Hypothyroidism is an insidious condition with a significant morbidity, and the subtle and non- specific symptoms and signs may be mistakenly attributed to other illnesses, particularly in postpartum women and older people. The earliest biochemical abnormality is an increase in serum TSH concentration associated with normal serum free T4 and T3 concentrations (subclinical hypothyroidism or mild thyroid failure), followed by a decrease in serum free T4 concentration, at which stage, most patients have symptoms and benefit from treatment (overt hypothyroidism). In iodine- replete communities, the cause is either chronic autoimmune dis ease (atrophic autoimmune thyroiditis or goitrous autoimmune thyroiditis (Hashimoto’s thyroiditis)) or destructive treatment for hyperthyroidism, which may account for up to one- third of cases of hypothyroidism in the community.

congenital Hypothyroidism

 Congenital hypothyroidism affects approximately 1 newborn in 3500 to 4000 births and is the most treatable cause of intellectual disability. There is an inverse relationship between age at diagnosis and IQ in later life. In iodine- replete areas, 85% of the cases are due to sporadic developmental defects of the thyroid gland (thy roid dysgenesis), such as the arrested migration of the embryonic thyroid (ectopic thyroid) or a complete absence of thyroid tissue (athyreosis). The remaining 15% have thyroid dyshormonogenesis defects transmitted by an autosomal recessive mode of inheritance. Iodine deficiency (less than 25 μg per day), particularly in pre term infants, accounts for many cases in Eastern Europe, Asia, and Africa. Clinical diagnosis occurs in less than 5% of newborns with hypothyroidism because symptoms and signs are often minimal, so it is not possible to predict which infants are likely to be affected. Without prompt diagnosis and treatment, most affected children gradually develop growth failure, irreversible intellectual disability, and a variety of neuropsychological deficits. The apparent incidence of congenital hypothyroidism has more than doubled due to more inclusive diagnostic criteria, shifting demographics, and increasing survival of preterm infants. The greatest increase has occurred in mildly affected children. Congenital hypothyroidism may be transient or persistent, but the natural history cannot be predicted by severity at diagnosis. In premature infants, who are especially vulnerable to hypothyroidism, the rise in serum TSH may be delayed and therefore detected only by routine follow- up screening.

Asymptomatic Autoimmune Thyroiditis

 Raised serum concentrations of thyroid antibodies (antithyroid peroxidase (microsomal) (TPOAb) and antithyroglobulin (TGAb)) correlate with the presence of focal thyroiditis in thyroid tissue obtained by biopsy and at autopsy from patients with no evidence of hypothyroidism during life. Early post- mortem studies confirmed histological evidence of chronic autoimmune thyroiditis in 27% of adult women, with a rise in frequency over 50 years, and 7% of adult men, and diffuse changes in 5% of women and 1% of men. Patients with hypothyroidism caused by either atrophic or goitrous autoimmune thyroiditis usually have high serum concentrations of these same antibodies. These antibodies also are often detected in serum of patients with Graves’ disease and other thyroid diseases, but the concentrations are usually lower. There is considerable variation in the frequency and distribution of antithyroid antibodies because of variations in techniques of detection, definition of abnormal titres, and inherent differences in the populations tested.

A significant proportion of subjects in the community have asymptomatic chronic autoimmune thyroiditis of whom a substantial proportion have subclinical hypothyroidism (Figure 1). In the NHANES III survey the percentage of subjects with high serum thyroid peroxidase (TPO) and TG antibody concentrations increased with age in both men and women, and high concentrations were more prevalent in women than in men and less prevalent in blacks than in other ethnic groups. Using a competitive immunoassay procedure, the reported prevalence of detectable TGAb and TPOAb levels were 10% and 12% in the healthy population.

Fig1. Age and sex distribution of thyroid microsomal antibodies (Ab), raised serum TSH greater than 6 mU/ L (↑TSH), visible diffuse and multinodular goitre (G), and nodules (N) in the Whickham survey. Reproduced with permission from Tunbridge WMG, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al. The spectrum of thyroid disease in the community: the Whickham survey. Clin Endocrinol, 1977; 7: 485. Copyright © 2008, John Wiley and Sons, Blackwell Science.

A hypoechoic ultrasound pattern may precede TPOAb positivity in autoimmune thyroid disease, and TPOAb may not be detected in more than 20% of individuals with ultrasound evidence of thyroid autoimmunity.

Prevalence of Hypothyroidism

In iodine- replete communities, the prevalence of spontaneous hypothyroidism is between 1% and 2%, and it is more common in older women and ten times more common in women than in men. In the Whickham survey, the prevalence of previously diagnosed and treated hypothyroidism was 14/ 1000 women, increasing to 19/ 1000 women when possible, but unproven, cases were included. The overall prevalence in men was less than 1/ 1000. One- third had been previously treated by surgery or radioiodine for thyrotoxicosis. The mean age at diagnosis was 57 years. The Whickham data are com parable with other studies where the prevalence of newly diagnosed hypothyroidism ranged between 0.6 and 12/ 1000 women and between 1.3 and 4.0/ 1000 in men investigated in Northern Europe, Japan, and the United States. In the Colorado and NHANES III studies, the prevalence was 4/ 1000 and 3/ 1000, respectively. The prevalence is higher in surveys of older people in the community and lower in areas of iodine deficiency. The testing of hospital inpatients, predominantly elderly women, confirm a prevalence of 2%.

Subclinical Hypothyroidism

 The term subclinical hypothyroidism represents a compensated state in which increased TSH output is required to maintain normal circulating thyroid hormone levels. An elevated serum TSH is a sensitive indicator of some degree of thyroid failure and, in contrast to below normal serum TSH levels, a clear inverse relationship is found with free T4 levels. It is found either post radioiodine therapy or post surgery in up to 50% of apparently euthyroid patients. It may be evident for only a few months, but more often it represents a stage in the progression towards overt thyroid failure. Less frequent causes include external beam irradiation of malignant tumours of the head and neck, and drugs including lithium, amiodarone, and undiagnosed Addison’s disease. In the community, the most common aetiology is chronic autoimmune thyroiditis.

With respect to epidemiological studies, the definition of subclinical hypothyroidism varies from any increase in serum TSH to values more than 10 mU/ L or, more stringently, a serum TSH value more than 10 mU/ L and a positive test for circulating thyroid antibodies in serum. The term implies that patients should be asymptomatic, although symptoms are difficult to assess, especially in those in whom thyroid function tests have been checked because of non- specific complaints such as tiredness. Spontaneous recovery has also been described in subjects with subclinical hypothyroidism, although the frequency of this phenomenon is unclear. Normalization of serum TSH concentrations is more likely to occur in patients with negative antithyroid antibodies and serum TSH levels less than 10 mU/ L, and within the first 2 years after diagnosis.

Controversy exists regarding the upper limit of the reference range for serum TSH. Reference ranges are derived from a reference population that comprises a large group of subjects who do not have thyroid disease and are otherwise well. By convention, a reference range usually only comprises 95% of a reference population. Thus, 2·5% of ‘normal’ individuals will fall above the reference range and 2·5% will fall below the range. For serum TSH, the reference population shows a log normal distribution and has a diurnal variation with the reference range in thyroid disease- free individuals typically cited as between 0.4 and 4.0 mU/ L. The serum TSH reference range varies in different ethnic communities, trimesters of pregnancy, and progressively shifts towards higher concentration with age. Analysis of the NHANES III data suggest that the reference range for serum TSH rises with age as the 97.5 centile for those subjects aged more than 80 years was 7.49 mU/ L and 70% had a serum TSH more than the population defined upper limit of the reference range of 4.5 mU/ L of whom only 40% were antithyroid antibody positive.

In the original Whickham survey, 8% of women (10% of women over 55 years of age) and 3% of men had subclinical hypothyroidism. In the Colorado study, 9.4% of the subjects had a high serum TSH concentration, of whom 9.0% had subclinical hypothyroidism. Among those with a high serum TSH concentration, 74% had a value of between 5.1 and 10 mU/ L and 26% had a value greater than 10 mU/ L. The percentage of subjects with a high serum TSH concentration was higher for women than men in each decade of age and ranged from 4% to 21% in women and 3% to 16% in men. The NHANES III study found that 11% of those aged 20 to 29 had a serum TSH greater than 2.5 mU/ L, increasing to 40% in those aged 80 and over. Serum TSH concentrations were higher in whites than blacks, independent of serum antithyroid antibody concentrations. Approximately 2% of adolescents aged 12 to 19 years had a serum TSH greater than 4.5 mU/ L. Community studies of elderly persons have confirmed approximately 10% of subjects over 60 years having serum TSH values above the normal range. Subclinical hypothyroidism is found at higher frequency in areas where iodine intake is high most cases are not of autoimmune origin (Table 1). In surveys of hospital inpatients, the point prevalence rates were similar being between 3% and 6% with most subjects reverting to normal thyroid function three months following the acute illness.

Table1. The effect of environmental iodine intake on the prevalence of subclinical thyroid disease

Incidence of Hypothyroidism

After destructive treatment of hyperthyroidism with either radioiodine or surgery, the incidence of overt hypothyroidism is greatest in the first year. The incidence of hypothyroidism in patients with Graves’ disease was higher than that in patients with nodular goitre (55% vs. 32%) and increased in those given higher doses of radioiodine. If subclinical hypothyroidism is present one year or more after radioiodine or surgical treatment, then the annual rate of progression to overt hypothyroidism after either treatment is 2– 6%. Treatment of Graves’ disease with antithyroid drugs alone is also associated with the eventual development of hypothyroidism in 5– 20% of cases from either auto immune thyroiditis or the presence of TSH- blocking antibodies. The incidence of hypothyroidism after surgery, external radiation therapy of the neck, or both, in patients with head and neck cancer (including lymphoma) is as high as 50% within the first year after treatment, particularly in patients who underwent surgery and received high doses of radiation. The effect is dose- dependent, the onset is gradual, and subclinical hypothyroidism can be present for many years prior to the development of overt disease.

At the 20- year follow- up of the Whickham cohort the mean annual incidence of spontaneous hypothyroidism in the surviving women during the 20- year follow- up period was 3.5/ 1000 (95% CI, 2.8– 4.5), increasing to 4.1/ 1000 (95% CI, 3.3– 5.0) if all cases including those who had received destructive treatment for thyrotoxicosis were included [16]. The hazard rate increased with age to 13.7/ 1000 in women 75 to 80 years of age (Figure 2). The mean annual incidence during the 20- year follow- up period in men (all spontaneous except for one case of lithium- induced hypothyroidism) was 0.6/ 1000 (95% CI, 0.3– 1.2). The risk of having developed hypothyroidism was examined with respect to risk fac tors identified in the first survey. Either raised serum TSH or positive antithyroid antibodies alone or in combination are associated with a significantly increased risk of hypothyroidism in surviving women (Table 2). The annual risk of spontaneous overt hypothyroidism was 4% in those who had both high serum TSH and antithyroid antibody concentrations, 3% if only their serum TSH concentrations was high, and 2% if only their serum thyroid antibody concentration was high; at the time of follow- up the respective rates of hypothyroidism were 55%, 33%, and 27%. The probability of developing hypothyroidism was higher in those women who had serum TSH concentrations above 2.0 mU/ L and high serum titres of antithyroid microsomal antibodies at the first survey (Figure 3). Neither a positive family history of any thyroid disease, nor the presence of a goitre at either the first or the follow- up survey, or parity at first survey was associated with an increased risk of hypothyroidism.

Fig2. Age- specific hazard rates for the development of overt hyperthyroidism and hypothyroidism in women at 20- year follow- up of the Whickham survey. Reproduced with permission from Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: a twenty- year follow- up of the Whickham survey. Clin Endocrinol, 1995; 43: 60. Copyright © 2008, John Wiley and Sons, Blackwell Science.

Table2. Development of spontaneous hypothyroidism in surviving women and men at 20- year follow- up of Whickham survey: odds ratios (with 95% CI)

Fig3. Probability for development of hypothyroidism within 20 years with increasing values of serum TSH at first Whickham survey in 912 survivors. Reproduced with permission from Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: a twenty- year follow- up of the Whickham survey. Clin Endocrinol, 1995; 43: 60. Copyright © 2008, John Wiley and Sons, Blackwell Science.

Other incidence data for hypothyroidism are from short (and often small) follow- up studies and confirm that serum TSH concentrations in the upper part of the normal range in this study have a predictive value. In Tayside, UK the standardized incidence of primary hypothyroidism remained between 3.90 and 4.89/ 1000 women per year between 1993 and 2001. The incidence of hypothyroidism in men however significantly increased from 0.65 to 1.01/ 1000 per year (P = 0.0017) and the mean age at diagnosis of primary hypothyroidism decreased in women from 1994 to 2001.

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مواضيع ذات صلة

Thyroid Disease in Pregnancy

Hyperthyroidism

Clinical Manifestations of Iron Deficiency

Thyroid Imaging: nuclear Medicine Techniques - Thyroiditis

Thyroid Imaging: nuclear Medicine Techniques - Thyrotoxicosis

Pathobiology of Iron Deficiency

Outcome and Prevention of Infectious Diseases

Serum and Tissue Thyroid Hormone concentrations in NTI

Microorganism Entry, Invasion, and Dissemination: The Host’s Perspective

Microorganism Colonization of Host Surfaces

The Encounter Between Host and Microorganism

Systemic Approach to Anemia