Pathophysiology Of Thyroid Dysfunction PDF

BOK280-Block 3 Pathophysiology of thyroid dysfunction Prof Tahir Pillay, MBChB, PhD, FRCPath (Lon), FCPath(SA) Chief Specialist & Head of Pathology and Chemical Pathology University of Pretoria Honorary Professor of Chemical Pathology, University of Cape To...

BOK280-Block 3 Pathophysiology of thyroid dysfunction Prof Tahir Pillay, MBChB, PhD, FRCPath (Lon), FCPath(SA) Chief Specialist & Head of Pathology and Chemical Pathology University of Pretoria Honorary Professor of Chemical Pathology, University of Cape Town Outcomes and Assessment criteria Outcomes Identify the clinical presentation of thyroid disease in excess and hypofunctioning thyroid disease states Interpret thyroid function tests in thyroid disease Identify common thyroid disease states and patterns of biochemical thyroid abnormalities Assessment criteria List features of thyroid disease Apply your knowledge of the clinical features of thyroid disease to clinical cases Analyse and evaluate biochemical thyroid function tests State diagnoses associated with the thyroid disease profiles List common disease states in hypofunctioning and hyperfunctioning thyroid glands Apply your knowledge of clinical thyroid diseases to patient cases Learning objectives the biosynthetic pathways involved in thyroid hormone synthesis and their action; the mechanisms that regulate the hypothalamic–pituitary–thyroid axis; the causes and features of thyroid dysfunction and the investigations that should be performed when thyroid disease is suspected; how to interpret the results of thyroid function tests both for diagnosis and in monitoring treatment; the concept of subclinical thyroid disease and when treatment should be implemented in such patients; the mechanisms that lead to changes in thyroid function tests in nonthyroidal illness, and how to interpret results in such patients; the drugs that commonly give rise to abnormal thyroid function tests and the various mechanisms by which these drugs produce such an effect.  Regulation of synthesis and metabolism Negative feedback of T4 and T3 Conversion of T4 to T3 TBG (Thyroxine binding globulin) is the major binding protein, binds 70% of plasma T4 and 80% of plasma T3 Transthyretin (also called thyroxine binding prealbumin) and albumin binds thyroid hormone such more than 99.8% of thyroid hormones circulate bound to these 3 proteins Approx. 0.05% of plasma T4 and 0.2% of plasma T3 are free Thyroid hormones-mechanism of action Who should have thyroid function tests done?  Thyroxine is produced exclusively by the thyroid Biology active hormone is T3 85% of plasma T3 is formed by outer ring (5’) Monodeiodination of T4 in liver, kidneys and muscle  Trapping of iodide from plasma by a sodium iodine symporter in the thyroid. Oxidation of iodide to iodine by thyroid peroxidase. Incorporation of iodine into tyrosyl residues on thyroglobulin in the colloid of the thyroid follicle. Mono-iodotyrosine (MIT) and di-iodotyrosine (DIT) are formed. Production of T4 and T3 by coupling iodotyrosyl residues in the thyroglobulin molecule. Splitting off T4 and T3 from thyroglobulin following its reabsorption from the colloid. Release of T4 and T3 into the circulation. Causes of an abnormal TSH in some clinically euthyroid patients Situations in which first-line TSH is not ideal. The main causes of hyperthyroidism. Management of hyperthyroidism Radioiodine Carbimazole Thyroidectomy Measurement of TSH is not reliable in first 4-6 months Thyroid function testing when treating hyperthyroidism. The main causes of hypothyroidism. Management of hypothyroidism T4 replacement therapy Make the patient feel well and restore TSH and T4 within reference range Once stabilised, annual check If dose is changed, wait 6-8 weeks before doing lab tests Other situations Subclinical hypothyroidism- replace T4 or not? Only if TSH > 10 mU/L If TSH between 4.5 -10 mu/L; no treatment unless positive anti-TPO T4 therapy in central hypothyroidism-TSH of no value –maintain T4 in reference range Interpretation of thyroid function tests in suspected hypothyroidism. When are TFTs unreliable? NTI/Sick euthyroid syndrome Recovery from illness Neonate Pregnancy The effects of illness on the concentration of thyroid hormones and thyrotrophin. Thyroid function testing in patients with nonthyroidal illness (NTI).  NTI/Sick euthyroid Patients attending or admitted to a hospital suffering from any of a wide range of chronic or acute NTIs often have abnormalities in thyroid function tests. The abnormalities depend on the severity of the illness Recovery from illness When a patient recovers from illness, abnormalities in TSH, T4 and T3 eventually resolve. In some patients, TSH concentrations may rise transiently above the reference range in this recovery phase. In hospitalised patients, an elevated TSH is as likely to be due to recovery from nonthyroidal illness as primary hypothyroidism. Neonate Plasma TSH is widely used to screen for congenital hypothyroidism in the neonate. Marked changes in thyroid function occur in the early days of life, with an initial surge in TSH and thyroid hormone after delivery, followed by a marked decline in hormone levels over the next few days. Pregnancy Marked changes in thyroid hormone concentration and TSH occur throughout pregnancy, and it is essential to use trimester-related reference ranges. Tests affected by changes in thyroid status Examples of drugs that alter thyroid hormone synthesis, secretion and metabolism. Causes of abnormal results in euthyroid patients Abnormal TBG Genetic variants of albumin and pre-albumin – Familial dysalbuminaemic hyperthyroxinaemia Assay interference- patients with endogenous antibodies that interfere in assays Thyroid hormone resistance syndromes Rare; 1/40 000 Mutations in the beta nuclear T3 receptor Elevated FT4 and FT3 with normal or slightly raised TSH Generalized thyroid hormone resistance Pituitary thyroid HR Peripheral thyroid HR Other miscellaneous tests TRH test Distinguish secondary hyperthyroidism from THR AntiTPO (Thyroid peroxidase) Hashimoto’s thyroiditis Grave’s disease TRAbs (Thyrotropin receptor antibodies) Grave’s disease the differential diagnosis of hyperthyroidism where the clinical picture is not obvious; predicting relapse in treated hyperthyroid patients who are to have their anti-thyroid medication withdrawn. If TRAbs are still strongly positive, then the patient has a high risk of immediate relapse;