9Biosynthesis, Secretion, And Transport of Thyroid hormones Iodine is the most important element in the biosynthesis of thyroid hormones.Thyroglobulin acts as a performed matrix containing tyrosyl groups to which the reactive iodine attaches to form the hydroxyl residues of monoiodotyrosine (MIT) and diiodotyrosine (DIT).The coupling of two DIT molecules forms T4 .The coupling of one DIT molecules and one MIT molecule results in the formation of T3 or reverse T3 (rT3)Almost all circulating T4 and T3 hormones are bound to serum proteins ( thyroid hormone-binding proteins )
10Thyroid Hormone Synthesis Iodide trappingOxidation of iodide and iodination of thyroglobulinCoupling of iodotyrosine molecules within thyroglobulin (formation of T3 and T4)Proteolysis of thyroglobulinDeiodination of iodotyrosinesIntrathyroidal deiodination of T4 to T3
13Only 0. 03 % of T4 and 0. 3 % of T3 are not bound to proteins Only 0.03 % of T4 and 0.3 % of T3 are not bound to proteins . These fractions, called free T4 (FT4) and free T3 (FT3), are the physiologically active portions of the thyroid hormones .T3 is the most biologically active thyroid hormone and is three to four times more potent than T4.T3 is more active because it is not as tightly bound to the serum proteins as is T4, and has a greater affinity to target tissue receptors
16Thyroid function tests TSH :The single most sensitive, specific and reliable test of thyroid status .In primary hypothyroidism, [TSH] is increased.In primary hyperthyroidism, [TSH] is decrease or undetectableTotal T4 and Total T3 :More than 99% of T4 and T3 circulate in plasma bound to proteinBoth [total T4] and [total T3] change if [TBG] alters, e.g. in pregnancyFree T4 and Free T3Free thyroid hormone concentrations are independent of changes in the concentration of thyroid-hormone binding proteins → more reliable for diagnosis of thyroid dysfunction
17Interpreting results of thyroid function tests Primary hyperthyroidismPlasma [TSH] : ↓ due to feedback inhibition on the pituitaryPlasma free and total T4 and T3 concentrations : ↑
18Primary hypothyroidism: Plasma [TSH] : ↑Plasma [free T4] and [total T4] : ↓Plasma free T3 and total T3 measurements are of no value here, since normal concentrations are often observed .
20Evaluation of the Thyroid Disease(Ultrasonography) Most sensitive procedure or identifying lesions in the thyroid (2-3mm)90% accuracy in categorizing nodules as solid, cystic, or mixed (Rojeski, 1985)Best method of determining the volume of a nodule (Rojeski, 1985)Can detect the presence of lymph node enlargement and calcificationsNoninvasive and inexpensive
21Evaluation of the Thyroid Disease (Radioisotope Scanning) Prior to FNA, was the initial diagnostic procedure of choicePerformed with: technetium 99m pertechnetate or radioactive iodineTechnetium 99m pertechnetatecost-effectivereadily availableshort half-lifetrapped but not organified by the thyroid - cannot determine functionality of a nodule
26(Fine-Needle Aspiration) Evaluation of the Thyroid Disease Currently considered to be the best first-line diagnostic procedure in the evaluation of the thyroid nodule:Advantages:SafeCost-effectiveMinimally invasiveLeads to better selection of patients for surgery than any other test (Rojeski, 1985)
27Effects of Thyroid Hormone Fetal brain and skeletal maturationIncrease in basal metabolic rateInotropic and chronotropic effects on heartIncreases sensitivity to catecholaminesStimulates gut motilityIncrease bone turnoverIncrease in serum glucose, decrease in serum cholesterol
30Goiterogenesis Iodine deficiency results in hypothyroidism Increasing TSH causes hypertrophy of thyroid (diffuse nontoxic goiter)Follicles may become autonomous; certain follicles will have greater intrinsic growth and functional capability (mult inodular goiter)Follicles continue to grow and function despite decreasing TSH (toxic mul tinodular goiter)Sporadic vs. endemic goiter
31Simple (Colloid) Goiter Diffuse goiterUsually euthyroidPeaks in pubertyEndemic goiterCompensatory TSHFollicular cell hypertrophy and hyperplasiaGoiterogens (eg, cassava)Non endemic or sporadic less commonRare hereditary defects in thyroid hormone synthesisNote distension of follicles with colloid and flattening of epithelial cells
32Multinodular GoiterMost simple goiters become transformed into multinodular goiters.Nontoxic or toxic (induce thyrotoxicosis)No ophthalmopathy or dermopathyMay cause cosmetic disfigurement and tracheal compressionMay induce the superior vena caval syndromeDifferentiation of a dominant nodule from a thyroid tumour may be difficult.Retrosternal extension
35PresentationUsually picked up on routine physical exam or as incidental findingPatients may have clinical or subclinical thyrotoxicosisPatients may have compressive symptoms: tracheal, vascular, esophageal, recurrent laryngeal nerve
37Note fibrosis and variation of follicular size Multinodular GoitreNote fibrosis and variation of follicular size
38Gross and Microscopic Pathology Multinodular Goiter
39Figure 17-5. (A) Cross section of multinodular goiter Figure (A) Cross section of multinodular goiter. (B) Gross radioautograph of the thyroid in part a. Observe the variation in 131I uptake in different areas.
40Treatment of Diffuse or Multinodular Goiter Suppressive TherapyAntithyroid Medications: Propylthiouracil and MethimazoleI-131Surgical Therapy
42Tumours of Thyroid Gland 2-4% estimated incidence of palpable solitary nodules.Most are not neoplastic and 90% of neoplastic nodules are adenomas.Thyroid cancer is rare (30 per million per year).The younger the patient the greater the chance of neoplasia.A nodule in a male patient is more suspicious than in a female.
43Thyroid Adenoma Most are follicular adenomas Encapsulated Homogeneous, soft, fleshy cut surfaceFoci of haemorrhageRarely cause hyperthyroidismMost are “cold” on isotope thyroid scanCystic degeneration
44Malignant Thyroid Tumours Papillary carcinomaFollicular carcinomaMedullary carcinomaAnaplastic carcinomaLymphomaTumours metastatic to the thyroid
45HistorySymptomsThe most common presentation of a thyroid nodule, benign or malignant, is a painless mass in the region of the thyroid gland (Goldman, 1996).Symptoms consistent with malignancyPaindysphagiaStridorhemoptysisrapid enlargementhoarseness
46History (continued...) Risk factors Thyroid exposure to irradiation low or high dose external irradiation (40-50 Gy [ rad])especially in childhood for:large thymus, acne, enlarged tonsils, cervical adenitis, sinusitis, and malignancies30%-50% chance of a thyroid nodule to be malignant (Goldman, 1996)
47Risk factors (continued…) History (continued...)Risk factors (continued…)Age and SexBenign nodules occur most frequently in women years (Campbell, 1989)Men have a higher risk of a nodule being malignant
48History (continued…) Family History History of family member with medullary thyroid carcinomaHistory of family member with other endocrine abnormalities (parathyroid, adrenals)
49Evaluation of the thyroid Nodule (Physical Exam) Examination of the thyroid nodule:consistency - hard vs. softsize - < 4.0 cmMultinodular vs. solitary nodulemulti nodular - 3% chance of malignancy (Goldman, 1996)solitary nodule - 5%-12% chance of malignancy (Goldman, 1996)Mobility with swallowingMobility with respect to surrounding tissuesWell circumscribed vs. ill defined borders
50Evaluation of the Thyroid Nodule (Blood Tests) Thyroid function teststhyroxine (T4)triiodothyronin (T3)thyroid stimulating hormone (TSH)CalcitoninThyroglobulin (TG)Serum Calcium
51Evaluation of the Thyroid Nodule (imaging) Chest radiographComputed tomographyMagnetic resonance imagingRadioimaging usually not used in initial work-up of a thyroid nodule
52Evaluation of the Thyroid Nodule (Ultrasonography) Most sensitive procedure or identifying lesions in the thyroid (2-3mm)Best method of determining the volume of a nodule (Rojeski, 1985)Can detect the presence of lymph node enlargement and calcificationsNoninvasive and inexpensive
53Evaluation of the Thyroid Nodule (Radioisotope Scanning) Prior to FNA, was the initial diagnostic procedure of choice
54Evaluation of the Thyroid Nodule (Fine-Needle Aspiration) Currently considered to be the best first-line diagnostic procedure in the evaluation of the thyroid nodule:Advantages:SafeCost-effectiveMinimally invasiveLeads to better selection of patients for surgery than any other test (Rojeski, 1985)
55Fine-Needle Aspiration (continued…) FNA halved the number of patients requiring thyroidectomy (Mazzaferri, 1993)FNA has double the yield of cancer in those who do undergo thyroidectomy (Mazzaferri, 1993)
56Fine-Needle Aspiration (continued…) Pathologic results are categorized as:positive,negative, orindeterminate
58Chronic Thyroiditis Also known as Hashimoto’s disease Probably the most common cause of hypothyroidism in United StatesAutoantibodies include: thyroglobulin antibody, thyroid peroxidase antibody, TSH receptor blocking antibody
59Gross and Microscopic Pathology of Chronic Thyroiditis
60Presentation and Course Painless goiter in a patient who is either euthyroid or mildly hypothyroidpermanent hypothyroidismMay have periods of thyrotoxicosisTreat with levothyroxine
61Subacute Thyroiditis Most common cause of thyroid pain and tenderness Acute inflammatory disease most likely due to viral infectionTransient hyperthyroidism followed by transient hypothyroidism; permanent hypothyroidism or relapses are uncommon
67ACUTE INFECTIOUS THYROIDITIS Rare, serious, bacterial inflammatory disease of the thyroid.
68Protective mechanisms of the thyroid gland: very good perfusionefficient lymphatic drainagecapsulation of the thyroidhigh concentration of iodine
69Etiologic agents:Streptococcus pyogenes,Streptococcus pneumoniae,Escherichia coli,Pseudomonas aeruginosa,Salmonella typhi,anaerobes of the oropharyngeal cavity.
70RARE FORMS OF INFECTIOUS THYROIDITIS: the thyroid is rarely the seat of tuberculosis, syphilis, fungal infections (Aspergillus species), or parasites;Pneumocystis carinii infection of the thyroid has been reported in patients with AIDS.
71TREATMENT OF INFECTIOUS THYROIDITIS this type of thyroiditis requires the administration of appropriate antibiotics based on the findings of the culture from a fine-needle aspirate, and surgical drainage (or excision) of any area of fluctuance or abscess.
73CLINICAL PICTURE OF ACUTE INFECTIOUS THYROIDITIS the skin over the infected area is erythematous and warmthe white cell count and erythrocyte sedimentation rate are elevatedthyroid antibodies are absentserum T4 and T3 levels are usually normal as well as thyroid RAIU
74TREATMENT OF INFECTIOUS THYROIDITIS this type of thyroiditis requires the administration of appropriate antibiotics based on the findings of the culture from a fine-needle aspirate, and surgical drainage (or excision) of any area of fluctuance or abscess.
75Drug-Induced Thyroiditis Patients receiving cytokines such as IFN- or IL-2 may develop painless thyroiditisAmiodarone
78HypothyroidismClinical syndrome resulting from a deficiency of thyroid hormones, which in turn results in generalized slowing down of metabolic processes
79Classification of hypothyroidism Primary (thyroid failure)Secondary (Central):pituitary TSH deficithypothalamic deficiencyPeripheral resistance to the thyroid hormonesGoitrusNongoitrus
80Etiology of hypothyroidism • Primary:1. Hashimoto’s thyroiditisA/ with goiterB /thyroid atrophyend-stage autoimmune thyroid disease, following either Hashimoto’s thyroiditis or Graves’ disease2. Subacute thyroiditis3. Thyroidectomy or therapy for hyperthyroidism (drugs, 131I)4. Excessive iodide intake5. Other causesA/ Iodide deficiencyB/ GoitrogensC/ Inborn errors of thyroid hormone synthesis
81Etiology of hypothyroidism Secondary(Central):Hypopituitarism due to pituitary adenoma, pituitary ablative therapy, or pituitary destructionHypothalamic destructionPeripheral resistance to the action of thyroid hormones
82CretinismMain features: goiter, mental retardation, short stature , puffy appearance of the face and hands, neurologic signs
83Cretinism Symptoms of hypothyroidism in newborns: respiratory difficulty, cyanosis, jaundice, poor feeding, hoarse cry, umbilical hernia, marked retardation of bone maturation
84Hypothyroidism in children Retarded growthMental retardationPrecocious pubertyenlargement of the sella turcica
85Hypothyroidism in adults Common features:Easy fatigability, coldness, weight gain, constipation, menstrual irregularities, muscle crampsPhysical findings:cool,rough, dry skin, puffy face andhands, a hoarse, husky voice, slow reflexes, yellowish color of the skin(increased level of carotene)
86Hypothyroidism in adults Cardiovascular signs:Impaired muscular contraction,bradycardia, diminished cardiac output• Low voltage of ECG
87Hypothyroidism in adults Pulmonary function:Shallow, slow respirationsImpaired ventilatory response to hypercapnia or hypoxiaRenal function:Decreased glomerular filtrationImpaired ability to excrete water load
88Hypothyroidism in adults Anemia:Impaired hemoglobin synthesisIron deficiency (increased loss with menorrhagia, impaired absorption from intestine)Folate deficiency (imapired intestinal absorption)Pernicious anemia (vitamin B12 deficiency, autoimmune)
89Hypothyroidism in adults Neuromuscular system:Severe muscle crampsParesthesiasMuscle weaknessCentral nervous system:Chronic fatigueLethargyInability to concentrate
91DiagnosisIf TSH is low and hypothyroidism is still suspected, check the free thyroxine.If this is low the patient either has central (hypothalamic) hypothyroidism or is not hypothyroid.With hypothalamic hypothyroidism, there is always a deficiency of the other pituitary hormones---check cortisol
92THERAPY OF HYPOTHYROIDISM Treatmant of choice is L-thyroxine
94ThyrotoxicosisDefined as the clinical,physiologic,and biochemical findings that result when the tissues are exposed to,and respond to,excess thyroid hormone.RAIU is subnormal
95HyperthyroidismDenotes only those conditions in which sustained hyperfunction of the thyroid gland leads to thyrotoxicosis.Increased RAIU is the hallmark.
96Varieties of Thyrotoxicosis Associated with thyroid hyperfunction:Excess production of TSH(rare)Abnormal thyroid stimulator-Eg:Graves’ diseaseIntrinsic thyroid autonomy-Eg:Hyperfunctioning adenoma, Toxic multinodular goitreNot associated with thyroid hyperfunction:Disorders of hormone storage-Eg:Subacute thyroiditis, chronic thyroiditisExtrathyroid source of hormone- Thyrotoxicosis factitia,ectopic thyroid tissue- struma ovarii, functioning follicular Ca.
97Clinical featuresThe clinical manifestations include those that reflect the associated thyrotoxicosis
98Clinical features of thyrotoxicosis Neuromuscular:Nervousness,irritability,emotional liability,psychosisTremorHyperreflexiaMuscle weakness,proximalReproductive:Amenorrhoea,OligomenorrhoeaInfertility,impotence
99Thyrotoxicosis.. Gastrointestinal: Weight loss despite increased appetiteDiarrhea and steatorrheaVomitingCardiorespiratory:Palpitations,Sinus tachycardia,Atrial fibrillationIncreased pulse pressureAngina,cardiomyopathy and heart failure
101Hyperthyroidism Graves’ disease Also known as Basedow’s disease.Graves’ disease is a disorder with three major manifestations:1)Hyperthyroidism with diffuse goiter2)Ophthalmopathy3)Dermopathy.These three manifestations may not appear together.
102Incidence and prevalence Relatively common disease that can occur at any ageMore common in the 3rd and 4th decadeDisease is more frequent in women(7:1)Genetic factors play an important roleAn overlap exsists with other autoimmune diseases suggesting Graves is also a autoimmune thyroid disease
103Etiology and Pathogenesis Cause of Graves’ is unknownNo single factor is responsible for the entire syndrome
104Pathology Thyroid gland is diffusely enlarged,soft and vascular. There is parenchymatous hyperplasia and hypertrophy with lymphocytic infilteration.
105PathologyThe ophthalmopathy is characterized by an inflammatory infilterate of the orbital contentsThe dermopathy of Graves’ disease is characterized by thickening of the dermis,which is infilterated by lymphocytes and mucopolysaccharides
106Goiter Is diffuse and toxic and maybe asymmetric and lobular. There may be presence of bruit over the goiter
108OphthalmopathySigns of Graves’s ophthalmopathy are divided into two components:1) Spastic: Stare, lid lag and lid retraction which account for the “frightened” facies.2) Mechanical: Proptosis of varying degrees,ophthalmoplegia,and congestive occulopathy characterized by chemosis,conjunctivitis,periorbital swelling and the potential complications of corneal ulceration,optic neiritis and optic atrophy.
111DermopathyUsually occurs over the dorsum of the legs or feet and is termed localized or pretibial myxedema.The affected area is usually demarcated from the normal skin by being raised and thickened and having a peau d’ orange appearance;it may be pruritic and hyperpigmented.The most common presentation is non pitting oedema,but lesions maybe plaque like,nodular or polypoid.Clubbing of the fingers and toes accompanies and is termed thyroid acropachy
118Duration of treatment 18-24 months Side effects- Rash Leukopenia Agranulocytosis
119Ablative therapy (Surgery & Iodine) Indications:Relapse or recurrance following drug therapyA large goiterFailure to follow medical regimen.Radioactive iodine is simple,effective and economical
120Complications of ablative therapy Immediate complications of surgery:Bleeding,injury to recurrant laryngeal nerve and thyroid crises.Other complicationsHypothyroidismRadiation thyroiditis
121Complications of thyrotoxicosis 1)Cardiac- Heart failureAtrial fibrillation2)Thyrotoxic crises: or ‘storm’:Fulminating increase in signs and symptoms of thyrotoxicosis.Occurs in medically untreated or inadequately treated patients.May be precipitated by surgery or sepsisThe syndrome is characterized by extreme irritability,delirium or coma,fever 41°C or more,tachycardia,restlessness,hypotension,vomiting and diarrhea.
122Treatment of thyroid crisis Provide supportive care;Treat dehydrationAdminister glucose and salineVitamin B complex and glucocorticoidsDigitalization is required in those with atrial fibrillationImmediate and large doses of anti thyroid agents(eg-propylthiouracil 100mg every 2h)Iodine intravenously or by mouthPropranolol 40-80mg every 6hDexamethasone(2mg every 6h) and to be tapered later.
123Treatment of ophthalmopathy and Dermopathy Methylcellulose eye dropsTinted glassesPersistant diplopia can be corrected by surgeryPapilloedema,loss of visual field or acuity requires urgent treatment with prednisolone 60 mg daily.Majority of patients require no treatment other than reassurance.Dermopathy of Graves rarely requires treatment