Pathophysiology of Thyroid Disorders Ebenezer Nyenwe, MD Assistant Professor of Medicine Division of Endocrinology, Diabetes and Metabolism College of Medicine University of Tennessee Health Science Center Memphis, TN
Congenital Hypothyroidism and/or Goiter result from defects in iodine binding mechanism. Mutations in NIS. Abnormalities in synthesis of TG or TPO. Cyanates and Perchlorate compete with iodine for NIS thus predisposing to iodine deficiency and goiter (goitrogens). Pendred s syndrome is an autosomal recessive disorder due to mutation in pendrin gene- deafness, goiter and impaired thyroid hormone synthesis The release of thyroid hormone is inhibited by high iodine load (Wolff-Chaikoff effect) and Lithium
Thyroid hormone binding to TBG is inhibited by Phenytoin, Salicylate, salsalate, furosemide, fenclofenac and mitotane. Low TBG levels occur nephrotic syndrome High TBG levels Familial-X-linked genetic disorder Acquired- pregnancy, estrogen, hepatitis
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TSH secretion is decreased by- Dopamine, Dobutamine, Somatostatin, Acute high dose glucocorticoids, Baroxetene. Mutations in the TSH receptor can result in activation or inhibition of the receptor. A clone of such cells with constitutive activation could give rise to autonomous nodules.
Pathophysiology of Thyroid Disorders Iodine deficiency (IDD)- about a billion people live in iodine deficient regions. Goiter Hypothyroidism Impaired mental function (cretinism in severe cases) Impaired physical development Increased perinatal mortality Autoimmune thyroid disease TSH receptor Thyroid peroxidase Thyroglobulin
Goiter Goiter is the enlargement of the thyroid gland- Diffuse Solitary nodule or Multinodular Etiology- Autoimmune Familial Genetic abnormalities involving TG, NIS, TPO, pendrin and TSHR are associated with goiter and hypothyroidism. Growth factors- EGF, IGF-1, FGF, TGF and VEGF Environmental factors- iodine deficiency, cigarette smoking, drugs eg lithium, goitrogens. Neoplasia
Laboratory Investigations Thyroid function test- TSH, Total T 4, Free T 4, Total T 3, Free T 3 Thyroid antibodies- TSI, TPO, Thyroglobulin and anti TG Thyroxine binding globulin Imaging Thyroid ultrasound Radioactive iodine uptake and thyroid scan CT, MRI, PET scan Fine needle aspiration biopsy/cytology Histopathology
Ultrasound Features Suggestive of Malignancy Solid hypoechoeic nodule Absence of cystic elements Microcalcification Irregular shape Thick wall Absence of halo hypervascularity
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Features Suggestive of Thyroid Malignancy Age - < 20 or > 70 years Male History of Radiation Family history of Thyroid cancer or MEN 2 Rapid growth Recent dysphagia, dypsnoea or dysphonia
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Papillary CA
Abnormal Thyroid function Tests in Euthyroid subjects. Non thyroidal illness Pregnancy Psychiatric illness Liver disease Familial variant binding proteins Thyroid hormone resistance
Case # 1. A 24-year-old female college student who started using oral contraceptive pill six months ago was found to have abnormal thyroid function test (TFT) while being investigated for excessive weight gain. She had no history of heat or cold intolerance and no change in appetite or bowel habit. Her sleeping pattern had remained unchanged. She denied palpitation, tremors or sweating. Her menstrual cycle was normal. Physical examination revealed a young woman who was overweight (BMI= 28), pulse rate= 82/min, BP= 122/75 mmhg. No proptosis. Thyroid gland was not palpable. The rest of the physical exam was unremarkable. Labs. CMP= within normal limits CBC= Within normal limits TSH= 2.4 µu/ml ( 0.5-5.0) Free T4 = 1.8ng/dl (0.7-2.0) Total T3 = 210ng/dl ( 70-190) Total T4= 15µg/dl (5-12) 1. What abnormalities do you identify in her TFT? 2. What is the etiology of this woman s abnormal TFT? 3. What is your diagnosis? 4. What intervention would you recommend at this point? 5. What are the other causes of this abnormality?
Case #2 and # 3 A 22-year-old African-American woman presents with a two-month history of weight loss despite increased appetite, insomnia, heat intolerance and sweating. She has also noticed increasing episodes of palpitations and exertional dyspnea as well as difficulty with climbing stairs and combing her hair. On further questioning she admitted to tremors, fidgeting, lose bowel motions and scanty menstrual periods but no ammenorrhoea. Physical exam showed BMI= 20, pulse = 112/min, regular, large volume, BP= 144/62 mmhg, RR= 18/min. She had bilateral proptosis with lid lag and lid retraction on the left side but no ophthalmoplegia. She had soft, non-tender, diffuse thyromegaly, which was about two times enlarged with audible bruit, but no cervical lymphadenopathy. Auscultation of the heart revealed tachycardia with a third heart sound but no murmur. She had tremor of the out stretched hands which were warm and moist. Deep tendon reflexes were brisk but she had some difficulty standing up from her chair. Labs CMP= within normal limits CBC= Within normal limits TSH= 0.001 µu/ml ( 0.5-5.0) Free T4 = 3.8ng/dl (0.7-2.0) Total T3 = 228ng/dl ( 70-190) 1.What is your clinical Diagnosis? 2. What is the pathophysiology of her disease? 3. How would you confirm your clinical diagnosis? 4. What other tests might be helpful in her management? 5. What treatment would you recommend for this patient?
Patient presents 6 months after treatment with complaints of weight gain, constipation, somnolence and sluggishness with dry skin, hair loss and menorrhagia. Pulse= 54/min, BP= 130/98 mmhg. Thyroid gland which had diminished in size was very firm and non-tender. Deep tendon reflexes showed slow relaxation after initial normal upstroke. Labs TSH= 30.4 µu/ml ( 0.5-5.0) Free T4 = 0.31 ng/dl (0.7-2.0) Total T3 = 52 ng/dl ( 70-190) 1. What is your diagnosis? 2. What is the pathophysiology of her disease? 3. What treatment would you recommend at this time? 4. How long will you treat her?
Case #4 A 65-year-old man with history of diabetes, hypertension, hyperlipidemia admitted to the coronary care unit for acute myocardial infarction was found to have the following TFT on the third day of admission. TSH= 4.0 µu/ml ( 0.5-5.0) Free T4 = 1.1 ng/dl (0.7-2.0) Total T3 = 50 ng/dl ( 70-190) 1. What is you Diagnosis? 2. What is the reason for the low T3 in this patient? 3. How would you treat this patient?