THROID ABNORMALITIES AMIR ZIAEE 1
Thyroid Hormone Synthesis Table 330-2. Characteristics of Circulating T4 and T3 Hormone Property T4 T3 Serum concentrations Total hormone 8 μg/dl 0.14 μg/dl Fraction of total hormone in the free form 0.02% 0.3% Free hormone 21 10 12 M 6 10 12 M Serum half-life 7 d 0.75 d Fraction directly from the thyroid 100% 20% Production rate, including peripheral conversion 90 μg/d 32 μg/d Intracellular hormone fraction ~20% ~70% Relative metabolic potency 0.3 1 Receptor binding 10 10 M 10 11 M SOURCES OF T3 Thyroid gland %20 Peripheral tissue T4 to T3 Conversion %80 2
Factors thet impair peripheral conversion of T4 to T3 Physiological Pathologic pharmacologic Fetal and early neonatal life Old age? Fasting,malnutrition Hepatic or renal dysfunction Systemic illness Trauma,postoperative state Drugs ( PTU,glucocurticoids,propranolol,amiodarone) Oral cholecystographic agents MAJOR PLASMA CARRIER PROTEINS FOR TYROID HORMONES Thyroxine-binding globulin(tbg) Transthyretin (prealbumin) Albumin 3
Factors associated with altered binding of T4 by TBG Increased binding Pregnancy Neonatal state Estogens Tamoxifen OCP Acute intermittent porphyria Infectious and chronia active hepatitis Biliary cirrhosis Genetic factors Perphenazine HIV infection Decreased binding Androgens Large doses of glucocurticoids Active acromegaly Nephrotic syndrome Major systemic illness Genetic factors asparginase Hypothyroidism 4
Causes of hypothyroidism Primary Chronic autoimmune thyroiditisgoitrous & atrophic forms Radiation Surgery Infiltrative disease(amyloidosis,sclerodermia) Iodine deficiency Biosynthetic defect Drugs (lithium,iodine,contrast agents) Secondary Pituitary disease Hypothalamic disease Incidence of hypothyroidism* Female 40/10,000 Male 6/10,000 Prevalence of Hypothyroidism* Female %9.3 Male %1.3 *2779 people in UK with a medium age of 58 years Whickham survey 1995 Thyroid autoimmunity Suseptibility factors Humoral lfactors Cell mediated factors 5
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Figure 9-3. (A) The classic torpid facies of severe myxedema in a man. The face appears puffy, and the eyelids are edematous. The skin is thickened and dry. (B) The facies in pituitary myxedema is often characterized by skin of normal thickness, covered by fine wrinkles. Puffiness is usually less than in primary myxedema. The eyelids are often edematous. The palpebral fissure may be narrwowed because of blepharoptosis, due to diminished tone of the sympathetic nervous fibers to Müller's levator palpebral superious muscle and is the opposite of the lid retraction seen in thyrotoxicosis. The modest measurable exophthalmos seen in some patients with myxedema is presumably related to accumulation of the same mucous edema in the orbit as is seen elsewhere. It is not progressive and carries no threat to vision, as in the ophthalmopathy of Graves' disease. The tongue is usually large, occasionally to the point of clumsiness. Sometimes a patient will complain of this problem. Sometimes it is smooth, as in pernicious anemia (of course, pernicious anemia may coexist). Patients do not usually complain of soreness of the tongue, as they may in pernicious anemia. When anemia is marked, the tongue may be pale, but more often it is red, in contrast to the pallid face. TSH and Free T4 TSH TSH TSH TSH Free T4 Free T4 Free T4 Free T4 Primary hypothyroidism Mild or Subclinical hypothyroidism Central hypo. NTI Drug effect Normal 7
Recommended Uses for TPOAb Measurement Diagnosis of Autoimmune Thyroid Disease. Risk factor for Autoimmune Thyroid Disease. Risk factor for hypothyroidism during Interferon alpha, Interleukin-2 or Lithium therapy. Risk factor for thyroid dysfunction during amiodarone therapy. Risk factor for hypothyroidism in Down s Syndrome patients. Risk factor for thyroid dysfunction during pregnancy and for post-partum thyroiditis. Risk factor for miscarriage and in-vitro fertilization failure. Central Hypothyroidism Imaging (R/O SOL) Functional status of the other axes Transient hypothyroidism Postpartum thyroiditis Subacute thyroiditis After withdrawal of thyroid hormone Therapy in euthyroid patients Following I131 treatment for Graves disease Removal of toxic adenoma or subtotal thyroidectomy for Graves disease 8
Subclinical hypothyroidism Unlike patients with overt hypothyroidism, these patients have normal serum levels of T3 and T4 and only mildly elevated serum TSH levels. Such patients are often identified through routine screening or in the course of an evaluation of common nonspecific symptoms or hypercholesterolemia. Subclinical hypothyroidism The worldwide prevalence of subclinical hypothyroidism ranges from 1 to 10 percent; the highest age- and sex-specific rates are in women older than 60 years of age, approaching 20 percent in some reports Up to 75 percent of patients have only mildly elevated serum thyrotropin values (5 to 10 mu per liter), and 50 to 80 percent of patients have positive tests for antibodies against thyroperoxidase, depending on the age, sex, and serum thyrotropin levels. 9
It is prudent to keep TSH values in the lower normal range(0.4-2.0 mu/l), and to avoid TSH levels of <0.1 mu/l Special treatment situation Elderly patients Underlying CAD Pregnancy Concomitant drug administration Surgical patients Increased L-T4 dose requirement Decreased intestinal absorption of T4 Malabsorption(e.g.celiac disease,short bowel syn.) Dietary fiber supplements Drugs:colestipol,colestyramine,sucralfate,aluminium hydroxide,ferrus sulfate Increased need for T4 Weigt gain,pregnancy,estrogens Increased clearance for T4 Phenobarbital,phenytoin,carbamazepin,rifampin Precise mechanism unknown sertraline,chloroquine,lovastatin 10
Risk of a suppressed TSH Effects on Bone Mass Cardiac Effects Bone effects Overt thyrotoxicosis is associated with increased bone turne over and negative calcium balance Significant bone loss in postmenopausal(but not in premenopausal) women at the lumbar spine(effect size 0.348,95% 95%CI 0 0.492 to 0.202) and the femoral neck(effect size 0.276,95% CI o.470 to 0.089) The detrimental effect appeared more marked on cortical than on trabecular There is little evidence from retrospective studies of an actual increase in Fx incidence Cardiac effects Increased heart rate Atrial fibrillation, 3-fold greater risk of Af over the next decade in thyrotoxic 60-year- olds Increase in myocardial contractility Impaired diastolic relaxation and ventricular filling Modest increase in LV wall thickness 11
NTI The global pattern of changes in thyroid physiology that occur durig illness. NTI Low T3 due to inhibition of 5`-monodeiodinase Reverse T3 Low T4 due to reduced protein binding and circulating inhibitors of binding Pituitary thyroid axis Effects of drugs Modifications of thyroid-related hormones during fasting or illness Severity of illness Mild FT4 FT3 rt3 TSH Normal Reduced up to %50 Increased up to twofold Increased up to severalfold Normal Moderate Increased Reduced up Increased up to Normal to %90 Severe Reduced Almost undetectable Variable Reduced 12
NTI Thyroid function should not be assesed in seriously ill patients t unless ther is a strong suspicion of thyroid dysfunction Relationship Between Total T4 & T3 In Various Disorders T4 T3 Low Normal.Iodine deficiency.t3 treatment.antithyroid drug therapy.t3- thyrotoxicosis.t3-binding autoantibodies.thyrotoxicosis of any cause.excess T4 ingestion.tbg excess.thr 13
Relationship Between total T4 & T3 In Various disorders T4 T3 low Normal.Iodine deficiency.t3 treatment.hypothyroidism.t4 treatment.euthyroid hyprethyroxinemia.thyrotoxicosis with acute or moderate NTI Relationship Between Total T4 & T3 In Various Disorders T4 T3 Low Normal Low.Severe hypo..acute &.Thyrotoxicosis.TBG chronic NTI with severe NTI deficiency.drugs.drugs.fetal life.severe NTI.Restricted nutrition 14
TSH 43 (TSH), or thyrotropin : a glycoprotein synthesized and secreted by : the thyrotropes Molecular weight : about 28,000 Structure : composed of two subunits, a and ß Alpha subunit : identical to alpha subunit of FSH, LH, HCG Both subunits are necessary for biological activity. 44 TSH : no carrier protein TSH : unaffected by changes (such as liver or kidney failure, estrogens, and androgens) in proteins that are known to affect thyroid hormone carrier proteins 45 15
Secretion : pulsatile with a diurnal rhythm. more than half of pulses occur between 10 PM and 4 AM. Average TSH levels l : 1.6 ± 0.6 mu/l, with: peak values of 3.1 ± 1.3 mu/l at approximately 2 AM and trough values of 0.7 ± 0.3 mu/l at about 4 PM. 46 Third-generation assays have three major advantages over second-generation assays: (1) help distinguish TSH suppression in hyperthyroid patients with coexistent illness from suppression in euthyroid patients with nonthyroidal illness; (2) allow the precise titration of thyroid hormone suppressive therapy; and (3) can distinguish the severity of subclinical hyperthyroidism. 47 TSH Reference Ranges Serum TSH values : higher in neonates and children. Mean euthyroid TSH values: approximate to 1.5 miu/l, (range 0.3 to 4.0 miu/l in iodine-sufficient populations) 48 16
Clinical situations associated with subnormal TSH values 49 Clinical situations associated with subnormal TSH values thyroid hormone excess endogenous hyperthyroidism or excess exogenous thyroid hormone points the activation of the negative feedback loop. Prolonged excessive thyroid hormone physiological "atrophy" of the thyroid stimulatory limb of the hypothalamic-pituitary thyroid axis. Thus several months are usually required for the reestablishment of TSH secretion after the relief of thyrotoxicosis. After excess thyroid hormone treatment after the transient hyperthyroidism associated with subacute or some variants of autoimmune thyroiditis Shorter suppression Severe illness 50 Clinical situations associated with subnormal TSH values -dose glucocorticoids Exogenous dopamine Pharmacological amounts of retinoids Points Acutely but not chronically In critically ill patients, this effect of dopamine can be superimposed on the suppressive effects of acute illness on thyroid function, reducing T4 production to even lower levels. Dopamine is sufficiently potent to suppress TSH to normal levels in sick patients with primary hypothyroidism. severe central hypothyroidism associated with very low serum TSH concentration has been reported in patients with cutaneous T-cell lymphoma treated with high-dose retinoid X receptor-selective ligand able to suppress TSH secretion. 51 17
hcg acute psychosis depression agitated psychoses Congenital central hypothyroidism a thyroid stimulator; In normal pregnancy as a slightly subnormal TSH during the first trimester (0.2-0.4 mu/l) ; frank, though mild, hyperthyroidism in patients with choriocarcinoma or molar pregnancy. may have high thyroid hormone levels and suppressed or elevated TSH values. Etiology,unkown low serum TSH; may result from mutations affecting TSH alpha gene or the Pit-1 gene 52 Interpretation of TSH and FT4 Results Low Normal Hyperthyroidism (pm mol/l) 4 FT Normal Euthyroidism Low Primary hypothyroidism TSH (miu/l) Interpretation of TSH and FT4 Results Low Normal (pm mmol/l) 4 FT Hyperthyroidism Euthyroid sick syndrome T4 autoantibodies Thyroid hormone resistance syndrome TSH-secreting pituitary adenoma Normal Subclinical Euthyroidism hyperthyroidism T3 thyrotoxicosis Pregnancy (first trimester) Drugs (eg. Glucocorticoids, dopamine, amiodarone) Thyroid hormone resistance syndrome TSH-secreting pituitary adenoma Subclinical (compensated) hypothyroidism Low Central hypothyroidism Central hypothyroidism Euthyroid sick syndrome (more severe, uncommon) Primary hypothyroidism TSH (miu/l) 18
Clinical situations associated with elevated TSH values 55 Clinical situations associated with elevated TSH values Points Primary hypothyroidism Iodine deficiency The serum free T4 is low normal or reduced but the serum free T3 values remain normal until the level of thyroid function has markedly deteriorated. Western Europe, South America, Africa and Asia. during the recovery phase after a severe illness A transient effect ; In such patients a "reawakening" of the hypothalamic-pituitary thyroid axis occurs with the improvement in their clinical state. 56 The remainder of the conditions associated with an elevated TSH are extremely rare : partial or complete TSH resistance inactivating point mutations of the TSH receptor gene. In a patient who has an elevated serum FT4, the presence of TSH at normal or increased levels should lead to a search for either resistance to thyroid hormone or a thyrotroph tumor. Hypothalamic-pituitary normal or even modest increases in TSH are explained by the lack of normal dysfunction TSH glycosylation in the TRH-deficient patient. The diagnosis is generally made by finding a serum free T4 index which is reduced to a greater extent than expected from the coincident serum TSH. either elevated or suppressed TSH, Psychiatric illness but the abnormal values are not usually in the range normally associated with symptomatic thyroid 57 dysfunction 19
Addison's disease The effect of glucocorticoids to suppress TSH secretion; TSH may be slightly elevated in the absence of primary thyroid disease. the presence of endogenous antimouse gamma globulin antibodies These antibodies, like TSH, can complex the two TSH antibodies resulting in artificially elevated serum TSH assay results in euthyroid patients; forming false bridges between the solid phase and signal antibodies. 58 Clinical situations in which measurements of serum thyrotropin alone may yeild misleading resuls condition Serum TSH Consequences of clinical action based on serum TSH value alone Serum Free T4 (if measured) Heterophil Abs N Failure to Dx thyrotoxicosis Central hypothyroidism TSH-secreting pit. Adenoma Thyroid hormone resistance Poor compliance with T4 therapy Delayed recovery of TSH secretion * TSH may be high in these conditions N* Failure to Dx hypothyroidism and investigate hypoth.-pit. Structure and function N* Failure to Dx thyrotoxicosis and investigate pit. Structure and function N* Failure to recognize the condition Inappropriate increase in dose of T4 N or low Failure to Dx impending hypothyroidism Low low59 Clinical Use of Tg Methods 60 20
Decreased thyroglobulin concentration TSH mediated Absent or decreased synthesis Thyroid hormone replacement Supraphysiologic doses of thyroid hormone Scarcity of thyroid tissue Congenital athyrosis Total thyroidectomy Thyroglobulin synthesis defects 61 Increased thyroglobulin concentration TSH mediated Acute and transient TSH administration Protirelin (TRH) administration Neonatal period (1-96 hours postpartum) Chronic stimulation Iodine deficiency Endemic goiter Goitrogens Reduced thyroid reserve Thyroxinebinding globulin deficiency Resistance to thyroid hormone Non-TSH mediated Substances with TSH-like bioactivity Thyroid-stimulating immunoglobulin in autoimmune (Graves') disease Chorionic gonadotropins trophoblastic disease Pregnancy Abnormal release Autonomous toxic nodules Solitary nontoxic nodules Multinodular goiter Subacute thyroiditis (early phase) Differentiated nonmedullary thyroid carcinoma Neonatal period Direct trauma to the thyroid gland Percutaneous needle aspiration Thyroid or parathyroid surgery Iodine-131 therapy Abnormal clearance Renal failure 62 PREVALENCE OF THYROID AUTOANTIBODIES AND THEIR ROLE IN IMMUNOPATHOLOGY Antibody General Population Graves' Disease Hypothyroid Autoimmune Thyroiditis Role in Immunopathology Anti Tg 3% 12% to 30% 35% to 60% None Anti TPO 10% to 15% 45% to 80% 80% to 99% Complement fixing?significance Anti-TSH receptor 1% to 2%[ 70% to 100% 6% to 60% Stimulate or block the TSH receptor Anti-Na+ /Isymporter 0% 20% 25% 50% to 70% impair I- uptake by symporter in vitro 21
Antibody Antithyroglobulin Clear Indication Serial thyroglobulin estimations for thyroid cancer Possible Indication Antithyroid peroxidase Diagnosis of Graves' disease Diagnosis of chronic autoimmune thyroiditis in patients with primary thyroid failure Predicting risk of hypothyroidism when TSH alone is elevated Predicting postpartum thyroiditis in at-risk women Differentiation between transient thyrotoxicosis owing to lymphocytic or subacute thyroiditis Diagnosis of chronic autoimmune thyroiditis in euthyroid patients with goiter or nodules Prediction of hypothyroidism in at-risk groups Antibody Anti-TSH receptor antibodies (TBII) Anti-TSH receptor antibodies by bioassay: stimulating (TSAb) or blocking (TSBAb) Clear Indication To distinguish postpartum thyroiditis from Graves' disease in postpartum thyrotoxicosis Predicting risk of fetal/neonatal thyrotoxicosis in women with previous ablative treatment for Graves' disease or current thionamide therapy Possible Indication In diagnosing euthyroid Graves' ophthalmopathy (TSAb more sensitive) To determine duration of therapy and risk of recurrence in patients receiving thionamide therapy for Graves' disease (especially children) In diagnosing euthyroid Graves' ophthalmopathy To predict transient hypothyroidism (TSBAb) When increased sensitivity in the detection of anti-tsh receptor antibodies is required Advantages and Disadvantages of Different Methods for Measurement of Autoantibodies to TPO and Tg Technique Precision Sensitivity Specificity Cost Immunofluor- escence Hemaggutin- ation ELIZA Low Low Variable Low Low Variable Low Radioassay Low 22
Introduction In the 1950s, only one thyroid test was available an indirect estimate of the serum total (free + protein-bound) ti d)thyroxin (TT4) concentration ti Since 1970, radioimmunoassay (RIA) and immunometric assay (IMA) improved the specificity and sensitivity of the methods Thyroid assay Total Hormone Measurements (TT4 and TT3) Total Hormone Measurements (TT4 and TT3) Technically, easier methods to measure TT4 and TT3 (nanomolar) FT4 and FT3 (picomolar) Serum TT4 measurement (four decades) : 1970s: RIA methods Currently: immunometric assay (IMA) Signals: Radioactivity Fluorescence Chemiluminescent enzymes 23
Total Hormone Measurements (TT4 and TT3) Total T4 reference have approximated 58 to 160 nmol/l (4.5-12.6 µg/dl) for more than two decades. TT3 reference values are also method dependent, with ranges approximating to 1.2-2.7 nmol/l (80 180 ng/dl) Free Hormone Tests (FT4 and FT3) Free Hormone Tests (FT4 and FT3) free hormone hypothesis: free fraction of hormone is responsible for the biologic activity of thyroid hormones at the cellular level 24
Free Hormone Tests (FT4 and FT3) Index Methods Free T4 Index (FT4I) Free T3 Index (FT3I) Absolute Methods Equilibrium Dialysis Ultrafiltration Gel Filtration/Adsorption chromatography Comparative Immunoassays Two-Step labeled Hormone One-step Labeled Hormone Analog Labeled Antibody Index Methods (FT4I and FT3I) require two separate measurements: TT4 or TT3 Thyroid Hormone Binding Ratio (THBR) or "Uptake test Free Hormone Indexes (FT4I and FT3I): simple calculations approximation of the free hormone concentration in the presence of abnormal binding proteins estimate free hormone concentrations: 40 y PRINCIPAL DRUGS THAT DISPLACE T4 FROM THYROXINE- BINDING GLOBULIN IN NORMAL HUMAN SERUM Drugs Salicylates Acetyl salicylic acid Salicyl salicyclic acid Furosemide Fenclofenac Mefenamic acid Flufenamic acid Diclofenac Difunisal Phenytoin Carbamazepine Mean Percent Increase in Free T4 Fraction 62 >100 5-30 90 31 10 7 37 45 30 25
The Heparin Artifact The effect of heparin in increasing serum free T4 is an important in vitro phenomenon that can lead to spuriously high estimates of circulating free T4 26
TBG excess T4 x T3RU = FT4I T3 x T3RU = FT3I TBG deficiency T4 x T3RU = FT4I T3 x T3RU = FT3I 27
Hyperthyroidism T4 x T3RU = FT4I T3 x T3RU = FT3I Hypothyroidism T4 x T3RU = FT4I T3 x T3RU = FT3I Questions? 28