Hypothyroidism And Hyperthyroidism Flashcards
The metabolism of virtually all nucleated cells of many tissues is controlled by what hormones
Thyroid hormones
Overactivity or under-activity of which gland is the most common of all endocrine problems
Thyroid gland
What is the anatomy of the thyroid gland
The thyroid gland consists of two lateral lobes connected by
an isthmus. It is closely attached to the thyroid cartilage and to the upper end of the trachea, and thus moves on swal-
lowing. It is often palpable in normal women.
Embryologically it originates from the base of the tongue
and descends to the middle of the neck. Remnants of thyroid
tissue can sometimes be found at the base of the tongue
(lingual thyroid) and along the line of descent. The gland has a rich blood supply from superior and inferior thyroid arteries.
The thyroid gland consists of follicles lined by cuboidal
epithelioid cells. Inside is the colloid (the iodinated glycopro-
tein thyroglobulin) which is synthesized by the follicular cells.
Each follicle is surrounded by basement membrane, between
which are parafollicular cells containing calcitonin-secreting
C cells.
What are the two hormones synthesized by the thyroid gland
Triiodothyronine (T3), which acts at the cellular level
L-thyroxine (T4), which is the prohormone
What’s the physiology behind thyroid hormone synthesis
Inorganic iodide is trapped by the gland by an enzyme dependent system, oxidized and incorporated into the glycoprotein thyroglobulin to form mono- and diodotyrosine and then T4 and Tz (Fig. 19.16).
More T4 than T3 is produced, but T4 is converted in some peripheral tissues (liver, kidney and muscle) to the more active T3 by 5’-monodeiodination; an alternative 3’-mono-deiodination yields the inactive reverse T3 (rTs). The latter step occurs particularly in severe non-thyroidal illness (see below).
In plasma, more than 99% of all T4 and Ty is bound to hormone-binding proteins (thyroxine-binding globulin, TBG; thyroid-binding prealbumin, TBPA; and albumin). Only free hormone is available for action in the target tissues, where Ty binds to specific nuclear receptors within target cells.
Many drugs and other factors affect TBG; all may result in confusing total T4 levels in blood, and most laboratories therefore now measure free T4 levels.
How is the hypothalamic-pituitary-thyroid axis controlled
Thyrotrophin-releasing hormone (TH), a peptide produced in the hypothalamus, stimulates the pituitary to secrete thyroid-stimulating hormone (TSH). TSH in turn stimulates growth and activity of the thyroid follicular cells via the G-protein coupled TSH membrane receptor (see Table
19.3). The T3 and T4 subsequently secreted into the circulation by follicular cells exert negative feedback on the hypothalamus.
Circulating Ta is peripherally deiodinated to T which binds to the thyroid hormone nuclear receptor (TR) on target organ cells to cause modified gene transcription. There are two TR receptors (TR-a and TR-B) and the tissue-specific effects of Ty are dependent upon the local expression of these TR receptors. TR-a knockout mice show poor growth, bradycardia and hypothermia, whilst TR-B knockout mice show thyroid hyperplasia and high Ta levels in the presence of inappropriately normal circulating TSH, suggesting a role for the latter receptors in thyroid hormone resistance
What is the dietary iodine requirement
Globally, dietary iodine deficiency is a major cause of thyroid disease, as iodine is an essential requirement for thyroid hormone synthesis. The recommended daily intake of iodine should be at least 140 Mg, and dietary supplementation of salt and bread has reduced the number of areas where ‘endemic goitre’ still occurs
Describe thyroid function tests
Immunoassays for free T4, free T3 and TSH are widely avail-able. There are only minor circadian rhythms, and measurements may be made at any time. Particular uses of the tests are summarized in Table 19.13, with typical findings in common disorders.
TSH measurement
In most circumstances, TSH levels can discriminate between hyperthyroidism, hypothyroidism and euthyroidism (normal thyroid gland function). Exceptions are hypopituitarism, and the ‘sick euthyroid’ syndrome where low levels (which normally imply hyperthyroidism) occur in the presence of low or normal T4 and T levels. As a single test of thyroid function TSH is the most sensitive in most circumstances, but accurate diagnosis requires at least two tests, e.g. TSH plus free Ta or free Ts where hyperthyroidism is suspected, TSH plus serum free T4 where hypothyroidism is likely.
TRH test
This has been rendered almost obsolete by modern sensitive
TSH assays except for investigation of hypothalamic-pituitary dysfunction. TRH (protirelin) is occasionally used to differentiate between thyroid hormone resistance and TSHoma in the context of raised fT and TSH levels. Typically, after TH administration there is a rise in TSH in thyroid hormone resist-ance, whilst in TSHoma there is a flat response due to continued autonomous TSH secretion which does not respond to TRH.
What are some problems in the interpretation of thyroid function tests
- Serious acute or chronic illness
Thyroid function is affected in several ways:
• Reduced concentration and affinity of binding proteins
• Decreased peripheral conversion of T4 to Ts with more rTs
• Reduced hypothalamic-pituitary TSH production.
Systemically ill patients can therefore have an apparently low total and free T4 and Tz with a normal or low basal TSH (the ‘sick euthyroid’ syndrome). Levels are usually only mildly below normal and are thought to be mediated by interleukins IL-1 and IL-6; the tests should be repeated after resolution of the underlying illness. - Pregnancy and oral contraceptives
These lead to greatly increased TBG levels and thus to high or high-normal total T4. Free Ta is usually normal. Normal ranges for free T4 and TSH alter with the normal physiological changes during pregnancy and TSH is often slightly suppressed in the first trimester, but this rarely causes clinical problems. - Drugs
Amiodarone decreases T4 to T3 conversion and free Ta levels may therefore be above normal in a euthyroid patient; conversely amiodarone may induce both hyper- and hypothyroidism - the TSH level is usually reliable.
Many drugs affect thyroid function tests by interfering with protein binding but this now rarely causes a problem with free T4 assays.
What are anti thyroid antibodies
Serum antibodies to the thyroid are common and may be either destructive or stimulating; both occasionally co-exist in the same patient. Destructive antibodies are directed against the microsomes or against thyroglobulin; the antigen for thyroid microsomal antibodies is the thyroid peroxidase (TPO) enzyme.
TPO antibodies are found in up to 20% of the normal population, especially older women, but only 10-20% of these develop overt hypothyroidism.
TSH receptor IgG antibodies (TRAb) typically stimulate, but occasionally block, the receptor; they can be measured in two ways:
• By the inhibition of binding of TSH to its receptors (TSH-binding inhibitory immunoglobulin, TBIl)
• By demonstrating that they stimulate the release of cyclic AMP (thyroid-stimulating immunoglobulin/antibody TSI, TSAb).
What is the pathophysiology of hypothyroidism
Underactivity of the thyroid is usually primary, from disease of the thyroid, but may be secondary to hypothalamic-pituitary disease (reduced TSH drive).
What are some causes of primary hypothyroidism
Atrophic (autoimmune) hypothyroidism. This is the most common cause of hypothyroidism and is associated with antithyroid autoantibodies leading to lymphoid infiltration of the gland and eventual atrophy and fibrosis. It is six times more common in females and the incidence increases with age. The condition is associated with other autoimmune disease such as pernicious anemia, vitiligo and other endocrine deficiencies (p. 939). Occasionally intermittent hypothyroidism occurs with subsequent recovery; antibodies which block the TSH receptor may sometimes be involved in the aetiology.
Hashimoto’s thyroiditis. This form of autoimmune thyroiditis, again more common in women and most common in late middle age, produces atrophic changes with regeneration, leading to goitre formation. The gland is usually firm and rubbery but may range from soft to hard. TPO antibodies are present, often in very high titres (>1000 IU/L). Patients may be hypothyroid or euthyroid, though they may go through an initial toxic phase, ‘Hashi-toxicity’. Levothyroxine therapy may shrink the goitre even when the patient is not hypothyroid.
Postpartum thyroiditis. This is usually a transient phenomenon observed following pregnancy. It may cause hyperthyroidism, hypothyroidism or the two sequentially. It is believed to result from the modifications to the immune system necessary in pregnancy, and histologically is a lymphocytic thyroiditis. The process is normally self-limiting, but when conventional antibodies are found there is a high chance of this proceeding to permanent hypothyroidism.
Postpartum thyroiditis may be misdiagnosed as postnatal depression, emphasizing the need for thyroid function tests in this situation.
What are some defects of thyroid hormone synthesis
lodine deficiency. Dietary iodine deficiency still exists in some areas as ‘endemic goitre’ where goitre, occasionally massive, is common. The patients may be euthyroid or hypothyroid depending on the severity of iodine deficiency.
The mechanism is thought to be borderline hypothyroidism leading to TSH stimulation and thyroid enlargement in the face of continuing iodine deficiency.
Dyshormonogenesis. This rare condition is due to genetic defects in the synthesis of thyroid hormones; patients develop hypothyroidism with a goitre. One particular familial form is associated with sensorineural deafness due to a deletion mutation in chromosome 7, causing a defect of the transporter pendrin (Pendred’s syndrome)
What are some clinical features of hypothyroidism
Hypothyroidism produces many symptoms. The alternative term ‘myxoedema’ refers to the accumulation of mucopoly-saccharide in subcutaneous tissues. The classic picture of the slow, dry-haired, thick-skinned, deep-voiced patient with weight gain, cold intolerance, bradycardia and constipation makes the diagnosis easy. Milder symptoms are, however, more common and hard to distinguish from other causes of nonspecific tiredness. Many cases are detected on biochemical screening.
Special difficulties in diagnosis may arise in certain circumstances:
• Children with hypothyroidism may not show classic features but often have a slow growth velocity, poor school performance and sometimes arrest of pubertal development.
• Young women with hypothyroidism may not show obvious signs. Hypothyroidism should be excluded in all people with oligomenorrhoea/amenorrhoea, menorrhagia, infertility or hyperprolactinaemia.
• The elderly show many clinical features that are difficult to differentiate from normal ageing.
What are some investigations for primary hypothyroidism
Serum TSH is the investigation of choice; a high TSH level confirms primary hypothyroidism. A low free T4 level confirms the hypothyroid state (and is also essential to exclude TSH deficiency if clinical hypothyroidism is strongly suspected and TSH is normal or low).
Thyroid and other organ-specific antibodies may be pres-ent. Other abnormalities include the following:
• Anaemia, which is usually normochromic and normocytic in type but may be macrocytic (sometimes this is due to associated pernicious anaemia) or microcytic (in women, due to menorrhagia)
• Increased serum aspartate transferase levels, from muscle and/or liver
• Increased serum creatine kinase levels, with associated myopathy
• Hypercholesterolaemia and hypertriglyceridaemia
• Hyponatraemia due to an increase in ADH and impaired free water clearance.
What is the clinical improvement for hypothyroidism
Replacement therapy with levothyroxine (thyroxine, i.e. T4) is given for life. The starting dose will depend upon the severity of the deficiency and on the age and fitness of the patient, especially their cardiac performance: 100 mg daily for the young and fit, 50 Mg (increasing to 100 Mg after 2-4 weeks) for the small, old or frail. People with ischaemic heart disease require even lower initial doses, especially if the hypothyroidism is severe and longstanding. Most physicians would then begin with 25 Mg daily and perform serial ECGs, increasing the dose at 3- to 4-week intervals if angina does not occur or worsen and the ECG does not deteriorate. Occasional patients develop ‘thyrotoxic’ (hyperthyroid) symptoms despite normal fT4 levels if dose if increased too rapidly.
Monitoring. The aim is to restore T4 and TSH to well within the normal range. Adequacy of replacement is assessed clinically and by thyroid function tests after at least 6 weeks on a steady dose. If serum TSH remains high, the dose of T4 should be increased in increments of 25-50 g with the tests repeated at 6-8 weeks intervals until TSH becomes normal.
Complete suppression of TSH should be avoided because of the risk of atrial fibrillation and osteoporosis. The usual maintenance dose is 100-150 ug given as a single daily dose. An annual thyroid function test is recommended - this is usually performed in the primary care setting, often assisted and prompted by district thyroid registers’.
Clinical improvement on T4 may not begin for 2 weeks or more, and full resolution of symptoms may take 6 months.
The necessity of lifelong therapy must be emphasized and the possibility of other autoimmune endocrine disease devel-oping, especially Addison’s disease or pernicious anaemia, should be considered. During pregnancy, an increase in T4 dosage of about 25-50 ug is often needed to maintain normal TSH levels, and the necessity of optimal replacement during pregnancy is emphasized by the finding of reductions in cognitive function in children of mothers with elevated TSH during pregnancy.
A few people with primary hypothyroidism complain of incomplete symptomatic response to T4 replacement. Combination T4 and T3 replacement has been advocated in this context, but randomized clinical trials show no consistent benefit in quality of life symptoms.
