Mohammad Reza Bakhtiari DCLS, PhD Pitfalls of TFTs Interpretation CME July 2006 Vol.24 No.7, http://keck.usc.edu HPT axis physiology Log-linear relationship between TSH and FT4 Patient Specific Set Point 1
New RI for TSH? Effects of Iodine Deficiency? J Clin Endocrinol Metab 90: 5483 5488, 2005) FT4 vs TSH Hypo Hyper FT4 and TSH (Hypo) THE LANCET Vol 357 February 24, 2001 2
FT4 and TSH (Hyper) THE LANCET Vol 357 February 24, 2001 Subclinical Thyroid States Subclinical hypothyroidism Subclinical hyperthyroidism Importance of Subclinical Thyroid Dysfunction Clin Biochem Rev Vol 24 November 2003 3
FT4 vs TSH 2 Hypo 1 + 1 4 4 3 Hyper FT4 and TSH (Zone 1) Rare (with discordant FT4 versus FT3) Interfering Abs to thyroid hormones (usually anti-tpo Abs) Hypo FDH=Familial dysalbuminaemic hyperthyroxinaemia Drugs (e.g. amiodarone, heparin) 1 1 Rare-other Intermittent T4 therapy / T4 overdose NTI (including acute psychiatric disorders) Neonatal period TSH-secreting pituitary adenoma (Hyper) Resistance to thyroid hormone Hyper Disorders of thyroid hormone transport or metabolism Resistance to thyroid hormone (RTH) vs TSH-secreting pituitary tumor (TSHoma) 1. Best Practice & Research Clinical Endocrinology & Metabolism 23, 5, 2009, 597 606 2. Clinical Endocrine Oncology. John Wiley & Sons, Jan 26, 2009 4
FT4 and TSH (Zone 2) Common Subclinical hypothyroidism Rare Heterophile (interfering) antibody Poor compliance with thyroxine Malabsorption of thyroxine Drugs (e.g. amiodarone, sertraline, cholestyramine) NTI recovery phase Hypo 2 Congenital TSH-receptor defects Resistance to TSH associated with other (unspecified) defects Pendred s syndrome some cases (associated with sensineural deafness and goitre) Hyper FT4 and TSH (Zone 3) Common Subclinical hyperthyroidism T3 Thyrotoxicosis Hypo Rare Recent treatment for hyperthyroidism Drugs (e.g. steroids, dopamine) NTI 3 Hyper FT4 and TSH * (Zone 4) Common NTI Recent treatment for hyperthyroidism y (TSH remains suppressed) Rare Central hypothyroidism Isolated TSH / TRH deficiency Hypo 4 4 Hyper 5
TSH Assay Interference (Heterophilic Antibodies) http://scantibodies.com/hbr.html TSH Assay Interference (Heterophilic Antibodies Sources) Exposure to animals (e.g. animal technicians, veterinarians, animal handlers) Alternate animal contact therapy (e.g. thymic cells, sheep cells, embryonic cells) Exposure to animal products (e.g. food preparation) Special diets (e.g. cheese) Deliberate immunization (e.g. therapies, vaccinations, certain imaging treatments) Blood transfusions Autoimmune diseases Dialysis Patent medicines (OKT3) Maternal transfer Cardiac Myopathy G.I. Disease (E. Coli) Rheumatoid factors can also act as heterophilic antibodies http://scantibodies.com/hbr.html Heterophilic Antibodies (Existence confirmation) 1. Discordant TSH results in an assay that utilizes different antibody pairs; 2. Altered TSH result following immunosubtraction [using polyethylene glycol (PEG) or protein G/A]; 3. Nonlinear TSH measurement following sample dilution Clinical Endocrinology (2011) 74, 673 678 6
Thyroid hormone autoantibodies (THAAb) Prevalence: up to 40% in autoimmune thyroid diseases; not necessarily lead to assay interference. autoantibody titer, specificity, and affinity, single-antibody technique: low hormone concentrations doubleantibody technique: apparent concentration of hormone will be spuriously high. 4 major approaches can assist in evaluation of assay interference: (a) measure TSH by a sensitive immunometric method; (b) measure thyroid hormone concentrations after immunoglobulin depletion; (c) use a comparative method (however, interference may be seen in more than one method; for suspected interference with FT4 assays, measure by equilibrium dialysis); (d) test for the presence of THAAb against the hormone or analog tracer used in the assay reagents. Clinical Endocrinology (2011) 74, 673 678 FT4 / FT3 Displacement Heparin Effect: can cause an artefactual elevation in measured concentrations of FT4/FT3 by displacement of T4 and T3 from their carrier proteins. Altered serum binding proteins Clin Biochem Rev Vol 24 November 2003 Altered serum binding proteins Quantitative (TBG excess) 1. Pregnancy, estrogens (OCPs, HRT, tamoxifen) 2. hepatic disorders 3. hereditary TBG excess Qualitative 1. familial dysalbuminaemic hyperthyroxinaemia (FDH) 2. transthyretin-associated hyperthyroxinaemia (TTR- AH)] Effects on RT3U Clinical Endocrinology (2011) 74, 673 678 7
Concept of Steady State Conditions Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003; 13:1-126. Thyroxin Replacement Therapy and Poor compliance of Thyroxine therapy Intermittent hormone ingestion may result in normal or even elevated TH levels, but fails to normalize TSH. Normal or Elevated T4 but Non-suppressed TSH Clinical Endocrinology (2011) 74, 673 678 Some Examples Non Thyroidal Illness (NTI) Euthyroid sick syndrome Gastrointestinal diseases Pulmonary diseases Cardiovascular diseases Renal diseases Infiltrative and metabolic disorders Inflammatory conditions Myocardial infarction Starvation Sepsis Burns Trauma Surgery Malignancy Bone marrow transplantation 8
Mechanisms of TFTs changes in NTI Journal of Endocrinology (2010) 205, 1 13 Pregnancy Induced TFTs Changed 9
Pregnancy Induced TFTs Changed http://www.thyroidmanager.org/ Oct. 28. 2012 Factors affecting Thyroid Physiology during normal Pregnancy Physiologic Change Increased renal I - clearance Decreased plasma I - and placental I - transport to the fetus Thyroid-related consequences Increased 24-hr RAIU In I- deficient women, decreased T4, increased TSH, and goiter formation Increased O2 consumption by fetoplacental unit, gravid uterus and mother Increased BMR First-trimester increase in hcg Increased serum TBG Increased plasma volume Inner-ring deiodination of T4 and T3 by placenta Increased free T4 and T3 Decreased basal TSH (partial blunting of the pituitary-thyroid axis) Increased total T4 and T3 Increased T4 and T3 pool size Accelerated rates of T4 and T3 degradation and production http://www.thyroidmanager.org/ Oct. 28. 20212 Changes of TFTs after Birth THYROID FUNCTION TESTING, Springer, 2010 10
Normal range for thyroid function tests in infants, children and adults THYROID FUNCTION TESTING, Springer, 2010 Relationship between serum T4 and T3 in various disorders* Serum T4 Serum T3 Low Normal High Low Severe hypothyroidism. TBG deficiency. # Severe nonthyroidal illness. Euthyroid hypothyroxinemia Nonthyroidal illness. Medications. Fetus. Restricted nutrition. Hyperthyroidism with severe nonthyroidal illness. Amiodarone. Normal Iodine deficiency. T3 treatment. Hypothyroidism. T4 treatment. t t Euthyroid hyper- thyroxinemia. Hyperthyroidism with nonthyroidal illness. T4 binding autoantibodies. High Iodine deficiency T3 treatment Antithyroid drugs T3 toxicosis T3 binding autoantibodies Hyperthyroidism. Excess T4 ingestion Hormone resistance. TBG excess # * Excludes short term changes related to initiation or cessation of therapy # Effect on total hormone concentration; free hormone concentration remains normal. http://www.thyroidmanager.org/chapter/clinical-strategies-in-the-testing-of-thyroid-function/ Indications for measurement of serum free T3 Clin Biochem Rev Vol 24 November 2003 11
Drug Effects on TFTs The South African Medicines Formulary (SAMF), Vol 24, No 7 (2006) Mechanisms of Drug Effects on TFTs Inhibit pituitary TSH secretion Dopamine, dobutamine, glucocorticoids, octreotide Iodine load increases thyroid hormone synthesis Contrast agents, amiodarone, topical preparations Impair thyroid hormone release Iodine excess, lithium, glucocorticoids, aminoglutethimide Inhibit T4-T3 5' deiodination Amiodarone, glucocorticoids, beta blockers * Contrast agents, e.g. iopanoic acid, ipodate Augment abnormal immune function Interleukin 1, interferon α, interferon β, Monoclonal antibody therapy Mechanisms of Drug Effects on TFTs (cont.) Modify binding of T4, T3 to plasma proteins a. Increase concentration of T4 binding globulin Estrogen, heroin, methadone Clofibrate, 5-fluorouracil, perphenazine, tamoxifen b. Decrease concentration of T4 binding globulin Glucocorticoids, androgens, l-asparaginase c. Displace T4 and T3 from binding proteins Furosemide, salicylates, phenytoin, carbamazepine Non-steroidal antiinflammatory agents # Heparin ψ Displace T4 from tissue pool Oral cholecystographic agents, some alkylating agents Modify thyroid hormone action Amiodarone, phenytoin Increase clearance of T4,T3 Barbiturates, phenytoin, carbamazepine, rifampicin Sertraline?, fluoxetine?, dothiepin? Impair absorption of ingested T4 Aluminium hydroxide, ferrous sulfate, cholestyramine, calcium carbonate, Colestipol, sucralfate, soya preparations,kayexalate 12
In a case of Discordant or Anomalous Results (Conclusion) After review of the clinical context, the following steps are helpful in evaluating anomalous thyroid results: a. Review of the medication history. b. Confirmation of serum TSH by an alternative method that identifies the degree of TSH suppression. c. Follow-up sampling to establish whether the abnormality is transient or persistent. d An alternative estimation of serum free T4, avoiding one-step methods that are known to frequently give spurious results, especially during critical illness. e. Measurement of serum total T4 to establish whether the serum free T4 estimate is disproportionately high or low, due to a pre-analytical or method-dependent artefact. f. Evaluation of the sample for possible heterophilic antibody interference; note that there are no established criteria that rule out such interference. g. Investigation of propositus and family members for evidence of unusual binding abnormalities or hormone resistance. Clin Biochem Rev Vol 24 November 2003 Thank you for your Attention http://reza-bakhtiari.persianblog.ir/ Bakhtiari09@gmail.com 13