Disorders of the Thyroid Gland

DISORDERS OF THE THYROID GLAND M.A. Keshavarz M.D. Assistant of Professor of Endocrinology Qazvin University of Medical Sciences • The normal thyroid is 12–20 g in size, highly vascular, and soft in consistency and consists of two lobes connected by an isthmus… Regulation of thyroid hormone synthesis • TSH is the dominant hormonal regulator of thyroid gland growth and function…its highest levels occur at night…. • A variety of growth factors, most produced locally in the thyroid gland, also influence thyroid hormone synthesis… • Cytokines and interleukins… • IGF-1… • Iodine excess & deficiency… THYROID EVALUATION  Determining serum thyroid hormone levels…  Measuring thyroid autoantibodies…  Imaging thyroid gland size and architecture…  Performing a thyroid gland biopsy (FNA)… THYROID HORMONE LEVELS • Serum TSH is measured by a third-generation immuno-metric assay and Total serum T4 and T3 by radioimmunoassay… • The plasma-binding proteins; increase the pool of circulating hormone, delay hormone clearance, and may modulate hormone delivery to selected tissue sites…including:  Thyroxine-binding globulin (TBG)  Transthyretin (TTR)  Albumin...  Two direct methods are used to measure unbound thyroid hormones : 1) unbound thyroid hormone competition with radiolabeled T4 (or an analogue) for binding to a solid-phase antibody… 2) physical separation of the unbound hormone fraction by ultracentrifugation or equilibrium dialysis…  An indirect method that is now less commonly used to estimate unbound thyroid hormone levels is to calculate the free T3 or free T4 index from the total T4 or T3 concentration and the thyroid hormone binding ratio (THBR). • The latter is derived from the T3-resin uptake test, which determines the distribution of radiolabeled T3 between an absorbent resin and the unoccupied thyroid hormone binding proteins in the sample… Abnormalities of Thyroid Hormone Binding Proteins Thyroid Autoantibodies • About 5–15% of euthyroid women and up to 2% of euthyroid men have thyroid antibodies; such individuals are at increased risk of developing thyroid dysfunction… • Almost all patients with autoimmune hypothyroidism, and up to 80% of those with Graves’ disease, have TPO antibodies, usually at high levels. • TSIs are antibodies that stimulate the TSH-R in Graves’ disease…(TRAb) • The main use of these assays is to predict neonatal thyrotoxicosis caused by high maternal levels of TRAb or TSI ( > 3 × upper limit of normal) in the last trimester of pregnancy…. • Serum Tg levels are increased in all types of thyrotoxicosis except thyrotoxicosis factitia caused by self-administration of thyroid hormone…. • Tg levels are particularly increased in thyroiditis, reflecting thyroid tissue destruction and release of Tg… • The main role for Tg measurement, however, is in the follow-up of thyroid cancer patients... TFT IN HYPOTHYROIDISM When T4 is lower than normal, always TSH is more than 10miu/ml • IN CASES THAT THIS RULE IS NOT SEEN; WHAT IS THE DIFF. DIGNOSIS:  Central hypothyroidism  Transition period from hyperthyroidism to Hypothyroidism  Decreased TBG  SES  T3 is the last parameters that declines in hypothyroidism.  If T3 is decreased but T4 is normal, what is diagnosis…? Non-Thyroidal Illness (SES)  Very common in hospitalized patients…  Low T3 is the hallmark of TFT…  T4 may be normal (usually), low or mildly high  TSH may be normal (usually), low or mildly high (usually<10miu/l) TFT IN HYPERTHYROIDISM Suppressed TSH is the earliest change in hyperthyroid TFT…  IF T4 IS ABOVE NL BUT TSH IS NOT SUPPRESSED WHAT IS DIFF. DIAGNOSIS…?  Antibodies (resoluion: use of other lab method …)  T4 treatment in hypothyroid patient (history)  TBG effect (T3RU…)  Transition period (history)  Familial dysalbuminemia (FreeT4 by dialysis …)  TSH secreting tumors or TRH … • TESTES MUST BE REQUESTED IN…  Hypothyroidism diagnosis : TSH (or TSH & T4)  Hypothyroidism follow up : TSH  Hyperthyroidism diagnosis : TSH & T4 (or TSH & T4 & T3)  Hyperthyroidism follow up: TSH & T4 & T3  Inpatients : TSH & T4 & T3 & T3RU CASES T4=5-12 , T3=90-190 , TSH=./5- 4.5 , T3RU=25-35% 1) T4=4 , T3=90 ,TSH=50 , T3RU=26% 2) T4=4 , T3=30 ,TSH=4 , T3RU =35% 3) T4=4 , T3=90 ,TSH=3 , T3RU=40% 4) T4=3, T3=80 ,TSH=8, T3RU=25% HYPOTHYROIDISM • The WHO estimates that about 2 billion people are iodine-deficient, based on urinary excretion data… • In areas of iodine sufficiency; autoimmune disease (Hashimoto’s thyroiditis) and iatrogenic causes are most common… Neonatal hypothyroidism • Hypothyroidism occurs in about 1 in 4000 newborns...and is due to: o thyroid gland dysgenesis in 80–85% o inborn errors of thyroid hormone synthesis in 10–15% o TSH-R antibody-mediated in 5% of affected newborns • The developmental abnormalities are twice as common in girls and the majority of infants appear normal at birth, but <10% are diagnosed based on clinical features, which include:  prolonged jaundice,  feeding problems,  hypotonia,  enlarged tongue,  delayed bone maturation,  umbilical hernia… • These are generally based on measurement of TSH or T4 levels in heel-prick blood specimens… • T4 is instituted (after diagnosis), at a dose of 10–15 μg /kg per day, and the dose is adjusted by close monitoring of TSH levels… • T4 requirements are relatively great during the first year of life… early treatment with T4 results in normal IQ levels, but subtle neuro-developmental abnormalities may occur in: i. With the most severe hypothyroidism at diagnosis ii. When treatment is delayed or suboptimal… • Iodine deficiency remains a common cause of hypothyroidism worldwide… • In areas of relative iodine deficiency, there is an increased prevalence of goiter and, when deficiency is severe, hypothyroidism and cretinism… • Iodine supplementation of salt, bread, and other food substances has markedly reduced the prevalence of cretinism… • In addition to overt cretinism, mild iodine deficiency can lead to subtle reduction of IQ… • The recommended average daily intake of iodine is 150–250 μg/d for adults, 90–120 μg/d for children, and 250 μg/d for pregnant and lactating women… • Urinary iodine is > 10 μg/dL in iodine-sufficient populations… Autoimmune Hypothyroidism • There is a marked lymphocytic infiltration of the thyroid with germinal center formation in Hashimoto’s thyroiditis … • The mean annual incidence rate of autoimmune hypothyroidism is up to 4 per 1000 women and 1 per 1000 men. • It is more common in certain populations, such as the Japanese, probably because of genetic factors and chronic exposure to a highiodine diet... • The mean age at diagnosis is 60 years, and the prevalence of overt hypothyroidism increases with age... • Subclinical hypothyroidism is found in 6–8% of women and 3% of men... And the annual risk of developing clinical hypothyroidism is about 4% when subclinical hypothyroidism is associated with positive TPO antibodies… • Antibodies to TPO and Tg are clinically useful markers of thyroid autoimmunity, but any pathogenic effect is restricted to a secondary role in amplifying an ongoing autoimmune response. • Up to 20% of patients with autoimmune hypothyroidism have antibodies against the TSH-R, and these antibodies, cause hypothyroidism and, especially in Asian patients, thyroid atrophy… • HLA-DR polymorphisms are the best documented genetic risk factors for autoimmune hypothyroidism, especially HLA-DR3, DR4, and -DR5 in Caucasians… • A weak association also exists between polymorphisms in CTLA-4, a T cell–regulatory gene, and autoimmune hypothyroidism. Clinical Manifestations • Symptoms become more readily apparent at usually TSH >10 mIU/L… Treatment • Adult patients under 60 years old without evidence of heart disease may be started on 50–100 μg levothyroxine (T4) daily… • Adjustment of levothyroxine dosage is made in 12.5- or 25-μg increments if the TSH is high… • In the elderly, especially patients with known coronary artery disease, the starting dose of levothyroxine is 12.5–25 μg/d with similar increments every 2–3 months until TSH is normalized… • The goal of treatment being a normal TSH, ideally in the lower half of the reference range… • Patients may not experience full relief from symptoms until 3–6 months after normal TSH levels are restored. • In patients of normal body weight who are taking ≥200 μg of levothyroxine per day, an elevated TSH level is often a sign of poor adherence to treatment… • Other causes of increased levothyroxine requirements must be excluded:  Malabsorption (e.g., celiac disease, small-bowel surgery),  Ingestion with a meal…,  Drugs that interfere with T4 absorption or metabolism…  Estrogen or selective estrogen receptor modulator therapy Myxedema • Myxedema coma still has a 20–40% mortality rate, despite intensive treatment, and outcomes are independent of the T4 and TSH levels. • Myxedema coma almost always occurs in the elderly and is usually precipitated by factors that impair respiration, such as drugs, pneumonia, CHF, MI, GIB or CVA... • Hypoventilation, leading to hypoxia and hypercapnia, plays a major role in pathogenesis and hypoglycemia & dilutional hyponatremia also contribute to the development of myxedema coma… • Clinical manifestations include reduced level of consciousness, sometimes associated with seizures, as well as the other features of hypothyroidism… • Levothyroxine can initially be administered as a single IV bolus of 500 μg, which serves as a loading dose and it’s usually continued at a dose of 50–100 μg/d… • If suitable IV preparation is not available, the same initial dose of levothyroxine can be given by NGT…. • Another option is to combine levothyroxine (200 μg) + liothyronine (25 μg) as a single, initial IV bolus followed by daily treatment… • An alternative is to give liothyronine (T3) intravenously or via nasogastric tube (ranging from 10 to 25 μg every 8–12 h…) and this treatment has been advocated because T4 → T3 conversion is impaired in myxedemacoma… • Supportive therapy should be provided to correct any associated metabolic disturbances… o Any precipitating factors should be treated, including the early use of broad-spectrum antibiotics… o External warming is indicated only if the temperature is <30°C… o Parenteral hydrocortisone (50 mg every 6 h) should be administered… o Hypertonic saline or IV glucose may be needed if there is severe hyponatremia or hypoglycemia… o Ventilatory support with regular blood gas analysis is usually needed during the first 48 h… THYROTOXICOSIS • Thyrotoxicosis is defined as the state of thyroid hormone excess and is not synonymous with hyperthyroidism, which is the result of excessive thyroid function… GRAVES’ DISEASE • Graves’ disease accounts for 60–80% of thyrotoxicosis and occurs in up to 2% of women but is one-tenth as frequent in men… • The disorder rarely begins before adolescence and typically occurs between 20 and 50 years of age. • A combination of environmental and genetic factors (polymorphisms in HLA-DR, the immunoregulatory genes CTLA-4, CD25, PTPN22, FCRL3, and CD226, as well as the TSH-R)…contribute to Graves’ disease susceptibility… • The concordance for Graves’ disease in monozygotic twins is 20-30% compared to <5% in dizygotic twins. • Smoking is a minor risk factor for Graves’ disease and a major risk factor for the development of ophthalmopathy. • Sudden increases in iodine intake may precipitate Graves’ disease, and there is a three-fold increase in the occurrence of Graves’ disease in the postpartum period… • Graves’ disease may occur during the immune reconstitution phase after highly active antiretroviral therapy (HAART) or … • The hyperthyroidism of Graves’ disease is caused by TSI that are synthesized in the thyroid gland as well as in bone marrow and lymph nodes.... • In particular, TPO antibodies occur in up to 80% of cases and serve as a readily measurable marker of autoimmunity. • • The clinical presentation depends on ;  the severity of thyrotoxicosis,  the duration of disease,  individual susceptibility to excess thyroid hormone,  the patient’s age… In the elderly, features of thyrotoxicosis may be subtle or masked, and patients may present mainly with fatigue and weight loss, a condition known as apathetic thyrotoxicosis… TREATMENT • The main anti-thyroid drugs are :  Thionamides :  Propylthiouracil (PTU),  Carbimazole (not available in the United States),  Methimazole (active metabolite)  Propranolol (20-40 mg every 6 h)  Radioiodine… • There is a small risk of thyrotoxic crisis after radioiodine, which can be minimized by pretreatment with anti-thyroid drugs for at least a month before treatment… • Some patients with mild Graves’ disease experience spontaneous relapses and remissions. • About 15% of patients who enter remission after treatment develop hypothyroidism 10–15 years later as a result of the destructive autoimmune process. • Rarely, there may be fluctuation between hypothyroidism and hyperthyroidism due to changes in the functional activity of TSH-R antibodies... • The clinical course of ophthalmopathy does not follow that of the thyroid disease… and anti-thyroid drugs or surgery have no adverse effects on the clinical course of ophthalmopathy. • Radioiodine treatment for hyperthyroidism worsens the eye disease in a small proportion of patients (especially smokers)… Thyroid storm • Thyrotoxic crisis is usually precipitated by acute illness (stroke, infection, trauma, diabetic ketoacidosis), surgery (especially on the thyroid), or radioiodine treatment of a patient with partially treated or untreated hyperthyroidism. • With life threatening exacerbation of hyperthyroidism, accompanied by fever, delirium, seizures, coma, vomiting, diarrhea, and jaundice. • The mortality rate (as high as 30% even with treatment) due to:  Cardiac failure,  Arrhythmia,  Hyperthermia Management of thyrotoxic crisis • Propylthiouracil (500–1000 mg loading dose and 250 mg every 4 h) • One hour after the first dose of propylthiouracil, stable iodide is given to block thyroid hormone synthesis via the Wolff-Chaikoff effect… • Propranolol (although other β-adrenergic blockers can be used, high doses of propranolol decrease T4 → T3 conversion, and the doses can be easily adjusted)... • Short-acting IV esmolol can be used to decrease heart rate while monitoring for signs of heart failure. • Additional therapeutic measures include hydrocortisone 300 mg IV bolus, then 100 mg every 8 h), antibiotics if infection is present, cooling, oxygen, and IV fluids… THYROIDITIS SUBACUTE THYROIDITIS • The patient usually presents with a painful and enlarged thyroid, sometimes accompanied by fever…. • It’s also termed de Quervain’s thyroiditis, granulomatous thyroiditis, or viral thyroiditis (mumps, coxsackie, influenza, adenoviruses, and echoviruses…) • The peak incidence occurs at 30–50 years, and women are affected three times more frequently than men. • The thyroid shows a patchy inflammatory infiltrate with disruption of the thyroid follicles and multinucleated giant cells within some follicles… • Finally, the thyroid returns to normal, usually several months after onset. • The release of thyroid hormones is initially associated with a thyrotoxic phase and suppressed TSH... hypothyroid phase then ensues, with low T4 and TSH levels that are initially low but gradually increase... • The diagnosis is confirmed by a high ESR and low uptake of radioiodine (<5%) or 99mTc pertechnetate (as compared to salivary gland pertechnetate concentration). • The white blood cell count may be increased, and thyroid antibodies are negative... • If the diagnosis is in doubt, FNA biopsy may be useful, particularly to distinguish unilateral involvement from bleeding into a cyst or neoplasm. • 600 mg of aspirin every 4–6 h or NSAIDs are sufficient to control symptoms in many cases... • 40–60 mg of prednisone, depending on severity (gradually tapered over 6–8 weeks, in response to improvement in symptoms and the ESR…) SILENT THYROIDITIS • Painless thyroiditis, or “silent” thyroiditis, occurs in patients with underlying autoimmune thyroid disease…. • Clinical course similar to that of subacute thyroiditis…and as in subacute thyroiditis, the uptake of 99mTc pertechnetate or radioactive iodine is initially suppressed. • The condition occurs in up to 5% of women 3–6 months after pregnancy and is then termed postpartum thyroiditis. • Typically, patients have a brief phase of thyrotoxicosis lasting 2–4 weeks, followed by hypothyroidism for 4–12 weeks, and then resolution; often, however, only one phase is apparent… • Differentiated with : 1) Painless goiter… 2) Normal ESR and the & 3) Presence of TPO antibodies... • Glucocorticoid treatment is not indicated for silent thyroiditis… • Propranolol, 20–40 mg three or four times daily. • Thyroxine replacement may be needed for the hypothyroid phase but should be withdrawn after 6–9 months, as recovery is the rule. • Annual follow-up thereafter is recommended… • The condition may recur in subsequent pregnancies.