Clinical Picture of Hyperthyroidism or Hypothyroidism
A woman reports fatigue and mild depression. The physical examination is unremarkable. No thyroid enlargement is present. Laboratory results include normal levels of haemoglobin, creatinine, and calcium and a normal erythrocyte sedimentation rate. The Thyroid Stimulating Hormone (TSH) level is 4.1 mIU per litre (reference range, 0.4 to 4.3), whereas the free thyroxine (T4) level is normal (19 pmol per litre; reference range, 11 to 25). How should she be further evaluated and her symptoms managed if, at all? After all, her results are within normal range so she must be fine, right?
Normal results – feeling crappy?
The only issue is that she doesn’t feel good so the decision comes down to either treating the person or the results. What she may have is subclinical hypothyroidism.
Subclinical hypothyroidism is biochemically defined as an elevated serum TSH level in combination with a serum free T4 level that is within the population reference range. The incidence of subclinical hypothyroidism varies among populations and ranges from 3 to 15%, with a higher incidence associated with increasing age, female sex, and a suboptimal iodine status. The relationship between serum TSH and free T4 is such that a small decrease in free T4 can result in a relatively large increase in serum TSH , which can subsequently lead to a TSH level that is above the reference range while the free T4 level is still within the reference range. In cases of progression to overt hypothyroidism, the TSH level typically continues to increase and the free T4 level falls below the reference range. In this respect, subclinical hypothyroidism can be seen as a mild form of thyroid failure, one that is caused by autoimmune thyroid disease in the majority of cases. A TSH cut-off level of 10 mIU per litre is commonly used to distinguish between mild and more severe subclinical hypothyroidism. Approximately 75% of patients with subclinical hypothyroidism have a TSH level of less than 10 mIU per litre.
Serum TSH and free T4 show substantial variability among healthy persons, whereas the range of variability within an individual healthy person tends to be relatively narrow. This finding suggests a unique set point of the hypothalamic–pituitary–thyroid axis for each person and probably explains why a TSH level of 10 mIU per litre can be accompanied by a normal free T4 level in one person but by a decreased free T4 level in another person.
Subclinical Hypothyroidism Symptoms
Although many patients with subclinical hypothyroidism are asymptomatic, such patients tend to report symptoms of overt hypothyroidism more often than age-matched controls; these symptoms are usually milder than those in patients with overt hypothyroidism and tend to increase in both number and severity with higher TSH levels. Some studies have shown higher rates of depressive symptoms and reduced quality of life, cognitive function, and memory among persons with subclinical hypothyroidism than among persons with normal thyroid function.
Increased rates of fatigue, muscle weakness, weight gain, cold intolerance, and constipation have also been reported variably in association with subclinical hypothyroidism. Elderly persons seem to have fewer symptoms than younger persons. One study involving patients older than 70 years of age even suggested that those who had subclinical hypothyroidism had a faster walking speed and better maintenance of physical function than did the euthyroid controls, but this finding was not confirmed in a more recent study.
Differences in study results may be related to differences in the way that patients were identified for inclusion in the studies (e.g., by biochemical screening of a population vs. selection of patients with pre-existing symptoms) as well as by differences in the age of the patients, the severity of the subclinical hypothyroidism, and the instruments that were used to assess symptoms.
What are the long-term consequences?
Concern exists regarding the long-term adverse effects of subclinical hypothyroidism, particularly with respect to the risk of cardiovascular disease. In a meta-analysis of individual participant data from 11 prospective cohorts totalling more than 55,000 participants, the risk of fatal and nonfatal events of coronary heart disease increased with higher baseline TSH levels, with hazard ratios for events of coronary heart disease of 1.00 (95% confidence interval , 0.86 to 1.18) among patients with a TSH level between 4.5 and 6.9 mIU per litre, 1.17 (95% CI, 0.96 to 1.43) among patients with a TSH level between 7.0 and 9.9 mIU per litre, and 1.89 (95% CI, 1.28 to 2.80) among patients with a TSH level between 10.0 and 19.9 mIU per litre (P<0.001 for trend). Subclinical hypothyroidism, particularly among persons with TSH levels of more than 7 mIU per litre, has also been associated with increased risks of congestive heart failure and fatal stroke in similar meta-analyses based on individual participant data. Subclinical hypothyroidism is associated with increased total cholesterol levels and low-density lipoprotein cholesterol levels and with subclinical measures of cardiovascular disease.
Obesity and Subclinical Hypothyroidism
Higher serum TSH levels are associated with increased body-mass index and increased waist circumference. However, substantial weight loss typically results in a decrease in the TSH level, which suggests that subclinical hypothyroidism is an unlikely cause of obesity.
Subclinical Hypothyroidism and Pregnancy
The risks of female infertility, spontaneous abortion, and other complications associated with pregnancy, such as gestational hypertension and preeclampsia, are increased in women with subclinical hypothyroidism and thyroid autoimmunity. During pregnancy, pronounced changes occur in thyroid homeostasis, including an increased demand for thyroid hormone, which is mediated by high levels of the pregnancy hormone human chorionic gonadotropin. These pregnancy-specific changes and the increased demand for thyroid hormone may worsen pre-existing mild thyroid dysfunction. Cut-off values for the levels of thyrotropin and free T4 for the diagnosis and treatment of subclinical hypothyroidism in pregnant women differ from those in nonpregnant women.
Hypothyroidism refers to the common pathological condition of thyroid hormone deficiency. If untreated, it can lead to serious adverse health effects and may be fatal as a result. Because of the large variation in clinical presentation and general absence of symptom specificity, the definition of hypothyroidism is predominantly biochemical. Overt or clinical primary hypothyroidism is defined as thyroid-stimulating hormone (TSH) concentrations above the reference range and free thyroxine concentrations below the reference range. Mild or subclinical hypothyroidism, which is commonly regarded as a sign of early thyroid failure, is defined by TSH concentrations above the reference range and free thyroxine concentrations within the normal range.
The Standard Treatment with Thyroxine
Whether the existing reference ranges of TSH and free thyroxine should be used to define thyroid dysfunction is a matter of debate. This issue is of clinical importance because the reference ranges are generally used as a threshold for treatment. Thyroid hormone replacement with levothyroxine (thyroxine) is the standard treatment for patients with hypothyroidism. However, a substantial proportion of patients treated with levothyroxine have persistent complaints despite reaching the biochemical therapy targets, which has prompted the question of whether levothyroxine treatment is sufficient for all patients or whether alternative therapies (e.g., combination with liothyronine preparations) could be adopted.
The prevalence and risk factors of hypothyroidism
The prevalence of overt hypothyroidism in the general population varies between 0·3% and 3·7% in the USA and between 0·2% and 5·3% in Europe,4–8 depending on the definition used. A meta-analysis of studies across nine European countries estimated the prevalence of undiagnosed hypothyroidism, including both overt and mild cases, at around 5%. Differences in iodine status affect the prevalence of hypothyroidism, which occurs more frequently both in populations with a relatively high iodine intake and in severely iodine-deficient populations. Hypothyroidism occurs more frequently in women, in older people (>65 years), and in white individuals, although data on ethnic differences are scarce. Hypothyroidism is more common in patients with autoimmune diseases, such as type 1 diabetes, autoimmune gastric atrophy, and coeliac disease, and can occur as part of multiple autoimmune endocrinopathies. Individuals with Downs’ syndrome or Turners’ syndrome have an increased risk of hypothyroidism. By contrast, tobacco smoking and moderate alcohol intake are associated with a reduced risk of hypothyroidism.
Signs and Symptoms of Hypothyroidism
Hypothyroidism has clinical implications related to nearly all major organs, but the cardiovascular system is the most robustly studied. Hypothyroidism results in increased vascular resistance, decreased cardiac output, decreased left ventricular function, and changes in several other markers of cardiovascular contractility.
Heart Disease and Hypothyroidism
Myocardial injuries and pericardial effusions are more common in patients with hypothyroidism than in matched euthyroid controls. Furthermore, patients with hypothyroidism have a higher prevalence of cardiovascular risk factors and often have features of metabolic syndrome, including hypertension, increased waist circumference, and dyslipidaemia. Hypothyroidism also increases total cholesterol, low-density lipoprotein, and homocysteine concentrations.
The association between hypothyroidism and coronary artery disease has been recognised for a long time.66 Subclinical hypothyroidism with TSH concentrations above 10 mIU/L has also been associated with an increased risk of heart failure. Patients with hypothyroidism undergoing percutaneous coronary intervention have more major adverse cardiovascular and cerebral events than those with normal thyroid function and those with adequately treated hypothyroidism. By contrast, the association with stroke is less evident and might be apparent only in younger individuals (<65 years).
Patients with hypothyroidism have fewer neurological deficits post-stroke than controls without elevated TSH concentrations; normally after a stroke localised hypothyroidism is observed as a result of deiodinase induction in the ischaemic brain area.
The risk of coronary heart disease in patients with subclinical hypothyroidism does not differ by thyroid peroxidase antibody concentrations, suggesting that autoimmunity per se is not a contributing factor to the association. Hypothyroidism can present with cognitive impairments and dementia but the association is controversial, because results from several population-based cohort studies showed a protective effect of elevated TSH concentrations on the risk of dementia.
Cognition Decline and Hypothyroidism
Patients with acute hypothyroidism, in the context of thyroid cancer treatment, show a decline in mood and quality of life. Hypothyroidism is considered a cause of reversible dementia; however, how often this occurs and in what proportion of patient’s dementia is truly reversible is unclear. Other manifestations include neurosensory, musculoskeletal, and gastrointestinal signs and symptoms. Because of the pleiotropic effects of thyroid hormone, hypothyroidism can also affect the course of other disorders. For example, statin intolerance is more prevalent in individuals with hypothyroidism than in controls without hypothyroidism.
Other diseases associated with hypothyroidism
Hypothyroidism has also been associated with non-alcoholic fatty liver disease, cancer mortality, arthritis, kidney dysfunction, and diabetes; however, in most cases causality is suggested but not proven.
Primary hypothyroidism is defined by TSH concentrations above the reference range (most commonly used 0·4–4·0 mIU/L) and free thyroxine concentrations below the reference range, which is dependent on the type of assay used and the population studied. The US Preventive Service Task Force has suggested reserving the term overt hypothyroidism for cases in which patients present with symptoms. However, such a definition is challenging in practice because of the large variability in presentation of even severe hypothyroidism. Additionally, patients might recognise previous symptoms only after the initiation of levothyroxine treatment.
TSH has circadian fluctuations, with higher concentrations towards the evening. Patients with severe hypothyroidism show irregularity of TSH secretion. Seasonal variations have also been described, with higher TSH concentrations in winter and spring than in autumn and summer. No indications exist for routine measurement of total tri-iodothyronine, total thyroxine, or free tri-iodothyronine. Measurement of thyroid peroxidase antibody is not strictly necessary to diagnose hypothyroidism but is useful to affirm the diagnosis of autoimmune primary hypothyroidism. Hypothyroidism is often characterised by a hypoechogenic pattern on thyroid sonography, even in the absence of raised thyroid peroxidase antibody concentrations. However, in the absence of additional clinical indications, such as abnormal thyroid palpation, an ultrasound is not required.
Reference ranges of thyroid function tests
Most commercially available TSH and free thyroxine assays are immunoassays, and their reference ranges are statistically defined as between the 2·5th and 97·5th percentile in an apparently healthy population. Therefore, the reference ranges do not consider symptoms or the risk of adverse events or disease, which is demonstrated by studies showing an increased risk of adverse events with variations in thyroid function even within these reference ranges. Furthermore, the reference ranges differ with age, sex, and ethnic origin.
The applied reference ranges for thyroid function have been a matter of debate in recent years. The upper limit of TSH reference ranges typically increases with age in adults, and age-specific reference ranges gave conflicting results in younger individuals in studies from the UK and Australia. Nevertheless, in both studies, the use of age-specific reference ranges led to a reclassification from abnormal to normal thyroid function predominantly in older individuals.
Hyperthyroidism is a pathological disorder in which excess thyroid hormone is synthesised and secreted by the thyroid gland. It is characterised by normal or high thyroid radioactive iodine uptake (thyrotoxicosis with hyperthyroidism or true hyperthyroidism). Thyrotoxicosis without hyperthyroidism is caused by extrathyroidal sources of thyroid hormone or by a release of preformed thyroid hormones into the circulation with a low thyroid radioactive iodine uptake. Hyperthyroidism can be overt or subclinical. Overt hyperthyroidism is characterised by low serum thyroid-stimulating hormone (TSH) concentrations and raised serum concentrations of thyroid hormones: thyroxine (T4), tri-iodothyronine (T3), or both. Subclinical hyperthyroidism is characterised by low serum TSH, but normal serum T4 and T3 concentrations.
Prevalence of hyperthyroidism
The prevalence of hyperthyroidism is 0·8% in Europe, and 1·3% in the USA. Hyperthyroidism increases with age and is more frequent in women. The prevalence of overt hyperthyroidism is 0·5–0·8% in Europe, and 0·5% in the USA. Data for ethnic differences are scarce, but hyperthyroidism seems to be slightly more frequent in white people than in other races. The incidence of mild hyperthyroidism is also reported to be higher in iodine-deficient areas than in iodine-sufficient areas, and to decrease after introduction of universal salt iodisation programmes.
What causes hyperthyroidism?
The most common cause of hyperthyroidism in iodine-sufficient areas is Graves’ disease. In Sweden, the annual incidence of Graves’ disease is increasing, with 15–30 new cases per 100 000 inhabitants in the 2000s. The cause of Graves’ disease is thought to be multifactorial, arising from the loss of immunotolerance and the development of autoantibodies that stimulate thyroid follicular cells by binding to the TSH receptor. Several studies have provided some evidence for a genetic predisposition to Graves’ disease; however, the concordance rate in monozygotic twins is only 17–35%, suggesting low penetrance. The genes involved in Graves’ disease are immune-regulatory genes (HLA region, CD40, CTLA4, PTPN22, and FCRL3) and thyroid autoantigens such as the thyroglobulin and TSH-receptor genes.
Non-genetic risk factors for development of Graves’ disease include psychological stress, smoking, and female sex. Given the higher prevalence of Graves’ disease in women, sex hormones and chromosomal factors, such as the skewed inactivation of the X chromosome, are suspected to be triggers. Other factors such as infection (especially with Yersinia enterocolitica, due to a mechanism of molecular mimicry with the TSH receptor), vitamin D and selenium deficiency, thyroid damage, and immunomodulating drugs are also suspected. Further studies to ascertain the more precise role of these factors in the cause of Graves’ disease are needed.
Other common causes of hyperthyroidism are toxic multi-nodular goiter and solitary toxic adenoma. Although in iodine-sufficient areas about 80% of patients with hyperthyroidism have Graves’ disease, toxic multi-nodular goiter and toxic adenoma account for 50% of all cases of hyperthyroidism in iodine-deficient areas, and are more predominant in elderly people. Thyroid nodules become autonomous and produce thyroid hormones independent of signals from either TSH or TSH-receptor antibodies Less common causes of hyperthyroidism include thyrotropin-induced thyrotoxicosis and trophoblastic tumours, in which TSH receptors are stimulated by excess TSH and human chorionic gonadotropin, respectively.
Complications seen in hyperthyroidism
Clinical manifestation varies depending on several factors, such as the patient’s age and sex, comorbidities, duration of the disease, and cause. Older patients present with fewer and less pronounced symptoms than do younger patients, but are more likely to develop cardiovascular complications. When compared with people older than 60 years with a healthy thyroid, those who are hyperthyroid have three times the risk of atrial fibrillation. Embolic stroke related to atrial fibrillation secondary to hyperthyroidism is significantly more prevalent than embolic stroke related to atrial fibrillation from non-thyroidal causes. However, anticoagulant therapy in patients with atrial fibrillation secondary to hyperthyroidism is still debated. Atrial fibrillation is also thought to be an independent predictor of the development of congestive heart failure in patients with hyperthyroidism.
An increased risk of all-cause mortality was reported in patients with hyperthyroidism, with heart failure being the main cause of cardiovascular events.
Another serious complication associated with hyperthyroidism is thyrotoxic periodic paralysis. It is more prevalent in Asian patients: incidence ranges from 0·2% in North America to 2% in Japan. It is characterised by the triad of muscle paralysis, acute hypokalaemia, and thyrotoxicosis, and caused by a shift of potassium into the muscle cells. Mutations in potassium channels, which are transcriptionally regulated by thyroid hormones, might be responsible for the disease. If suspected, treatment with low doses of potassium and non-selective β blockers should be initiated as soon as possible to prevent arrhythmias and restore muscle function.
Other complications of long-standing thyrotoxicosis include osteoporosis and abnormalities in the reproductive system, such as gynaecomastia in men and decreased fertility and menstrual irregularities in women.
Diagnosis of Hyperthyroidism
Serum TSH should be measured first, because it has the highest sensitivity and specificity in the diagnosis of thyroid disorders. If low, serum free T4 or free T4 index, and free or total T3 concentrations should be measured to distinguish between subclinical hyperthyroidism (with normal circulating hormones) and overt hyperthyroidism (with increased thyroid hormones). It also identifies disorders with increased thyroid hormone concentrations and normal or only slightly raised TSH concentrations, as in patients with TSH-secreting pituitary adenomas or peripheral resistance to thyroid hormone. The modalities preferred for assessing the cause of thyrotoxicosis vary widely. Different population characteristics, cultural backgrounds, and socioeconomic reasons partly explain these differences. American Thyroid Association (ATA) and American Association of Clinical Endocrinologists (AACE) guidelines for hyperthyroidism and thyrotoxicosis recommend a thyroid radioactive iodine uptake test, unless the diagnosis of Graves’ disease is established clinically. The use of thyroid ultrasound and assessment of TSH-receptor antibodies (TRAb; ie, thyroid-stimulating immunoglobulins, or thyroid-stimulating antibodies) are preferred in Europe, Japan, and Korea. The US guidelines consider measurement of TRAb as an alternative way to diagnose Graves’ disease, especially when the radioactive iodine uptake test is unavailable or contraindicated. This recommendation is shared by the Brazilian Thyroid Consensus that consider TRAb testing useful only in selected cases and prefer radioactive iodine uptake for initial assessment of thyrotoxicosis. In our clinical practice, we follow the approach of our European and Asian colleagues, using ultrasound and TRAb measurements.
A thyroid radioactive iodine uptake test in patients with Graves’ disease would show diffusely increased uptake. However, radioactive iodine uptake would be normal or high with an asymmetrical and irregular pattern in toxic multinodular goitre, and a localised and focal pattern in toxic adenoma, with suppressed uptake in the remaining thyroid tissue. Radioactive iodine uptake in patients with thyrotoxicosis from extrathyroidal sources of thyroid hormone or from release of preformed thyroid hormones, as in silent or painful thyroiditis, will be very low.
Thyroid ultrasound and thyroid radioactive iodine uptake have similar sensitivity for the diagnosis of Graves’ disease (95·2% and 97·4%, respectively). Advantages of ultrasound are absence of exposure to ionising radiation, and higher accuracy in the detection of thyroid nodules and lower cost than with radioactive iodine uptake. Moreover, colour-flow Doppler ultrasound differentiates between Graves’ disease (increased blood flow, diffusely enlarged hypoechogenic) and destruction-induced thyrotoxicosis (decreased blood flow). The differences in approach between European and American endocrinologists might be a result of the different epidemiology of hyperthyroidism, because nodular goitre is the predominant cause of hyperthyroidism in many European areas.
TRAb assays have become more reliable and inexpensive in recent years. Furthermore, TRAb measurements are useful to predict patients at risk for relapse after discontinuation of antithyroid drugs, and to detect fetal or neonatal thyrotoxicosis in women with Graves’ disease, since these antibodies readily cross the placenta.
The take home message of thyroid disorders
Firstly, the correct diagnosis is essential for the effective treatment of thyroid disease. After all, if you are treating a hyperthyroidism condition by boosting thyroid levels, you could easily get sicker and could even bring on a heart attack! Get it right by looking carefully at your symptom picture and as always, see a health care professional if you have any doubt.
The blood tests required for an accurate diagnosis are the following:
- Free T3
- Free T4
- Reverse T3 (rT3)
- Thyroid antibodies
Most commonly, a TSH is often ordered by your doctor just to screen for thyroid problems. This is fine if it is just part of a normal check-up but if you have thyroid symptoms, a full panel of thyroid hormones needs to be tested. In Australia, you may need to pay for your reverse T3 and thyroid antibodies however; the rest of the tests should be bulk billed.
Once you get these results, check them carefully. You may have (for example) a TSH of 4.2, where the upper range is 4.3, yet your results are within the ‘normal’ limits, but not the healthy range. No one wants ‘average’ results. We should be striving for optimal results for optimal health.