has reduced biologic activity. In central
hypothyroidism, serum free T4 is usually low, differentiating it from subc linical primary
hypothyroidism. Adrenal insufficiency may be associated with TSH elevations that are
reversed with glucocorticoid replacement.
3.2 Etiology of subclinical hypothyroidism
The same conditions that cause overt hypo -thyroidism can cause su bclinical
hypothyroidismand the most common cause is chronic autoimmune (Hashimoto’s)
thyroiditis. Other causes include inadequate replacement therapy for overt
hypothyroidism, drugs impairing thyroid function (e.g. amiodarone, lithium), subacute,
postpart um and painless thyroiditis, thyroid injury (from partial thyroidectomy,
radioactive iodine therapy, externaleuthyroid persons. Most guidelines recommend
rechecking serum TSH within 3 –6 months to confirm persistence of elevated TSH.

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3.3 Prevalence of sub clinical hypothyroidism
Using an upper limit of normal for TSH as 4.5 mIU/L, the National Health and
Nutrition Examination Survey (NHANES III) of an unselected U.S population found
subclinical hypothyroidism in 4.3% of the reference population. A local p rospective
observational study in a restructured hospital found subclinical hypothyroidism in 2.2%
of admitted geriatric patients. There is debate on what the upper limit of normal for TSH
should be. Higher rate of progression to overt disease as well as h igher levels of
antithyroid antibodies found in persons with TSH at the upper range of normal support
lowering of the upper limit to narrow the range of normal for TSH, whereas spontaneous
normalisation occurring in some patients with mildly elevated TSH a nd the possibility of
over treatment leading to iatrogenic hyperthyroidism with its antecedent ill effects
argues against lowering the upper limit. As such, the true prevalence of subclinical
hypothyroidism is somewhat uncertain because of the inability to specify the normal
range of TSH.
3.4 Consequences of subclinical hypothyroidism
The clinical risks associated with subclinical hypothyroidism have been
extensively studied, with particular focus on the risk of progression to overt
hypothyroidism (i.e . the natural history of subclinical hypothyroidism), its effect on the
cardiovascular system, namely coronary heart disease (CHD) and mortality as well as
heart failure.
3.5 Progression to overt hypothyroidism (natural history of subclinical
hypothyroid ism)
Some patients with subclinical hypothyroidism progress to overt disease while in
some patients, thyroid function may normalise. Several factors influence progression to
overt disease. Progression to overt disease is more likely with higher degree of T SH
elevation and the presence of antithyroid peroxidase antibodies. A twenty -year follow up
in the Whickham Study20 had shown that in the presence of antithyroid peroxidase

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antibodies, the annual rate of progression to overt hypothyroidism was 4·3% compare d
to 2·6% if thyroid antibodies were negative.
Other factors affecting risk of progression to overt hypothyroidism include the
underlying aetiology of hypothyroidism (for example, higher likelihood of progression
seen post -radioiodine therapy and underlyi ng autoimmune thyroid disease) and the age
of the patient (risk of progression appears to be less common in children and
adolescents). More -over subclinical hypothyroidism may be a transient disease with
spontaneous normalisation of TSH levels. Recovery of thyroid function is more likely if
basal TSH levels were below 10 mIU/L, coupled with the absence of antithyroid
peroxidase antibodies.
3.6 Cardiovascular events and mortality
Cohort studies have reported conflicting results, with some studies findi ng no
association between subclinical hypothyroidism and cardiovascular events/mortality,
and many others finding a positive association between the two.
Rodondi et al. established the Thyroid Studies Collaboration to collect individual
participant data f rom 11 international prospective cohorts, and suggested that subclinical
hypothyroidism was associated with an increased risk of CHD events and mortality in
those with higher TSH levels, particularly when TSH >10 mIU/L. Risks did not
significantly differ a ccording to the age of the patient, even though a number of other
studies suggest that the negative effects of subclinical hypothyroidism on cardiovascular
risk may be less evident in older patients. A meta -analysis by Razvi et al. also suggested
that the risk of ischaemic heart disease and cardiovascular mortality is higher in patients
who are younger than age 65 years. The effects of subclinical hypothyroidism in the
elderly is discussed further under the section on ‘Special populations groups affecting
treatment considerations: elderly’.
Patients with subclinical hypothyroidism were also found to have other markers of
increased cardiovascular risk such as raised C -Reactive Protein, increased arterial

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stiffness, endothelial dysfunction and increased carot id intima thickness. With regard to
cardiovascular risk factors, a recent meta -analysis of cross sectional data suggested
association between subclinical hypothyroidism and systolic hypertension. Available
data linking subclinical hypothyroidism to hyperli pidemia is conflicting. Some studies
show an association with subclinical hypothyroidism while others show no correlation.
Thus based on data, subclinical hypothyroidism may potentially increase the risk of
atherosclerosis and coronary artery disease.
3.7 Heart failure
Two cohort studies have assessed the relation between subclinical hypothyroidism
and heart failure in elderly patients. The first study looked at subjects aged 70 years and
above and found the risk of heart failure to be increased w ith TSH level of 7.0 mIU/L or
greater. The risk of heart failure was greater with higher levels of TSH (relative risk of
2.6 with TSH 7·0 –9·9 mIU/L and 3·26 for those with serum TSH of 10 mIU/L or
greater). The other study53 looked at subjects aged 65 year s and above and noted
increased heart failure risk only in those with a TSH concentration of 10 mIU/L or
greater. In this same study53, patients with subclinical hypothyroidism who were treated
with levothyroxine had significantly lower risk of heart failu re events.
A review by Biondi and Cooper noted consistent association between subclinical
hypothyroidism and left ventricular diastolic dysfunction while the association with
systolic dysfunction is less consistent. Resting and exercise doppler echocardio graphy
and radionuclide studies showed slowed ventricular relaxation and impaired ventricular
filling indicating diastolic dysfunction in subclinical hypothyroid patients compared to
euthyroid subjects.
Finally, Gencer et al. performed a pooled analysis o f individual participant data
from six prospective cohorts in the United States and Europe and found an increased risk
of heart failure events when TSH >10 mIU/L.

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3.8 Others
The effect of subclinical hypothyroidism on cognitive and neuropsychological
function yielded conflicting results from studies. One study showed no cognitive and
neuropsychological dysfunction in subjects with subclinical hypothyroidism when
compared to healthy controls, while another found cognitive impairment in subjects with
subcli nical hypothyroidism which normalised after thyroxine replacement.
3.9 Special population groups affecting treatment considerations
Pregnant women
Physiological changes during pregnancy can be reflected in thyroid function tests.
For example, increa sed thyroid binding globulin (TBG) during pregnancy increases
serum total T4 and T3 compared to non -pregnant states, while first trimester human
chorionic gonadotrophin (hCG) increases serum free T4 with appropriate suppression of
TSH. Changes in thyroid p hysiology probably relate to the need for maternal free T4 to
be delivered to foetus in the first trimester for neural development. It is clear that
trimester -specific ranges are required for correct diagnosis of thyroid disease in
pregnancy. Guidelines co sponsored by the American Thyroid Association and the
American Association of Clinical Endocrinologists (ATA/AACE) had recommended
using trimester -specific upper limit of normal reference ranges for TSH, if available at
the particular laboratory. If trimes ter-specific ranges are unavailable for the particular
laboratory, upper -normal reference ranges of 2.5 mIU/L, 3 mIU/L and 3.5 mIU/L are
recommended for the first, second and third trimester respectively. The Endocrine
Society (JCEM 2012) also suggested tr imester -specific TSH ranges if available at the
particular laboratory. If trimester -specific ranges are unavailable, they suggest an upper
normal limit of 2.5 mIU/L for the first trimester and 3 mIU/L for both the second and
third trimesters.
Subclinical hypothyroidism in pregnancy is associated with poor obstetric
outcomes including stillbirths, abruptio placentae, pre -eclampsia and preterm delivery

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with resultant low birth weight. One study suggested developmental delay in infants
born to mothers with su bclinical hypothyroidism.
While a Cochrane review published in 2013 on interventions for hypothyroidism
pre- and during pregnancy found insufficient evidence to recommend the use of
intervention with thyroxine for improving outcome, it is worth noting tha t the review
only included four trials of moderate risk of bias and involved mainly hypothyroid
subjects or those with positive thyroid antibodies.
In contrast, the ATA/AACE guidelines specifically mention pregnancy as a
possible consideration for treatin g patients with subclinical hypothyroidism. The
guidelines recommend thyroxine therapy if TSH is greater than 2.5 mIU/L and the
patient has or previously had positive anti -thyroid peroxidase antibodies.
Independent of anti -thyroid peroxidase status, treat ment should also be considered
if serum TSH is above the trimester -specific upper limit of normal reference ranges (viz.
2.5 mIU/L, 3 mIU/L and 3.5 mIU/L for the first, second and third trimester
respectively).
Due to the complexity of management and poss ibility of adverse foetal outcomes,
our advice for family physicians is to co -manage a pregnant patient with subclinical
hypothyroidism with the obstetrician and endocrinologist.

The elderly
It has been known that elevated TSH levels occur with increasin g frequency with
aging, with 40% and 14.5% of elderly individuals in one study65 having TSH levels >2.5
and 4.5 mIU/L respectively.
The effect of subclinical hypothyroidism on the elderly has generated conflicting
results. Rodondi et al. had found that su bclinical hypothyroidism increased risk of CHD
events and mortality particularly when TSH >10 mIU/L, even in the elderly while
several studieshad noted that the risk of cardiovascular disease (CVD) and mortality was

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not seen in the elderly as compared to t he younger population.
Rodondi et al. ’s findings of increased cardiovascular risk in the elderly have been
called into question by two recent studies published in 2013. In the Cardiovascular
Health Study42, Hyland et al. noted that elderly patients aged 6 5 years and above with
subclinical hypothyroidism did not have increased risk of coronary heart disease, heart
failure or cardiovascular deaths regardless of serum TSH levels. The investigators also
did not find any subset of older adults to target for the rapy, and concluded that their
findings did not support the treatment of subclinical hypothyroidism in this group. It has
previously been shown that treatment with L -thyroxine did not confer any benefits in the
elderly, even though treatment of younger pat ients with subclinical hypothyroidism was
associated with fewer cardiovascular events.
A review by Pasqualetti et al. covered existing literature and affirmed that while
the negative effects of subclinical hypothyroidism on cardio -vascular events and
mort ality are well established in adults ≤60 years old, the effect is less evident in the
moderately old (<70 –75 years old) and may be absent in those aged >80 years66.
However as quoted by the authors, one study reported increased risk of heart failure in
subjects aged 70 –82 years with known cardiovascular risk factors or pre -existing
cardiovascular disease when TSH was persistently elevated. The authors concluded that
any decision to treat elderly patients with subclinical hypothyroidism should take into
account factors which include level of serum TSH and pre -existing cardiovascular risk.
In the Leiden study of subjects aged 85 years and older, abnormally high levels of
TSH was not associated with functional disability, depressive symptoms nor cognitive
impa irment but was instead associated with a lower mortality rate. These findings
suggest that raised TSH in the elderly may be as a result of age -related physiological
change in set -point.

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3.10 When should we treat?
Most authors as well as the ATA/AACE gui delines recommend treatment with
thyroxine for individuals with subclinical hypothyroidism and TSH >10 mIU/L;
opinions differ in management when TSH ranges between 4.5 and 10 mIU/L, with some
authors recommending routine treatment and others against.
Bion di and Cooper had proposed that the decision to treat or not to treat
subclinical hypothyroidism when serum TSH is above the upper reference range yet
below 10 mIU/L should be based on consideration of whether symptoms are present, the
underlying aetiology of hypothyroidism (e.g. whether there was evidence of
autoimmune thyroiditis such as positive anti -thyroid peroxidase antibodies), presence of
atherosclerotic disease or risk factors or heart failure. This is consistent with the
ATA/AACE guidelines1. For patients with TSH <10 mIU/L for whom the decision is not
for treatment, clinical assessment and monitoring of TSH levels can be performed every
6–12 months3. Up to 60% of subclinically hypothyroid patients with TSH <10 mIU/L
may revert to normal with repea t testing of serum TSH.

How do we treat?
The ATA/AACE guidelines approximate the daily thyroxine requirement of
patients with low levels of functional thyroi d reserve at 1.6 μg/kg body weight. Most
patients with subclinical hypothyroidism require smaller dosages to achieve
euthyroidism, with 25 –75 μg being sufficient for most, except those with higher TSH
levels.
One study used the initial TSH level to determ ine the starting dose of thyroxine:
25 μg for TSH 4 –8 mIU/L, 50 μg for TSH 8 –12 mIU/L, 75 μg for TSH >12 mIU/L.
With the above dosing, euthyroidism was achieved with few adjustments after two
months. For elderly patients and those with pre -existing cardiac disease, lower starting
doses of thyroxine with a slower rate of dose increase is recommended.

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The path forward
While there is a better understanding of the management of subclinical
hypothyroidism, many c linical uncertainties still remain and research findings to answer
key questions are often conflicting. Most of the current evidence is derived from cohort
studies and there is a lack of randomised clinical trials on important clinical outcomes.
Rodondi et al. commented in an editorial that additional observational data is
unlikely to adequately address the uncertainties regarding the risks of subclinical
hypothyroidism and the benefits/harm of therapy. The authors suggested that these
concerns would be be st addressed with appropriate randomised controlled trials.
One such study is currently underway — the Thyroid Hormone Replacement for
Subclinical Hypothyroidism (TRUST) study is a multi -centre randomised -placebo
controlled trial to assess the impact of t hyroxine replacement in 3,000 older adults with
persistent subclinical hypothyroidism.
CHAPTER I V. SUBCLINICAL HYPERTHYROIDISM
Subclinical hyperthyroidism is characterised by a serum TSH level below the
lower reference limit in combination with a normal free thyroxine level. The definition
only applies if the thyroid function has been stable for weeks, the hypothalamic –
pituitary -thyroid axis is normal, and there is absence of recent or ongoing severe illness4.
Patients with subclinical hyperthyroi dism may have typical symptoms of thyroid
hormone excess such as palpitations, tremor, heat intolerance, sweating, anxiety,
reduced feeling of well -being, hostility, and inability to concentrate80.

Epidemiology
Subclinical hyperthyroidism often reflects ingestion of thyroid hormones,
typically thyroxine, and in that context is considered 'exogenous' in origin. If low serum
TSH is found in the absence of thyroid hormone use, then it is labelled 'endogenous'. For
both categories, given the inverse (but nonl inear) relationship between serum free T4

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and TSH, complete suppression of serum TSH (to <0·1 mU/l) is generally considered of
more pathophysiological significance than the finding of a low but detectable serum
TSH (0·1 –0·4 mU/l). Exogenous subclinical hyp erthyroidism is more common than
endogenous and is present in around 20 –40% of the subjects prescribed thyroid
hormones.[1–3] As expected, low serum TSH is more common in those prescribed
thyroxine in higher doses, indicating a degree of over -treatment.[2] Studies of those not
taking thyroid hormones also reveal a high prevalence of subclinical hyperthyroidism,
with variations in f requency depending on age, gender, race and iodine intake within the
population. The National Health and Nutrition Survey (NHANES) in the United States
revealed 1·8% of the general population to have low but detectable serum TSH and only
0·7% to have fully suppressed serum TSH (after exclusion of 'exogenous' cases),[4] with
similar findings from a population prevalence study in Scotland.[5] Both of these studies
revealed a higher prevalence in women and a rise in frequency with age. Our own study
of almost 6000 community -based subjects aged over 65 years attending general
practices in the West Midlands region of England revealed a p revalence of subclinical
hyperthyroidism of 2·1% in that age group, again being more common with increasing
age. Ninety of 128 subjects with subclinical hyperthyroidism had low but detectable
serum TSH, with a relatively small proportion having fully suppr essed TSH.[6]
The causes for subclinical hyperthyroidism are shown in Table 1 . As well as
thyroxine therapy, previous Graves' hyperth yroidism may be associated with
suppression of TSH for weeks or even months after successful treatment, although if
longstanding indicates persistent thyroid autonomy. Up to 75% of subjects with nodular
goitre may also have TSH suppression, again indicatin g thyroid autonomy. It should be
noted, however, that 'non -thyroidal' illnesses and therapies with various drugs probably
represent the commonest causes for subclinical hyperthyroidism, especially in hospital
outpatient or inpatient populations, the most c ommon biochemical finding being low but
detectable serum TSH.

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The natural history of subclinical hyperthyroidism depends upon its cause and
severity (i.e. the degree of reduction in serum TSH below the reference range). Some
subjects in whom TSH suppressio n (usually complete) is associated with Graves'
hyperthyroidism or nodular goitre will progress to overt hyperthyroidism, although the
incidence is relatively low at around 1 –3% per year. In contrast, those in whom low
serum TSH values reflect 'non -thyroid al' illness or drug therapy typically have low but
detectable serum TSH, and the biochemical abnormality often disappears after recovery
from illness or cessation of drug therapy. A large study demonstrated that reduced serum
TSH (<0·35 mU/l) returned to n ormal in more than half after a follow -up period of 5
years.[7] This finding is compatible with one of our early screening and follow -up studies
in the elderly which showed that of those with low but detectable TSH at initial testing,
TSH had returned to normal in 76% at one year, compared with those with undetectable
TSH of whom 88% had persistently undetectable TSH.[8] A 10 -year follow -up of the
same group showed that only 4·3% of those with low serum TSH developed overt
hyperthyroidism.[9]

4.1 Differential diagnosis of suppressed serum TSH
Before making a diagnosi s of subclinical hyperthyroidism, it is important to
consider some conditions that may result in TSH suppression. The differential diagnosis
of low serum TSH includes transient suppression during subacute, silent or post -partum
thyroiditis, non -thyroidal i llness, psychiatric illness, central hypothyroidism, TSH
suppression by drugs such as corticosteroids or age -related decreased thyroid hormone
clearance or altered hypothalamic -pituitary -thyroid axis set -point. While these
conditions may cause a similar lo oking biochemical picture, they are not causes of
subclinical hyperthyroidism.

4.2 Etiology of subclinical hyperthyroidism

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The most common cause of subclinical hyperthyroidism is exogeneous ingestion
of L -thyroxine, for example as occurs in over -replacem ent for hypothyroidism or
intentional TSH suppressive therapy for a variety of thyroid diseases. Endogeneous
subclinical hyper -thyroidism, which occurs in the absence of thyroxine intake, reflects
autonomous thyroid function and is commonly due to Graves’ Diseases, multinodular
goitre or solitary toxic nodules. In older persons, toxic multinodular goitre is probably
the most common cause23. Determining the underlying aetiology of subclinical
hyperthyroidism is important as it has some bearing on the natural history. This is
further discussed later.

4.3 Prevalence of subclinical hyperthyroidism
The prevalence of subclinical hyperthyroidism, taking into account endogeneous
and exogeneous causes varies between 0.7 and 12.4%. This variability is partly due to
differences in investi -gators’ definitions of the lower limit of normal for TSH14.
Endogeneous subclinical hyperthyroidism is more prevalent in the elderly and in
females.

4.4 Consequences of subclinical hyperthyroidism
Decreased serum TSH has been assoc iated with progression to overt
hyperthyroidism, atrial fibrillation, reduced bone mineral density, and cardiac
dysfunction94,95.

4.5 Progression to overt hyperthyroidism (natural history of subclinical
hyperthyroidism)
The frequency with which subclinica l hyperthyroidism progresses to overt disease
depends upon degree of TSH suppression as well as the underlying aetiology.
Data has suggested that the course of subclinical hyperthyroidism due to Graves’

Page | 43
disease is more variable, with higher chance of spon taneous remission as compared to
persisting unchanged in multinodular goitre, while patients with solitary autonomous
nodules are more likely to progress to overt disease96. Patients with low but still
detectable (0.1 –0.4 mIU/L) serum TSH appeared less lik ely to progress to overt diseases
compared to patients with undetectable (<0.1mIU/L) serum TSH.

4.6 Cardiovascular effects
A meta -analysis97 of cohort studies demonstrated association between subclinical
hyperthyroidism and significantly increased cardio vascular risk for the general
population and increased all -cause mortality for individuals with comorbidities.
When TSH was iatrogenically suppressed by exogeneous L -thyroxine, there was
increased cardiovascular risk, particularly if TSH is suppressed to undetectable levels14.
Iatrogenic TSH suppression has been associated with significantly increased left
ventricular mass, raised heart rate, raised systolic blood pressure99 and reduced exercise
capacity.
Similarly, subclinical hyperthyroidism due to endo geneous causes had
cardiovascular effects with data showing associated increased heart rate106–108 , increase
in atrial arrhythmias106,107 and increased left ventricular mass.
The frequency of atrial fibrillation is increased in patients with subclinical
hyperthyroidism. A meta -analysis by Collet et al.110 pooled individual data from five
prospective cohort studies and found that subclinical hyperthyroidism is associated with
an increased risk of atrial fibrillation (hazard ratio of 1.68, confidence interv al of 1.16 –
2.43). The risk of atrial fibrillation was even higher if TSH levels were less than 0.10
mIU/L (hazard ratio 2.54) compared with 0.1 to 0.44 mIU/L (hazard ratio 1.63). Even
within the normal range, there was association between atrial fibrillati on and TSH levels
with individuals having TSH levels in the lower quartile having a higher risk of atrial
fibrillation compared to those in the highest quartile111. Higher risk of atrial fibrillation

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with subclinical hyperthyroidism is particularly evident in elderly persons.
All-cause mortality, especially that due to cardio -vascular disease was also
increased in the elderly population115. This supports treatment of subclinical
hyperthyroidism in the elderly age group.

4.7 Bone metabolism
While some stu dies showed no relation between subclinical hyperthyroidism and
increased bone turnover rate116,117, these studies are small and not double blinded with
results consistently seen only in pre -menopausal women.
Two meta -analyses assessed the effect of exoge neous subclinical hyperthyroidism
and concluded that suppressed TSH levels induced by L -thyroxine therapy increased the
risk of bone loss in postmenopausal women. Both studies did not show TSH suppressive
therapy to adversely affect bone mineral densitomet ry in pre -menopausal women. One
meta -analysis found that post -menopausal women had significant excess of annual bone
loss of 0.91% per year after 9.9 years in comparison to control119. The other meta –
analysis studied 1,250 subjects enrolled in 41 studies a nd noted significant bone loss in
the lumbar spine and femoral region in post -menopausal women.
Calcium supplementation has been shown to be protective against bone loss in
post-menopausal women on suppressive L -thyroxine therapy. Addition of intranasal
calcitonin did not appear to improve bone density as compared to calcium alone.
Exogeneous subclinical hyperthyroidism was not shown to affect bone metabolism in
men. Some, but not all, studies show an increased fracture risk in patients with
exogenous subc linical hyperthyroidism from thyroxine therapy124–126. Fracture risk
appears to be related to older age and degree of TSH suppression. If TSH levels remain
within the normal range, thyroxine therapy itself was not associated with the increased
risk of frac tures.
As for endogeneous subclinical hyperthyroidism, a few studies have shown

Page | 45
adverse effects on bone density in post -menopausal women. Two prospective studies
showed improvement in bone mineral densitometry following treatment of post –
menopausal women with endogenous subclinical hyperthyroidism. Pre -menopausal
patients with Graves’ Disease on maintenance anti -thyroid drug treatment whose TSH
remained suppressed had higher levels of serum and urinary bone turnover markers
compared to those in whom TSH le vels had normalised129. One study130 demonstrated an
increased fracture risk in older men, but not women, with endogenous subclinical
hyperthyroidism, while another11 failed to associate an increased risk of fractures with
elderly persons of either sex. In a small prospective study, there was no obvious
improvement in bone mineral densitometry after six months of treatment with
antithyroid drugs in premenopausal women with endogenous subclinical
hyperthyroidism. No prospective data are available for fractur e risk in treated versus
untreated women4.
The major difficulty in assessing the effects on bone loss stems from smaller
numbers of patients with endogeneous subclinical hyperthyroidism, fewer studies
compared to those on exogeneous subclinical hyperthyr oidism and difficulty
ascertaining duration of underlying disease14. Adverse bone effects appear to be related
to duration of disease as well as concomitant risk factors for osteoporosis80.
4.8 Cognitive impairment
With regard to cognitive impairment and dementia, data is conflicting. Some
authors suggest subclinical hyperthyroidism may be associated with dementia. In a study
involving 1843 participants aged 55 years and older followed up for an average of two
years, it was found that those with reduced TS H levels at baseline had a more than three –
fold increased risk of dementia and of Alzheimer’s disease, especially so in those
positive for anti -thyroid peroxidase antibodies133, suggesting possible role of
autoimmunity. Another two smaller studies correlat ing dementia patients and their TSH
levels found a positive association between dementia (especially vascular dementia) and

Page | 46
depressed TSH levels134,135. However, two cross sectional studies of older patients failed
to demonstrate an association with cognit ive impairment nor depression and
anxiety136,137. Thus it is difficult to draw a firm conclusion on the ill -effects of
subclinical hyperthyroidism on cognitive function and further studies are needed.

4.9 Special population groups affecting treatment cons iderations
Pregnant women
The diagnosis of true subclinical hyperthyroidism during pregnancy may be
difficult. As mentioned above, physiological changes of normal pregnancy may alter
thyroid function tests56. In the first trimester, there is a transient rise in free T4 and T3
due to weak thyroid -stimulating activity138 of peak levels of circulating hCG. The first –
trimester rise in free T4 and T3 is usually within the normal range, although this is
sometimes exceeded. This rise leads to concomitant TSH sup pression, sometimes to low
or undetectable levels56,139,140 leading to a biochemical picture which may be mistaken
for subclinical hyperthyroidism. Women with hyperemesis gravidarum may have higher
degrees of TSH suppression due to higher levels of circula ting hCG140 with higher
thyrotropic activity141–143. Biochemical changes in thyroid function due to physiological
changes of pregnancy do not require therapy144.
Graves Disease is the most common cause of hyperthyroidism during pregnancy.
Thyrotropin rece ptor antibody (TRAb) levels should be measured when the etiology of
hyperthyroidism in pregnancy is uncertain144. As maternal TRAb can cross the placenta
and affect foetal thyroid function, if TRAb is raised (particularly in gestational weeks
22–26) the pr egnancy should be monitored for evidence of foetal thyroid dysfunction59.
A study involving 25,765 women undergoing prenatal thyroid screening found a
prevalence of subclinical hyperthyroidism of 1.7%. Gestation in this group was less
likely tobe complicated by gestational hypertension. There was also no significant
difference for other adverse pregnancy and neonatal outcomes. Treatment of women

Page | 47
with subclinical hyperthyroidism during pregnancy was not recommended based on the
above findings. This is in line with recommendations of the Endocrine Society, which
concluded there was no evidence that treatment improves pregnancy outcome.

4.10 When should we treat?
No consensus exists with regard to the treatment of subclinical hyperthyroidism
with recommendations being based on expert opinion. Decision to treat and management
strategies would take into account factors such as underlying aetiology, severity of
disease (viz. degree of TSH suppression), presence of symptoms and the patient’s risk
factors (such as age, cardiovascular risk, osteoporotic risk).
The ATA/AACE guidelines state that for TSH levels persistently below 0.1
mIU/L, treatment should be strongly considered in the following: symptomatic
individuals, individuals above 65 years of a ge, post -menopausal women who are not on
estrogens or bisphosphonates; patients with cardiac risk factors, heart disease or
osteoporosis.
This is confirmed by other authors as the main aim in treatment is to prevent the
onset of associated complications, in particular atrial fibrillation, osteopenia and
osteoporosis.
When TSH is persistently below the lower limit of normal but above 0.1 mIU/L,
treatment of subclinical hyperthyroidism should be considered in the following:
symptomatic individuals, individu als above 65 years of age, patients with cardiac
disease144. The principal benefit of treatment in this population group is to prevent atrial
fibrillation.
The decision to treat should always be considered against the possible side effects
from treatment. Incidence of radioactive iodine -induced hypothyroidism is 3 –6% yearly
and patients generally have to be followed up lifelong.

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Anti-thyroid therapy may be complicated by 5 –10% incidence of allergic
dermatitis and serious drug reactions (such as agranulocyt osis and drug -induced
hepatitis). The latter may occur in approximately 0.3 –0.5% of patients13. We present our
recommended approach for subclinical hyperthyroidism in Fig. 2.

How do we treat?
Available treatment modalities are the same as that for overt hyperthyroidism:
anti-thyroid medications, radioactive iodine (RAI) and surgery.
The ATA/AACE guidelines recommend that the treatment of subclinical
hyperthyroidism be based on its etiology. RAI therapy is appropriate in the elderly as
toxic multinodular goitre is the most common cause144. A study using impedance
cardiography in women with endogenous subclinical hyperthyroidism undergoing RAI
has also noted success150.
Anti-thyroid therapy has also been found to be effective: improvements in various
cardi ac parameters have been reported in patients with endogenous subclinical
hyperthyroidism after restoration of euthyroidism with methimazole106. One study
involving elderly patients with subclinical hyperthyroidism and atrial fibrillation found
anti-thyroid therapy to be beneficial in restoring a normal sinus rhythm102.
Treatment with beta -blockers alone may be sufficient to control the
cardiovascular -related morbidity from subclinical hyperthyroidism, especially that from
atrial fibrillation39. In patients with Exogenous subclinical hyperthyroidism the addition
the cardio -selective beta-of blocker bisoprolol to thyroxine therapy for six months
significantly reduced the occurrence of supraventricular arrhythmias with improvement
of diastolic functi on.
The path forward
There are at least two ongoing randomised controlled trials regarding treatment of
subclinical hyperthyroidism. One of the trials aims to provide evidence that restoration

Page | 49
of euthyroidism (normal TSH) improves thyrotoxic symptoms and signs as well as the
quality of life, at the same time lowering the risk of subsequent atrial fibrillation and
bone loss in subjects with endogenous subclinical hyperthyroidism. Another randomised
controlled trial from the UK compares RAI versus usual car e in the elderly.

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CONCLUSIONS
 Subclinical hyperthyroidism of exogenous origin is most often due to overzealous
L-thyroxine replacement therapy. Treatments that suppress the thyroid gland,
such as thyroid hormone therapy for patien ts with neck irradiation earlier in a
patient’s life, or treatments for thyroid cancer, thyroid nodules, or goiter, can also
cause subclinical hyperthyroidism.
 Subclinical hyperthyroidism of endogenous origin is most often due to the
presence of an autono mously functioning thyroid adenoma or a multinodular
goiter, but may also be seen early in the course of Graves’ disease.
 Subclinical hyperthyroidism can be associated with subtly altered cardiac function
and clinically apparent heart disease.
 The effects on bone include a reduction in bone mineral density and an increase in
serum osteocalcin (a marker of bone formation) and urinary hydroxyproline and
pyrrolidine cross links (a marker of increased bone resorption or turnover)
 In addition to effects on bone and heart, subclinical hyperthyroidism is associated
with other potentially important biological changes. These include reductions in
serum total and LDL cholesterol as well as increases in serum glutathione S –
transferase, alanine aminotransferase, and
γ-glutamyltransferase. Serum creatine kinase levels also decline in subclinical
hyperthyroidism.
 Regardless of whether the cause of subclinical hyperthyroidism is exogenous or
endogenous, serum sex hormone -binding concentrations increase. Finally,
patients with subclinical hyperthyroidism have a reduced sleep requirement and
report a better mood than normal subjects.
 Low serum TSH (<0.1 mU/L) is associated with a threefold higher risk (versus
normal TSH) of atrial fibrillation.

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 Patients with low serum TSH l evels should be carefully monitored.
 Exogenous subclinical hyperthyroidism should be prevented or minimized by
careful titration of L -thyroxine using TSH measurements.
 The goal is to adjust the L -thyroxine dose to maintain normal serum TSH level.
The sma llest possible dose of L -thyroxine to attain this end should be employed.
 When L -thyroxine is given to suppress TSH secretion, to decrease goiter size,
prevent recurrent goiter, or control thyroid carcinoma, subclinical
hyperthyroidism is more likely to o ccur.
 Low TSH levels in endogenous hyperthyroidism are often transient, and mandate
a period of observation. Antithyroid treatment can be considered in cases where
TSH levels are very low or undetectable, and other contributing factors have been
ruled ou t.

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Declaration

I hereby declare that the diploma thesis entitled " Subclinical Thyroid Disorders "
is written by me and has not been presented before at another college or institution of
higher education in the country or abroad. Also, I declare that all sources used, including
the Internet sources, are indicated in the paper, considering the rules for avoiding
plagiarism: – all text f ragments are reproduced exactly, even the proper translations from
other languages are written in quotes and have detailed reference source; – paraphrasing
in own words of text written by other authors has detailed reference; – summary of the
ideas of othe r authors has a detailed reference to the original text.

Date 05.11.2015

Name and surname of student
Badarnah Amjad (Original signature)