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  2. 2. INTRODUCTION • First endocrine disorder treated by replacement with the deficient hormone • Development of purified thyroid hormone preparationsmimic the function of the normal thyroid gland with thyroid hormone replacement therapy. • Safe and well tolerated by most patients • Thyroid glandthyroxine (T4) and triiodothyronine (T3). • Autoimmune disorders of the thyroid glandglandular destruction and hormone deficiency (hypothyroidism)/thyrotoxicosis
  3. 3. ANATOMY • two lobes connected by an isthmus. • Location:Anterior to the trachea between the cricoid cartilage and the suprasternal notch. • 20 g in size, highly vascular, and soft in consistency. • Four parathyroid glandsparathyroid hormone are located posterior to each pole of the thyroid.
  6. 6. • Thyroid releases 100-125 nmol of T4 daily • only small amounts of T3. • Half-life of T4--7-10 days • Compensatory mechanisms maintain T3 levels.
  7. 7. Thyroid Hormone Transport • Bound to plasma proteins: TBG, TTR, Albumin • 99.98% of T4 and 99.7% of T3 are protein-bound.
  8. 8. Causes of Hypothyroidism
  9. 9. Epidemiology • The National Health and Nutrition Examination Survey (NHANES 1999-2002) of 4392 individuals3.7% hypothyroid. (defined as TSH levels exceeding 4.5 mIU/L)[22] • World Health Organization (WHO) data from 130 countries taken from January 1994 through December 2006 found inadequate iodine nutrition in 30.6% of the population. • WHOurinary iodine concentrations100 to 199 μg/L in the general population. • 150-249 μg/L in pregnant women.
  10. 10. • Age-related demographics:The frequency increases with age. • Most prevalent in elderly populations-The Framingham study found hypothyroidism (TSH > 10 mIU/L) in 5.9% of women and 2.4% of men older than 60 years.[24] • Sex-related demographics:2 to 8 times higher in females. • Race-related demographics:NHANES 1999-2002 whites (5.1%) and Mexican Americans than in African Americans (1.7%).
  11. 11. • Iodine deficiencymore common in less-developed countries. • Out of an estimated world population of 5.8 billion in different regions, 3.8% are estimated to be suffering from iodine deficiency in some form, though only 12% is affected by goitre. • Areas of adequate iodine intake-Autoimmune thyroid disease (Hashimoto disease). • Prevalence of antibodies is higher in women and increases with age.
  12. 12. Primary hypothyroidism Types of primary hypothyroidism include the following: • Chronic lymphocytic (autoimmune) thyroiditis • Postpartum thyroiditis • Subacute (granulomatous) thyroiditis • Drug-induced hypothyroidism • Iatrogenic hypothyroidism
  13. 13. Chronic lymphocytic (autoimmune) thyroiditis • Most frequent cause of acquired hypothyroidism • Thyroid antigens as foreign  chronic immune reaction ensues resulting in lymphocytic infiltration of the gland  progressive destruction of functional thyroid tissue. • Anti–thyroid peroxidase (anti-TPO) antibodies are the hallmark of this disease. • Antibody levels can vary over time. • Absence of antibodies does not exclude the diagnosis
  14. 14. Postpartum thyroiditis • Up to 10% of postpartum  develop lymphocytic thyroiditis in the 2-12 months after delivery. • Transient (2-4 months). • Increased risk of permanent hypothyroidism or recurrence of postpartum thyroiditis with future pregnancies. • In a 12-year longitudinal study, Stuckey et al found that hypothyroidism developed in 27 of 71 women (38%) who had a past history of postpartum thyroid dysfunction (PPTD). In comparison, only 14 of 338 women (4%) who had not had PPTD developed hypothyroidism.[5]
  15. 15. Subacute granulomatous thyroiditis • Also known as de Quervain disease, • Relatively uncommon disease • Most frequently  middle-aged women. • Low grade fever, thyroid pain, dysphagia, and elevated erythrocyte sedimentation rate (ESR). • Self-limited • inflammatory conditions or viral syndromes may be associated with transient hyperthyroidism  transient hypothyroidism.
  16. 16. Drug-induced& iatrogenichypothyroidism • The following medications reportedly have the potential to cause hypothyroidism: • Iodine excess (including iodine-containing contrast media and amiodarone), • lithium, • antithyroid drugs, • p-aminosalicylic acid, • interferon- • tyrosine kinase inhibitors – Sunitinib, imatinib[6] • Bexarotene[7]
  17. 17. • Radioactive iodine (I-131) for treatment of Graves disease  results in permanent hypothyroidism within 3-6 months after therapy. • External neck irradiation (for head and neck neoplasms, breast cancer, or Hodgkin disease) • Thyroidectomy-approximately 15-30%
  18. 18. Genetics • Genome-wide association studies FOXE1 gene  hypothyroidism. • 10% of patients with congenital hypothyroidism have an error in thyroid hormone synthesis.[9] • Mutations in the TPO gene appear to be the most common error of hormone synthesis, causing failure to produce adequate amounts of TPO.[10] • Mutations in the TSHR and PAX8 genes  congenital hypothyroidism without goiter.[11, 12]
  19. 19. • Pendred syndrome  mutation in the SLC26A4 gene defect in the organification of iodine congenital sensorineural hearing loss, enlarged thyroid gland. autosomal recessive manner.[13] • Autoimmune polyendocrinopathy typeIAIRE genecharacterized by the presence of Addison disease, hypoparathyroidism, and mucocutaneous candidiasis. • Autoimmune polyendocrinopathy type 2 (Schmidt syndrome) is associated with adrenal insufficiency and hypothyroidism
  20. 20. Iodine deficiency or excess • Most common cause of hypothyroidism. Excess iodine can transiently inhibit iodide organification and thyroid hormone synthesis (the Wolff-Chiakoff effect). • Healthy individualsphysiologic escape from this effect. In patients with iodine overloadsodium-iodide symporter shuts downallows intracellular iodine levels to drop and hormone secretion to resume. • The Wolff-Chiakoff effect is short-livedsodium-iodide symporter is capable of rapidly downregulation. • exposure to excess iodineprofound and sustained hypothyroidism in individuals with abnormal thyroid glands.[15]
  21. 21. Goitre can be classified as per WHO classification • Grade 0 – no goitre presence is found (the thyroid impalpable and invisible) • Grade 1 – neck thickening is present in result of enlarged thyroid, palpable,not visible in normal position of the neck. • Grade 2 – neck swelling, visible when the neck is in normal position, corresponding to enlarged thyroid – found in palpation.
  22. 22. Central hypothyroidism[16, 17] • Central hypothyroidismhypothalamic-pituitary axis is damaged. The following potential causes should be considered : Pituitary adenoma-exerting pressure on normal pituitary cells Tumors impinging on hypothalamus Lymphocytic hypophysitis- cause death of cells. Sheehan syndrome History of brain or pituitary irradiation
  23. 23. • Drugs (eg, dopamine, prednisone, or opioids)-decreased TSH secretion. • Congenital non goiterous hypothyroidism type 4Mutation in theTSHB geneautosomal recessive pattern • TRH resistanceTRHR geneautosomal recessive manner. hypothyroidism and, unsurprisingly, have insensitivity to thyrotropin secretion.[19] • TRH deficiencymutation in the TRH geneautosomal recessive manner.[20]
  24. 24. • Sign or symptom Affected patients(%) • Weakness 99 Skin changes (dry or coarse skin) Lethargy 97 Slow speech 91 Eyelid edema 91 Cold sensation 90 Decreased sweating 89 Cold skin 89 Thick tongue 83 Facial edema 82 Coarse hair 79 Skin pallor 76 Forgetfulness 67 Constipation 66
  25. 25. • Menstrual disturbances,infertility • Paresthesias, nerve entrapment syndromes • Blurred vision • Decreased hearing • Fullness in the throat, hoarseness Hashimoto thyroiditis is difficult to distinguish clinically, but the following symptoms are more specific to this condition: • Feeling of fullness in the throat • Painless thyroid enlargement • Exhaustion • Transient neck pain, sore throat, or both
  27. 27. LABORATORY ASSESSMENT 1.Tests of the Hypothalamic-Pituitary-Thyroid Axis • TSH secretion: precise and specific indicator of the thyroid status • Normal range of the serum TSH:0.5 to 4.7 mU/L • Diurnal variation of TSH secretion with peak values in the early evening
  28. 28. TSH as a screening test :misleading INCREASED TSH • TSH-secreting pituitary tumor • Thyroid hormone resistance • Assay artifact DECREASED TSH • 1ST trimester of pregnancy (due to hCG secretion), • After treatment of hyperthyroidism • Response to high doses of glucocorticoids or dopamine Secondary hypothyroidism: • Low to high-normal TSH level, inappropriate for the low T4 level.
  30. 30. Sick Euthyroid Syndrome • Acute, severe illness causes abnormalities of TSH or thyroid hormone levels in the absence of underlying thyroid disease • Major cause cytokines such as IL-6. • M/C hormone patterndecrease in total and unbound T3 levels (low T3 syndrome) with normal levels of T4 and TSH. • Magnitude of the fall in T3 correlates with the severity of the illness. • T4 conversion to T3 via peripheral deiodination is impaired, leading to increased reverse T3 (rT3).
  31. 31. • Very sick patients :fall in total T4 and T3 levels (low T4 syndrome) • TSH levels may range from <0.1 to >20 mIU/L Diagnosis of SES • Previous history of thyroid disease and TFT • Evaluation of the patient's acute illness • Measurements of Rt3 with unbound thyroid hormones and TSH. • Diagnosis of SES is presumptive • Resolution of the test results with clinical recovery can clearly establish this disorder.
  33. 33. CLINICAL IMPROVEMENT • Wt loss of 2 to 4 kg • Pulse rate increase • Appetite improves, Constipation disappears • Psychomotor activity increases • Hoarseness ,changes in skin and hair improve last
  34. 34. Special Treatment Considerations PREGNANCY:Increase in serum TBG • The mean increment in dose is 50μg/dayapparent by the end of the first trimester, though may be delayed to as late as the 6th month of gestation in some women. • A similar up-titration of thyroxine dose may be required in women who are on estrogen preparations including the oral contraceptive pill.
  35. 35. • TOC : Synthetic levothyroxine • Most patients with postpartum thyroiditis require treatment during the hypothyroid phase • Long-term follow-up of patientsrisk of permanent hypothyroidism • Subclinical hypothyroidism in pregnancy requires replacement treatment
  36. 36. Hypocortisolemia: • Co-existence of thyroid hormone deficiency and glucocorticoid deficiency • Important to replace glucocorticoid before starting thyroxine. • Thyroxine therapy may lead to an increased metabolism,increased demand of cortisol increasing the likelihood of precipitating an adrenal crisis.
  37. 37. Central hypothyroidism: • Important to replace glucocorticoid before starting thyroxine. • Monitoring of therapyserum T4 levels instead of serum TSH levelssample should be collected prior to ingesting the morning dose of thyroxine.
  38. 38. Ischemic heart disease: • Thyroxine therapyimproves myocardial function reduces peripheral vascular resistance • Increases the myocardial oxygen demand angina in 2% patients. • Patients with pre-existing angina should ideally undergo a cardiac evaluation prior to initiating thyroxine therapy. • Therapystarted at 25μg/day or even less and increased no faster than at 4 weekly intervals.
  39. 39. Patients unable to take oral thyroxine: • Intravenous thyroxine can be given in a dose approximately 70% of the oral dose, which reflects the fractional absorption of the oral dose.
  40. 40. Persistently elevated TSH despite thyroid hormone replacement • poor compliance- try ‘catch up’ when a physician visit approachesfree T4 NORMAL,TSH ELEVATED • Tissue-level unresponsiveness to thyroid hormoneRARE • Only 300 families have been identified with this genetic mutation.
  41. 41. Myxedema Coma • Myxedema coma is a severe life threatening situation • Most commonly occurs in individuals with undiagnosed or untreated hypothyroidism who are subjected to an external stress, such as low temperature, infection, myocardial infarction, stroke. • Respiratory depression,Bradycardia, Hypotension, decreased intestinal motility, Hyponatremia, Altered sensorium, Infections and Hypothermia. • Most patients need ventilatoryat least 24-48 hoursmeasurement of arterial blood gases is mandatory.
  42. 42. TREATMENT • Management includes maintaining of vital parameters • Administration400 to 500 mcg of L-thyroxine through nasogastric tube initially and subsequently 100 mcg/day. • route is suboptimalconcerns of erratic absorption(gastric atony) • Corticosteroids may be given along with assisted ventilation and O2 administration. • Hypothermiainsulating blankets.
  43. 43. Subclinical Hypothyroidism • Persistently elevated TSH levels and free thyroxine (T4) levels are not below normal • May resolve on its own or remain unchanged. • Rest of the patients proceed to develop overt hypothyroidism (low free T4 and raised TSH levels) within a few years. • Patients with raised TSH elevations and detectable anti-thyroid antibody levelsincreased risk of developing overt disease.
  44. 44. • mild hypothyroid symptoms • subtle serum lipoprotein • cardiac function abnormalities • Progression to overt hypothyroidism5 to 20% per year in patients with both mildly elevated TSH levels and antithyroid antibodies.
  45. 45. Important clinical pointers when monitoring thyroid replacement therapy • Serial TSH measurements in patients with an intact hypothalamic-pituitary axis. • Important to keep in mind that changes in TSH levels lag behind changes in thyroid hormone levels. • Subsequent to adjustment of levothyroxine dosage, TSH levels should be assessed only at least after four weeks. • Changes in TSH levelsafter eight weeks of therapy with thyroid hormone replacement.
  46. 46. • Adequacy of treatment in patients with pituitary insufficiency measurements of free T4 and T3 levels. • Increasing age is associated with declining thyroid binding and serum albumin levels,dosage requirementreduced by up to 20%. • Elderly patientsannual monitoring for thyroid function in order to avoid over replacement.
  47. 47. • Most hypothyroid patientstested annually for TSH or free T4 levelsno data exists to support this practice. • Stable maintenance dosage of levothyroxine is achieved, it is adequate to maintain a euthyroid state until the patient becomes 6o to 70 years old.
  48. 48. Potential adverse effects of treatment • Regular monitoring of serum TSH levelsmid- normal serum TSH values ensuresis safe and free from adverse events. • In the event that thyroxinesuppressive dosesafter carcinoma thyroid surgerypotential adverse effectsskeletal and cardiovascular system. • A TSH value of <0.1mU/lrisk factor for atrial fibrillation, left ventricular hypertrophy and enhanced risk for ischemic heart disease.
  49. 49. References: • WILLIAMS TEXT BOOK OF ENDOCRINOLGY • HARRISONS 18TH EDITION • Facts of Iodine Supplementation-RK Marwaha*, S Gopalakrishnan* -© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59 • Update Article-Drugs and Thyroid Joe George*, Shashank R Joshi* © JAPI • VOL. 55 • MARCH 2007 • Hypothyroidism shashank r Joshi-MEDICINE UPDATE • Management of Hypothyroidism in Adults-Nikhil Tandon-© SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59 • Thyroid Disorders in Pregnancy-Samar Banerjee-©SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59 • Think Thyroid-Siddharth N Shah*, Shashank R Joshi**-©SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59 • Clinical Approach to Thyroid Disease-RV Jayakumar*-©SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59 • Laboratory Evaluation of Thyroid Function-Shashank R Joshi- ©SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59 • Thyroid Emergencies-Siddharth N Shah-©SUPPLEMENT TO JAPI • JANUARY 2011 • VOL. 59
  50. 50. 5-Stuckey BG, Kent GN, Ward LC, Brown SJ, Walsh JP. Postpartum thyroid dysfunction and the long-term risk of hypothyroidism: results from a 12-year follow-up study of women with and without postpartum thyroid dysfunction. Clin Endocrinol (Oxf). Sep 2010;73(3):389-95. [Medline]. 6-Wolter P, Dumez H, Schöffski P. Sunitinib and hypothyroidism. N Engl J Med. Apr 12 2007;356(15):1580; author reply 1580-1. [Medline]. Smit JW, Stokkel MP, Pereira AM, Romijn JA, Visser TJ. Bexarotene-induced hypothyroidism: bexarotene stimulates the peripheral metabolism of thyroid hormones. J Clin Endocrinol Metab. Jul 2007;92(7):2496-9. [Medline]. 9-Vono-Toniolo J, Rivolta CM, Targovnik HM, Medeiros-Neto G, Kopp P. Naturally occurring mutations in the thyroglobulin gene. Thyroid. Sep 2005;15(9):1021-33. [Medline]. 10-Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet. May 2005;42(5):379-89.[Medline]. [Full Text]. 11-Paschke R, Ludgate M. The thyrotropin receptor in thyroid diseases. N Engl J Med. Dec 4 1997;337(23):1675-81. [Medline].
  51. 51. 12-Macchia PE, Lapi P, Krude H, Pirro MT, Missero C, Chiovato L, et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet. May 1998;19(1):83-6. [Medline]. 13-Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet. Dec 1997;17(4):411-22. [Medline]. 15-Woeber KA. Iodine and thyroid disease. Med Clin North Am. Jan 1991;75(1):169-78. [Medline] 16-Yamada M, Mori M. Mechanisms related to the pathophysiology and management of central hypothyroidism. Nat Clin Pract Endocrinol Metab. Dec 2008;4(12):683-94. [Medline]. 17-Nebesio TD, McKenna MP, Nabhan ZM, Eugster EA. Newborn screening results in children with central hypothyroidism. J Pediatr. Jun 2010;156(6):990-3. [Medline]. 19-Bonomi M, Busnelli M, Beck-Peccoz P, Costanzo D, Antonica F, Dolci C, et al. A family with complete resistance to thyrotropin-releasing hormone. N Engl J Med. Feb 12 2009;360(7):731-4. [Medline]. 20-Katakami H, Kato Y, Inada M, Imura H. Hypothalamic hypothyroidism due to isolated thyrotropin-releasing hormone (TRH) deficiency. J Endocrinol Invest. Jun 1984;7(3):231-3. [Medline].