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jan 13
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- 1What can cause changes in the levels of thyroid hormones?• Excess: over-production due to increased TRH/TSH/TSH-like antibody, tumor
Deficiency: reduced production, reduced conversion from T4 to T3, lack of receptor response
Changes in binding proteins?
Changes in diet iodide? - 2Thyroid Hormone SynthesisActive iodide uptake by NIS (trapping) at basal surface of thyrocytes; iodide then exits apical membrane through
pendrin into colloid
Oxidation of iodide to iodine
Organification - iodination of tyrosine residues inthyroglobulin (Tg) to form mono- and diiodotyrosine (MIT and DIT) - 3part 2Coupling of MIT and DIT or DIT and DIT to form tri- and tetra-iodothyronine (T3 and T4)
Tg- T3/T4 endocytosis; T3/T4 removed from Tg and released into circulation
intrathyroidal deiodination of T4 to T3 - 4Thyroperoxidase (TPO)• TPO, a membrane-bound protein, catalyzes oxidation of I- by H2O2, iodination of Tg tyrosine residues, and
coupling of iodotyrosine residues
TPO expression is stimulated by TSH - 5TPO supressionAutoantibodies to TPO suppress its enzymatic activities leading to insufficient production of thyroid hormone –
hypothyroidism
TPO is inhibited by thiocarbamide drugs, e.g. methimazole, carbimazole, and propylthiouracil (PTU) - 6The Sodium-Iodide SymporterAn integral membrane protein in the basolateral membrane of thyroid epithelial cells
Transports Na+ and I– (and radioactive I-) into the cells against the electrochemical gradient for I–
TSH increases its transcription and membrane expression - 7Na I symp supression• Inactivating mutations in the symporter gene result in congenital hypothyroidism
Autoantibodies to the symporter protein adversely affect iodide transport
ClO4− & TcO4− compete with iodide for NIS, which has respectively therapeutic and imaging significance - 8Would diet iodide deficiency cause changes in plasma T4/T3 and TSH/TRH levels?• Long-term causes reduced T4/T3
• Increased TRH/TSH (no neg inhibi)
• Goiter? - 9The Wolff–Chaikoff effect:Excess iodide acutely inhibits thyroid hormone synthesis, in normal people
- 10U secrete more T4 than T3 but more peripeheral T3.
- 11The Hypothalamic-PituitaryThyroid AxisTRH stimulates TSH
TSH stimulates thyroid
Plasma T4/T3 levels are responsible for feedback inhibition
T4 converts to T3 in Hypothalamus and
pituitary - 12TSH-mediated regulation of thyroid glandIncreases follicular cell growth and
differentiation
Stimulates active iodide uptake (trapping)
Increases Tg synthesis and exocytosis to
colloid
Increases TPO activity - 13part 2Increases Tg endocytosis from colloid
Increases processing and secretion of
iodothyronines (T3&T4)
Also enhances blood flow through the thyroid - 14• Permissive Actions- Induce hormone receptors,
induce response elements, enable responsiveness to other hormones such as growth promotion via GH synthesis and target tissue responsiveness to GH and
IGF >> bone growth - 15Direct ActionsInduce specific responses such as
thermogenesis and oxygen consumption
(calorigenesis) via enhanced mitochondrial uncoupling protein (UCP) expression. Increase cell membrane Na+/K+-ATPase, leading to increased in oxygen
consumption >>Basal metabolic rate - 16Metabolic Effects of T3/4Stimulates lipolysis and release of free fatty acids and glycerol
Affects cholesterol metabolism
• Generally stimulates many aspects of carbohydrate metabolism, including GI glucose absorption - 17part 2• Increase protein degradation
Stimulates hepatic conversion of carotene to vitamin A; yellowish tint of the skin in hypothyroidism-carotenemia - 18• Affects cholesterol metabolism• Stimulates metabolism of cholesterol to bile acids
Facilitates rapid removal of LDL from plasma by increasing LDL receptors in the liver - 19T3Local Vasodilation
Decreased Systemic Vascular Resistance
Cardiac Chronotropy and Inotropy - 20Extra heat production• increase in body temperature, cutaneous vasodilation, increased sweating
- 21• Increased basal metabolic rate• Increased appetites and weight loss
- 22• Increased catecholamine effectstachycardia, increased cardiac output and pulse pressure
- 23Thyroid hormone excessExtra heat production
Increased basal metabolic rate
Proteins breakdown-muscle weakness
Increased bowel movements (hyperdefecation)
CNS effect - nervousness, tremor, brisk reflex
Increased catecholamine effects - 24Thyroid hormone deficiency-Reduced heat production
-Decreased basal metabolic rate
-Increased levels of total and LDL cholesterol
Decreased bowel movements (constipation)
Decreased catecholamine effects
Nerve system– chronic fatigue, lethargy, and inability to concentrate, delayed reflex - 25Reduced heat productionCold intolerance, hypothermia, dry skin, slow respirations
- 26Decreased basal metabolic rate• Decreased appetites and weight gain
- 27Decreased catecholamine effects• bradycardia, decreased cardiac output and pulse pressure
- 28Mechanism of Thyroid hormone action:Binds to nuclear receptor attached to promotor/regulator region of
specific genes
transcription and translation
↑ protein synthesis - 29Functions of T4/T3Effects on Fetal Development
Effects on Cardiovascular System
Sympathetic Effects - 30Effects on Fetal DevelopmentPlacenta has a high content of Type III, 5-deiodinase
inactivates most maternal T4 and T3. However, small quantities are essential
for fetal brain and muscle development. - 31Effects on Cardiovascular SystemCause positive inotropic and chronotropic effects on the heart.
T3 – direct vasodilating effect on vascular smooth muscles
lowers peripheral vascular resistance
↑ cardiac output. - 32Sympathetic EffectsThyroid hormones increase transcription of β1- adrenergic receptors making the tissues more sensitive to catecholamines esp. in heart.
- 33Thyroxine binds toTBG > transthyretin >Albumin
T4 - major circulating form
Potency - T3 4x > T4 - 34LevothyroxineSynthetic thyroxine or T4
Oral absorption (40 – 80%).
Plasma protein binding = 99.96%
Absorption affected by food. T4 absorption ↑ by fasting. - 35• Metabolism:Hepatic to T3 (active); T4 deiodination in kidney and periphery; glucuronidation/conjugation also occurs;
undergoes entero-hepatic recirculation.
Classified as a Narrow Therapeutic Index drug - 36USE1° hypothyroidism
• Pituitary TSH suppression - 37MECHANISM:via nuclear receptors to alter gene expression
altered protein synthesis in target tissue. - 38Drugs contraindicated w/ the use of T4SODIUM POLYSTYRENE SULFONATE (Kayexalate®) and CHOLESTYRAMINE (Questran Light®) resins interact w/ T4
reduced T4 absorption from the gut leading to ↓ blood T4 levels - 39part 2RIFAMPIN and PHENYTOIN increase CYP450 enzymes therefore ↑ excretion of T4 by the liver. Dose adjustment of T4 would be warranted.
Dietary constituents like Ca++ ions, Fe++ sulfate can ↓ T4 absorption - 40LiothyronineOral absorption (95%).
• Plasma protein binding = 99.6%
• Faster Metabolism – cleared faster
• Classified as a Narrow Therapeutic Index drug - 41USE1° hypothyroidism
• Pituitary TSH suppression
• T3 alone used in treatment of initial myxedema and myxedema coma. - 42Adverse Effects:Fever
Anxiety
Tachycardia
Palpitations
Increased appetite
Tremors
FAT PIT - 43Graves Dz..
- 44Thyrotoxicosis↑ levels of T3 /T4 as a result from any cause including self administration
Thyrotoxicosis factitia - 45typesPropylthiouracil
• Methimazole - 46USETreat hyperthyroidism
only drugs to treat this - 47Why a clinical delay?Thyroid gland has a large reservoir of the hormone
- 48Both PTU and methimazole cross placental barrier but what is the pharmacokinetic advantage of PTU over methimazole if their use is warranted?Plasma protein binding - PTU > methimazole
- 49Why is the pharmacological onset of PTU faster compared to Methimazole?PTU Inhibits peripheral deiodinase, methimazole DOES NOT
- 50Propylthiouracil v/s MethimazoleIn pregnancy, PTU recommended in 1st trimester followed by methimazole in the 2nd/3rd trimesters.
- 51Side-Effects of ThioaminesGranulocytopenia (rare but reversible)
Skin rashes and allergic reactions (more common)
PTU has BB warning to cause liver injury - 52liver injuryliver failure, liver transplantation or even death. Monitoring liver function test or
hepatocellular integrity does not ↓ the risk of liver injury b/c of sudden onset. - 53Methimazole assoc. w/rare development of fetal abnormalities such as aplasia cutis and choanal atresia
which is why u dont give 1st semester - 54MechanismInhibitor of the organification and hormone release 90% beta and 10% gamma emitter
- 55Downside of 131-Iodine treatmentPrecipitates Hypothyroidism
PREGNANCY CATGORY X: definite risk of fetal injury from (emitting beta particles). Risk >> benefits. Must avoid in pregnancy or if trying to get pregnant. - 56USESTreat hyperthyroidism and certain carcinomas is an adjunct to surgery.
- 57IodineSTRONG IODINE SOLUTION = LUGOL’S SOLUTION contains 5% IODINE + 10% KI
- 58mechanisminhibits thyroid hormone synthesis and
release, prevents iodotyrosine and iodothyronine synthesis by blocking organification - 59WOLFF-CHAIKOFF EFFECT:High I- intrathyroidal concentrations inhibit thyroid peroxidse (TPO) (stop production of T3 and T4)
- 60“Escape phenomenon”production of T3 and T4 isnt forever
-Downregulation of Na+/I- symporter.
-↑ follicular leakage causing I- within the thyroid follicles. - 61USES of IodineReduce size and vascularity of thyroid gland, therefore is used prior to thyroidectomy.
During thyrotoxic crisis
During nuclear disaster
----NOT USED TO Tx HYPERTHYROIDISM - 62β- ADRENERGIC BLOCKERSPropranolol and atenolol - suppress the adrenergic activity
Propranolol – can also block peripheral deiodinase - 63GLUCOCORTICOIDSalso block peripheral deiodinase
- 64CALCIUM CHANNEL BLOCKERSdiltiazem or verapamil control tachycardia and supraventricular tachyarrhythmias.
- 65Sodium Iodide 123IGiven Orally.
Concentrated and bound by thyroid gland. Unbound drug is rapid excreted by
the kidneys. - 66useDx of thyroid function. Short T1/2 = 13 hrs, low energy γ rays utilized for
uptake and imaging studies.
Pregnancy Category C: Animal studies show no fetal harm. - 67Thyrotropin alpha (Thyrogen® usew/ radioiodide to:
(a) assess integrity of Iodide uptake pump (thyroid failure)
(b) promote radioiodide uptake by thyroid carninomas - 68SETachycardia
caution with cardiac dz. - 69Hyperthyroidism vs ThyrotoxicosisThyrotoxicosis is defined as the state of
thyroid hormone T4 excess and is not
synonymous with hyperthyroidism, which is the result of excessive thyroid function - 70the major etiologies of thyrotoxicosis arehyperthyroidism caused by Graves' disease, toxic MNG, and toxic adenomas
- 71Which imaging modality may help you distinguish between the different causes of thyrotoxicosis?I123 uptake scan
- 72primary hypothrodism u havehigh TSH and low T4
- 73hyperthrodism u havelow TSH with high T4
- 74The following diagnosis are all possible diagnosis with these labs low TSH and high Free T4 EXCEPTits hyperthroidsm which is caused by
Graves Disease
Toxic Multinodular Goiter
Toxic Adenoma
not caused by TSH secreting pituitary adenoma*** - 75Which of the following lab sets would be consistent with a TSH secreting pituitary adenoma?TSH high, free T4 high
- 76TSH high Free T4 low what do u do?give Levothyroxine
- 77How do you adjust the levothyroxine dose in a patient who has primary hypothyroidism and is pregnant?increase dose becus there will be more throid binding protein due to increase estrogen
- 78Subclinical Hypothyroidismdefined biochemically as a normal serum free thyroxine (T4) concentration in the presence of an elevated serum thyroid-stimulating hormone (TSH) concentration.
- 79Thyrotoxicosisstate of thyroid hormone excess and is not synonymous with hyperthyroidism, which is the result of excessive thyroid function.
defined biochemically as normal serum free thyroxine (T4) and triiodothyronine (T3) concentrations in the presence of a subnormal thyroid-stimulating hormone (TSH) (<0.5 mU/L - 80etiologyhyperthyroidism caused by Graves' disease, toxic MNG, and toxic adenomas.
- 81Graves DiseaseGraves disease accounts for 60–80% of thyrotoxicosis.
As in autoimmune hypothyroidism, a combination of environmental and genetic factors contribute to Graves' disease susceptibility. - 82caused byTSI that are synthesized in the thyroid gland as well as in bone marrow and lymph nodes.
- 83Other Causes of ThyrotoxicosisDestructive thyroiditis (subacute or silent thyroiditis) typically presents with a short thyrotoxic phase due to the release of preformed thyroid hormones and catabolism of Tg. True hyperthyroidism is absent, as demonstrated by a low radionuclide uptake.
Thyrotoxicosis factitia; Low or absent thyroid radionuclide uptake. Can be distinguished from destructive thyroiditis by the clinical features and low levels of Tg.
Struma ovarii; particularly teratomas of the ovary - whole-body radionuclide studies can demonstrate ectopic thyroid tissue - 84part 2TSH-secreting pituitary adenoma is a rare cause of thyrotoxicosis. It can be identified by the presence of an inappropriately normal or increased TSH level in a patient with hyperthyroidism, diffuse goiter, and elevated T4 and T3 levels- Elevated levels of the α-subunit of TSH, released by the TSH-secreting adenoma, support this diagnosis, which can be confirmed by demonstrating the pituitary tumor on MRI or CT scan.
- 85part 3Thyrotoxicosis caused by toxic MNG – antithyroid drugs maybe tried, but do not typically cause remission, typically use radioactive iodine or surgery
Thyrotoxicosis hyperfunctioning solitary nodules (toxic adenoma)- Treatment typically radioactive iodine - 86labsTSH low, Free T4 high- Primary hyperthyroidism
TSH normal or increased, Free T4 High- TSH secreting pituitary adenoma, or thyroid hormone resistance
In Graves' disease, the TSH level is suppressed and total and unbound thyroid hormone levels are increased - 87txThionamides
Surgery
Radioactive Iodine - 88Acute Thyroiditisis rare and due to suppurative infection of the thyroid.
- 89presentIn children and young adults, the most common cause is the presence of a piriform sinus, a remnant of the fourth branchial pouch that connects the oropharynx with the thyroid. Such sinuses are predominantly left-sided.
The patient presents with thyroid pain, often referred to the throat or ears, and a small, tender goiter that may be asymmetric.
Fever, dysphagia, and erythema over the thyroid are common, as are systemic symptoms of a febrile illness and lymphadenopathy. - 90Subacute ThyroiditisThis is also termed de Quervain's thyroiditis, granulomatous thyroiditis, or viral thyroiditis. Many viruses have been implicated
- 91prsentThe peak incidence occurs at 30–50 years, and women are affected three times more frequently than men.
The thyroid shows a characteristic patchy inflammatory infiltrate with disruption of the thyroid follicles and multinucleated giant cells within some follicles.
The follicular changes progress to granulomas accompanied by fibrosis.
Finally, the thyroid returns to normal, usually several months after onset. - 92part 2The patient usually presents with a painful and enlarged thyroid, sometimes accompanied by fever.
There may be features of thyrotoxicosis or hypothyroidism, depending on the phase of the illness.
Malaise and symptoms of an upper respiratory tract infection may precede the thyroid-related features by several weeks.
In other patients, the onset is acute, severe, and without obvious antecedent - 93part 3The patient typically complains of a sore throat, and examination reveals a small goiter that is exquisitely tender.
Pain is often referred to the jaw or ear.
Complete resolution is the usual outcome, but permanent hypothyroidism can occur, particularly in those with coincidental thyroid autoimmunity. A prolonged course over many months, with one or more relapses, occurs in a small percentage of patients. - 94labsThyroid function tests characteristically evolve through three distinct phases over about 6 months: (1) thyrotoxic phase, (2) hypothyroid phase, and (3) recovery phase.
In the thyrotoxic phase, T4 and T3 levels are increased, reflecting their discharge from the damaged thyroid cells, and TSH is suppressed.
The diagnosis is confirmed by a high ESR and low radioiodine uptake. - 95txRelatively large doses of aspirin or NSAIDs are sufficient to control symptoms in many cases.
If this treatment is inadequate, or if the patient has marked local or systemic symptoms, glucocorticoids should be given. The usual starting dose is 40–60 mg prednisone, depending on severity. The dose is gradually tapered over 6–8 weeks, in response to improvement in symptoms and the ESR. - 96part 2If a relapse occurs during glucocorticoid withdrawal, treatment should be started again and withdrawn more gradually. Thyroid function should be monitored every 2–4 weeks using TSH and unbound T4 levels. Symptoms of thyrotoxicosis improve spontaneously but may be ameliorated by β-adrenergic blockers; antithyroid drugs play no role in treatment of the thyrotoxic phase.
Levothyroxine replacement may be needed if the hypothyroid phase is prolonged, but doses should be low enough (50 to 100 mcg daily) to allow TSH-mediated recovery. - 97Silent ThyroiditisPainless thyroiditis, or "silent" thyroiditis, occurs in patients with underlying autoimmune thyroid disease.
It has a clinical course similar to that of subacute thyroiditis, except that there is little or no thyroid tenderness. - 98presentThe condition occurs in up to 5% of women 3–6 months after pregnancy and is then termed postpartum thyroiditis.
Typically, patients have a brief phase of thyrotoxicosis lasting 2–4 weeks, followed by hypothyroidism for 4–12 weeks, and then resolution; often, however, only one phase is apparent. - 99labsThe condition is associated with the presence of TPO antibodies antepartum, and it is three times more common in women with type 1 diabetes mellitus.
As in subacute thyroiditis, the radioactive iodine uptake is initially suppressed. In addition to the painless goiter, silent thyroiditis can be distinguished from subacute thyroiditis by a normal ESR and the presence of TPO antibodies. - 100txGlucocorticoid treatment is not indicated for silent thyroiditis.
Severe thyrotoxic symptoms can be managed with a brief course of propranolol, 20–40 mg three or four times daily. - 101Chronic ThyroiditisRiedel's thyroiditis is a rare disorder that typically occurs in middle-aged women.
- 102presentIt presents with an insidious, painless goiter with local symptoms due to compression of the esophagus, trachea, neck veins, or recurrent laryngeal nerves.
Dense fibrosis disrupts normal gland architecture and can extend outside the thyroid capsule.
Despite these extensive histologic changes, thyroid dysfunction is uncommon.
The goiter is hard, nontender, often asymmetric, and fixed, leading to suspicion of a malignancy. - 103FNA and thyroid nodulesSuspicion for cancer is greater inpatient with a thyroid nodule and patient history of neck irradiation in childhood or adolescence; PTC, MTC, or MEN 2 in first-degree relatives; previous thyroid surgery for cancer; increased calcitonin levels in the absence of interfering factors
- 104dxSee sonographic patterns below and recommendations for Fine needle aspiration
6 results for FNA include- malignant, atypia of undetermined significance/follicular lesion of undetermined significance, follicular neoplasm/suspicious for follicular neoplasm, non-diagnostic, benign, suspicious (for malignancy)
Nodules that are hot on scintigraphy should be excluded from FNA biopsy - 105Papillary CancerPTC is the most common type of thyroid cancer, accounting for 70–90% of well-differentiated thyroid malignancies.
- 106dxMicroscopic PTC is present in up to 25% of thyroid glands at autopsy, but most of these lesions are very small (several millimeters) and are not clinically significant.
Characteristic cytologic features of PTC help make the diagnosis by FNA or after surgical resection; these include psammoma bodies, cleaved nuclei with an "orphan-Annie" appearance caused by large nucleoli, and the formation of papillary structures. - 107part 2PTC tends to be multifocal and to invade locally within the thyroid gland as well as through the thyroid capsule and into adjacent structures in the neck. It has a propensity to spread via the lymphatic system but can metastasize hematogenously as well, particularly to bone and lung. Because of the relatively slow growth of the tumor, a significant burden of pulmonary metastases may accumulate, sometimes with remarkably few symptoms
- 108Follicular CancerThe incidence of FTC varies widely in different parts of the world; it is more common in iodine-deficient regions.
- 109dxFTC is difficult to diagnose by FNA because the distinction between benign and malignant follicular neoplasms rests largely on evidence of invasion into vessels, nerves, or adjacent structures – so dx can only be made after surgery, not by FNA alone
FTC tends to spread by hematogenous routes leading to bone, lung, and central nervous system metastases. - 110prognosisMortality rates associated with FTC are less favorable than for PTC, in part because a larger proportion of patients present with stage IV disease.
Poor prognostic features include distant metastases, age >50 years, primary tumor size >4 cm, Hürthle cell histology, and the presence of marked vascular invasion - 111geneticsRAS mutations also occur in FTCs. In addition, a rearrangement of the thyroid developmental transcription factor PAX8 with the nuclear receptor PPARγ is identified in a significant fraction of FTCs.
- 112Anaplastic Thyroid CancerATC is a poorly differentiated and aggressive cancer.
The prognosis is poor, and most patients die within 6 months of diagnosis - 113dxBecause of the undifferentiated state of these tumors, the uptake of radioiodine is usually negligible, but it can be used therapeutically if there is residual uptake.
- 114txChemotherapy has been attempted with multiple agents, but it is usually ineffective.
External beam radiation therapy can be attempted and continued if tumors are responsive. - 115Medullary Thyroid CarcinomaFrom parafollicular (C-cells)
MTC can be sporadic or familial and accounts for about 5% of thyroid cancers.
There are three familial forms of MTC: MEN 2A, MEN 2B, and familial MTC without other features of MEN - 116dxElevated serum calcitonin provides a marker of residual or recurrent disease.
It is reasonable to test all patients with MTC for RET mutations, as genetic counseling and testing of family members can be offered to those individuals who test positive for mutations. - 117txThe management of MTC is primarily surgical.
Unlike tumors derived from thyroid follicular cells, these tumors do not take up radioiodine. External radiation treatment and chemotherapy may provide palliation in patients with advanced disease. - 118SurgeryAll well-differentiated thyroid cancers should be surgically excised.
In addition to removing the primary lesion, surgery allows accurate histologic diagnosis and staging, and multicentric disease is commonly found in the contralateral thyroid lobe.
Lymph node spread can also be assessed at the time of surgery, and involved nodes can be removed. - 119part 2Near-total thyroidectomy is preferable in almost all patients; complication rates are acceptably low if the surgeon is highly experienced in the procedure.
Postsurgical radioablation of the remnant thyroid tissue is increasingly being used as it may destroy remaining or multifocal thyroid carcinoma, and it facilitates the use of Tg determinations and radioiodine scanning for long-term follow-up by eliminating residual normal or neoplastic tissue. - 120TSH Suppression TherapyAs most tumors are still TSH-responsive, levothyroxine suppression of TSH is a mainstay of thyroid cancer treatment.
A reasonable goal is to suppress TSH as much as possible without subjecting the patient to unnecessary side effects from excess thyroid hormone, such as atrial fibrillation, osteopenia, anxiety, and other manifestations of thyrotoxicosis. - 121part 2For patients at low risk of recurrence, TSH should be suppressed into the low but detectable range (0.1–0.5 mIU/L). For patients at high risk of recurrence or with known metastatic disease, complete TSH suppression is indicated if there are no strong contraindications to mild thyrotoxicosis. In this instance, unbound T4 must also be monitored to avoid excessive treatment.
- 122Radioiodine TreatmentWell-differentiated thyroid cancer still incorporates radioiodine, though less efficiently than normal thyroid follicular cells.
Radioiodine uptake is determined primarily by expression of the NIS and is stimulated by TSH, requiring expression of the TSH-R. The retention time for radioactivity is influenced by the extent to which the tumor retains differentiated functions such as iodide trapping and organification. After near-total thyroidectomy, substantial thyroid tissue often remains, particularly in the thyroid bed and surrounding the parathyroid glands. Consequently, 131I ablation is necessary to eliminate remaining normal thyroid tissue and to treat residual tumor cells.
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- Karteikarten am jan 13, erstellt von Shylla T am 26/12/2020.
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