case 3: hyperthyroidism Flashcards
1
Q
lab test
A
- Serum TSH (sensitive assay) – best indicator of thyroid status
- Free T4 – best indicator of thyroid hormone levels
2
Q
Interpretation of Blood Test Results
A
- The blood level of TSH:
– decreased TSH - The blood levels of thyroid hormones (TH):
– increase free T4, increase T4, increase T3
the increase in TH produces negative feedback on TSH
3
Q
Tentative Diagnosis
A
- From the blood test:
– increase in free T4, increase T4, increase T3 and decrease in TSH - Tentative diagnosis – hyperthyroidism
- Typical symptoms for hyperthyroidism
– Increased metabolic state (+)
– Nervousness (+)
– Rapid pulse (+)
– Increased appetite w/ dramatic weight loss (+)
– Heat intolerance (+)
– Protruding eyes (bulging eyes) (+)
– Goiter (case dependent) (+)
4
Q
Thyroid Gland
A
- The largest endocrine organ
– The only palpable endocrine gland
– 2 lobes joined by the isthmus - Follicles
– 20-30 million follicles per gland
– Follicular cells secrete thyroid
hormones (TH)
– Interior filled with colloid fluid - synthesis of TH
- Parafollicular cells (C cells) secrete
calcitonin, part of thyroid gland - Parathyroid glands attach to
thyroid gland, NOT a part of the
thyroid gland - 4 nodules
- Hypothalamus secretes TRH
(thyrotropin-releasing
hormone) -> anterior pituitary
secretes TSH (thyroid-
stimulating hormone) ->
thyroid gland secretes thyroid
hormones - Thyroid hormones (T4 & T3)
– Secreted by follicular cells
– T4 is the pre hormone of T3
(bioactive in target cells)
– Regulate basal metabolic
rate, growth & development - go through BBB
low levels of T4 and T3 will have less negative feedback on anterior pituitary and cause increase in TSH and hypertrophy of thyroid so they can secrete more TH (including T4 and T3)
5
Q
Epidemiology of Thyroid Disorders
A
- Iodide is an essential component of thyroid hormones (T4 & T3)
- Iodide deficiency is leading cause of brain damage worldwide (740 million worldwide, 13% of the world population)
- In the US, there is an increase in thyroid disorders since 1975:
– decrease Use of iodate conditioner in bread-making
– decrease Ingestion of iodized salt (due to hypertension)
– decrease use of iodized salt in cooking
– Subsets of the US population, especially women of childbearing age, have an increased prevalence of mild iodine deficiency
6
Q
Thyroid Uptake of Iodide
A
- Ingested iodide (I-) & iodate (IO3-) are absorbed as I- in the gut
– I- from seafood, iodized table salt; iodate from bread - Thyroid gland concentrates iodide from plasma
– In the thyroid, 8,000 μg (8 mg) I- present as thyroglobulin
– Daily secretion – 80 μg I- as T3 and T4 - About 1% of the pool of I- in the thyroid is secreted per day as thyroid hormones (TH, T4, T3 & rT3), i.e. the stored I- can last 100 days of synthesis without further uptake of I-
7
Q
Synthesis of TH (1) – Follicular Cells
A
- I- trapping – absorption of iodide (I-) from blood into the cells
– Absorption by secondary active transport (Na/I symporter), driven by
electrochemical gradient of Na+. How?- in order for the symporter to work, the intracellular concentration of Na has to be maintained low and pumped out of the cell into interstitial fluid by Na/K pump. this allows the symporter to absorb more I-, Na follows concentration gradient, cellular concentration of Na is low so there can be continuation of I- uptake even though I- in the cell is high
- ATP is required and for the symporter to work, Na intracellular content must be low by using energy to keep Na out through Na ATPase
- -> Secretion of I- into colloid by pendrin (an anion exchange protein)
- Synthesis of thyroglobulin (seen in colloid, NOT blood)-> secretion of thyroglobulin into the follicle
colloid thru exocytosis
8
Q
Synthesis of TH (2) – Colloid & Cells
A
- Cellular synthesis of thyroglobulin -> secretion of
thyroglobulin into the follicle colloid thru exocytosis - In the colloid of follicle
– -> Oxidation – oxidized to iodine (I, atom) by thyroid peroxidase
– -> Organization – attached iodine to tyrosines of thyroglobulin
– -> Iodination – formation of monoiodo tyrosine (MIT) & diiodo-
tyrosine (DIT) within thyroglobulin - MIT + DIT = T3 (triiodothyronine)
- DIT + DIT = T4 (tetraiodothyronine, thyroxine)
- Back in the follicular cell
– T3/T4-thyroglobulin enter follicular cell thru endocytosis
– Proteolysis – secretion of T4 & T3 into blood
9
Q
Transport of TH in the Blood
A
- TH bind to several plasma proteins
- thyroid binding globulin (most proteins are bound to) present in blood (different from thyroid globulin which is present in colloid?) for transport of T3 and T4 70%
- transthyretin 15%
- albumin 15%
- % bound for all three together, T4=99.98% T3=99.5% - T3 cleared quickly from blood; T4 is slower
- t1/2 T4= 8 days T3= 1 day
- The major storage compartment for TH is the blood
- Half life in blood for free TH is much shorter, only free TH can enter target tissue
10
Q
Conversion of T4 to T3
A
- production of T4 is 10x higher than T3
- T4 is higher in the serum
- T3 10x higher in potency at R
- Free TH is more readily available to enter the target cells
– Measurement of free TH is preferable - T4 is the major secretory product
- protein bound to T4 is highest amount of TH in blood
if T4 lose one Iodine, it can become either T3 or reverse T3
11
Q
T3 & T4 – Mechanism of Action
A
- In the target tissues (most cells of the body, esp. liver & kidney):
– T4 is converted to T3 (bioactive) and reverse T3 (non-functional) - RXR (retinoid X receptor) – nuclear R, activated by retinoid acid
T4 is lipid soluble and enters from the blood into membrane of target cell and converted into T3 by losing one iodine, associated w binding protein and goes to nucleus, then T4 is dissociated from intracellular protein then enters nucleus. in the nucleus it’s converted into T3 (bioactive) then binds to nuclear TH receptor then attaches to DNA
12
Q
Effects of Thyroid Hormones (TH)
A
- Target tissues – virtually all cells in the body
- TH – increase basal metabolic rate (BMR), O2 consumption & heat production *** most important fxn
- Liver – TH regulate carbohydrate and lipid metabolism
- Growth & development
– Normal growth & development of skeletal & cardiac muscle, bones
& brain
– Fetal development – brain and skeletal - TH -> increase sensitivity to catecholamines (E, NE, dopamine)
– increase Autonomic reflexes
– Heart – increase heart rate & myocardial contractility
13
Q
Hyperthyroidism – Overview
A
- Thyrotoxicosis – any process that causes increased levels of unbound (free) TH in the blood
- Hyperthyroidism – elevation of thyroid hormones (TH, T4 & T3)
– Primary hyperthyroidism – increase in TH due to increase autonomous production by thyroid gland per se (low TSH)
– Secondary hyperthyroidism – increase in TH due to increase TSH stimulation (high TSH) (something happened to pituitary gland) - Symptoms (can you explain it based on the functions of TH?)
– Nervousness, rapid pulse, palpitation (atrial fibrillation), emotional liability, tremor
– Sweating, insomnia (NS too excited), heat intolerance, warm/moist skin (too much protein activity leads to protein degradation), weight loss (burning too much energydespite increased appetite —> increase in catecholamines and metabolic rate
– Menstrual changes, hypercalcemia (stimulate osteoclast)
– Protruding eyes (bulging eyes), goiter (case dependent)
14
Q
Hyperthyroidism – Differential Diagnosis
A
- Primary hyperthyroidism – decrease TSH; increase T3 & T4
– Graves’ disease (most common, 50-60%)
– Subacute thyroiditis (15-20%, a destructive release of preformed TH)
– Toxic multinodular goiter (15-20%, more in elderly people)
– Toxic adenoma (3-5%, a single hyperfunctioning adenoma)
– Other causes – lymphocytic thyroiditis, postpartum thyroiditis, Hashitoxicosis (the initial hyperthyroid phase of Hashimoto’s disease) - Secondary hyperthyroidism – increased TSH -> increase T3 & T4
– Pituitary adenoma
– Amiodarone-induced hyperthyroidism - Amiodarone – oral treat life-threatening ventricular arrhythmias
15
Q
Anti-Thyroglobulin Antibodies
A
- Thyroglobulin (found in follicle) ≠ thyroxine-binding protein
- Anti-thyroglobulin Ab (TgAb) – often found in patients with Graves’ disease, Hashimoto’s thyroiditis, or thyroid carcinoma
- TgAb – present in 1 in 10 normal individuals -> of limited use in the diagnosis of these diseases
