W5 Thyroid disorders and Osteoporosis (MAH) Flashcards
Thyroid Disorders:
Clinical thyroid diseases may be either disorders of? (2)
Symptomatic usually?
What test to determine?
- thyroid function (hyper- or hypo-function)»_space; pharmaceutical management
- thyroid structure (nodules, cancer, or goiter)»_space; managed through MDT collaboration
- Patients present with symptoms or signs that may be vague or undifferentiated
- Blood analysis required
Thyroid gland and hormones:
Where is it located?
What are the functions?
- 2 lobes either side trachea plus isthmus
- Increases the basal metabolic rate
- Control metabolism of carbs, proteins and fats
- Maintenance of water and electrolyte balance
- Regulation of plasma [ca]
- In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth
- The impact of thyroid hormone on CNS is important. During the prenatal period, it is needed for the maturation of the brain
- In adults, it can affect mood. Hyperthyroidism can lead to hyperexcitability and irritability. Hypothyroidism can cause impaired memory, slowed speech, and sleepiness
- Thyroid hormone affects fertility, ovulation, and menstruation
What are the thyroid hormones? (2)
How are they regulated?
Thyroxine or tetraiodothyronine (T4)
Triiodothyronine (T3) - active form
By the hypothalmic-pituitary axis
Hypothalamic-pituitary-thyroid axis:
Which hormones are released and from where? (4)
What feedback mechanism is it regulated by?
- Thyrotropin-releasing hormone (TRH) from the hypothalamus
- Thyroid-stimulating hormone (TSH) from the anterior pituitary gland, and T4 work in synchronous harmony to maintain proper feedback mechanisms and homeostasis.
- Thyroid gland releases T3 and T4
- The HPT axis is regulated via negative feedback, at the level of the hypothalamus and the pituitary.
- Excess concentrations of thyroid hormones feedback to both the hypothalamus and the pituitary to cause a reduction in both TRH and TSH production. This decreases the rate of thyroid hormone production via the HPT axis. This physiological regulation of the HPT axis is lost in thyrotoxicosis.
- Iodine involved e.g. iodine deficient regions = ↑prevalence of goiter
- Target tissue: Heart, Liver, Bone, CNS
Physiology of thyroid hormone production and synthesis
What is the functional unit of the thyroid gland called?
- The functional unit of the thyroid gland is the follicle
- Follicles are composed of a single layer of epithelial cells (thyroid follicular cells) surrounding a central space filled with colloid
- The follicular cells synthesize thyroglobulin, a large tyrosine-rich glycoprotein, and secrete it
- Colloid is essentially a pool of thyroglobulin
- Key thyroid hormones include thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH), T4, and T3
- Only 1% of total thyroid hormone is in the unbound or free state and available for metabolic purposes. The rest is bound to globulin, prealbumin, and albumin
- Calcitonin is a peptide produced by the parafollicular cells of the thyroid gland. It reduces resorption of calcium in the bone and lowers the serum calcium
Thyroid hormone synthesis and secretion:
Step 1 Thyroglobulin synthesis
What is produced by Thyrocytes?
Step 2 iodine uptake and hormone synthesis:
Thyrocytes in the thyroid follicles produce a protein called
thyroglobulin (TG).
TG does not contain any iodine, and it is a precursor protein stored in the lumen of follicles. It is produced in the rough endoplasmic reticulum. Golgi apparatus pack it into the vesicles, and then it enters the follicular lumen through exocytosis.
Step 3:
Actions of thyroid hormone?
What are the classes of TRs?
TH is exerted through nuclear TH receptors (TRs), which are ligand-inducible transcription factors (see chemistry lectures)
Two classes of TRs, a and β
α1, α2, α3,
β1, β2, and β3,
3 truncated forms
Rα isoforms - brain, heart, skeletal muscle and adipose tissues
TRβ isoform - liver, heart and pituitary, and mediates the regulation of cholesterol metabolism,
TRβ isoform – regulates –ive feedback regulation of TSH in the pituitary
Actions of Thyroid Hormones
- T4 is synthesised more than T3
- Highly bound to Thyroid Binding Globin – only free ligand can exert effects
- T4 is converted to T3 in target tissues by deiodinases 1 and 2 (D1 and D2)
- Deiodinase 3 (D3) converts T3 to the inactive rT3
- Unliganded TR heterodimerizes with retinoid X receptor (RXR) and binds to a thyroid hormone response elements (TRE) and then to a corepressor; thus, repressing gene expression
- T3 binding to the ligand-binding domain results in movement of the carboxyterminal helix 12, disruption of corepressor binding, and promotion of coactivator binding, which then leads to recruitment of polymerase III and the onset of gene transcription
Thyroid function tests:
What does high levels of TSH mean?
What does low levels of TSH mean?
TSH level high= more TH needed
TSH level low, normal to high T3 and T4, levels= feedback isnt work (hypothyroidism)
- Functional thyroid diseases are extremely common.
- Results often form the entire basis of any diagnosis.
- Even subtle abnormalities in thyroid function are now considered as potential “disease states,” necessitating both accurate biochemical testing and understanding of differing population definitions of “thyroid disease.”
Hypothyroidism symptoms?
- Cold intolerance
- Dec sweating
- Weight gain
- Constipation
- Depression and irritability
- Irregular and heavy periods
- Brittle nails
- Slow HR
- Muscle or joint pain
- Puffy face
- Feeling faint
Hyperthyroidism symptoms?
- Heat intolerance
- Inc sweating
- Weight loss of gain
- Diarrhoea
- Nervousness and anxiety
- Nail thickening and flaking
- Muscles weakness
- Racing heart
- Short and light periods
- Puffy or bulging eyes
(body processes speed up)
Symptoms of hypo and hyperthyroidism? (3)
- Fatigue
- Insomnia
- Hair loss
Thyrotoxicosis (hyperthyroidism):
What is this?
signs and symptoms?
Excess thyroid hormone action on target tissues
Typical features caused by stimulation of metabolism and cateocholamines
e.g. weight loss with increased appetite
S/S:
↑metabolic rate, ↑appetite, Heat intolerance, arrythmias
↑nervousness, hyperkinesis, sweaty, clammy skin
Sympathetic overactivity – tachycardia, sweating and tremor
Extreme: high output heart failure
Upper eyelids retract – wide stare
Treatment depends on the underlying cause
Causes of thyrotoxicosis? (3)
- Graves’ disease
-Organ specific autoimmune disease
-Common in women
-Antibodies to TSH receptor (TRAB)
Remission with antithyroid drugs in 30-40% of cases - Toxic multi-nodular goitre
-No remission with antithyroid drugs - Toxic solitary nodule
-No remission with antithyroid drugs
Hyperthyroidism (Treatment)
Background:
- All drugs will cause hypothyroidism – management needed
- Care when pregnant carbimazole can cross placenta
- Propranolol reduces the peripheral conversion of T4 to T3 thus alleviating symptoms
- Surgery is also an option as a definitive treatment
MOA of antithyroid drugs largely unknown
-Inhibition of Iodide oxidation
-Inhibition of iodination of tyrosine
-Inhibition of coupling of iodotyrosines
Doesn’t affect thyroid hormone precursors or circulating levels
Thus 2-4 week for symptom relief
Hyperthyroidism (Treatment)
3 drug classes?
- Thiomide anti-thyroid drugs
Carbimazole, methimazole, propylthiouracil
Given orally
Carbimazole rapidly hydrolysed in plasma to methimazole short half-life 12-15 hrs
Control of thyrotoxicosis, induction of remission in Graces’ disease - Iodides
Radioactive iodine-131 used as a definitive treatment of relapsed Graves’, or toxic nodules
Potassium iodide (Lugol’s iodine) used for thyrotoxic crisis aka thyroid storm - B-adrenoreceptor blockade
Propranolol or atenolol
Given for symptom relief
What is Thyroid storm?
Thyroid suddenly produces and releases large amounts of thyroid hormone
Sudden event: surgery / infection
S/S: fever, tachycardia, dehydration and confusion
Tx Potassium iodide and Carbimazole, rehydration, iv B blockers and steroids
High mortality
Patients with contraindications to thionamides need to be managed with supportive measures, aggressive beta blockade, iodine preparations, glucocorticoids, and bile acid sequestrants for about a week in preparation for a thyroidectomy. Plasmapheresis may be attempted if other measures are not effective.
Advice: Seek immediate medical care
Hypothyroidism
Pathophysiology:
definition?
symptoms?
common cause?
treatment?
- Insufficient secretion of Thyroid Hormones
- Common s/s: Lethargy, weight gain, cold intolerance
- Common cause:
autoimmune thyroiditis (Hashimoto’s disease)
-congenital dysfunction,
-iodine deficiency
-Tx for thyrotoxicosis
Lab: ↑ TSH, ↓ T4
Tx – thyroid replacement therapy:
2 potential meds
levothyroxine sodium (T4) - inactive form
liothyronine sodium (T3) (rare)
Osteoporosis
How to reduce the risk?
If you have prolonged untreated hyperthyroidism with other risk factors, a bone mineral density scan will help assess your risk of osteoporosis and bone fractures.
- A well-balanced diet rich in calcium and vitamin D and/or supplements
- Limit alcohol intake to within recommended limits
- Avoidance of smoking
- Regular, high impact exercise, such as power-walking
- Hormone Replacement Therapy (HRT)
- The Royal Osteoporosis Society recommends a daily calcium intake of:
700 mg for adult men and women,
an extra 550 mg if you are breastfeeding;
and a daily intake of around 1000 mg if you are taking osteoporosis drug treatments
What is the link between thyroid disease and osteoporosis?
- Thyroid hormone affects the rate of bone replacement.
- Osteoporosis is a condition in which the bones become porous, fragile and prone to fracture. It can affect men as well as women.
- Primary hyperparathyroidism also causes osteoporosis (PTH test)
Hyperthyroidism and osteoporosis - Too much thyroid hormone increases the rate at which bone is lost
- Treating the hyperthyroidism (overactivity) reduces the rate of bone loss
Hypothyroidism and osteoporosis - Too much levothyroxine can cause increased bone loss
- Be sure to have an annual thyroid function test to ensure your thyroid hormone levels are not too high
Risk Factors
* Personal history of broken bone
* Family history of osteoporosis
* Early menopause
* Previous steroid therapy
* Anorexia nervosa
* Low body weight
* Lack of exercise or mobility
* Poor diet
* Smoking
* Excessive alcohol intake
* Prolonged untreated hyperthyroidism
* Prolonged over-treated hypothyroidism
* Other illnesses such as rheumatoid arthritis, coeliac disease, primary
hyperparathyroidism
Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development
Thyroid hormone regulates proliferation and/or differentiated actions ofmultiple cell types in bone including
chondrocytes,
osteoblasts
Osteoclasts
TH effects medicated via ligand-inducible nuclear receptors/transcription factors, thyroid hormone receptor (TR) α and β
TRα seems to be critically important in regulating bone cell functions
Which gland is responsible for the synthesis and secretion of thyroid hormones?
Adrenal, pituitary, thyroid, parathyroid or pineal gland?
= Thyroid gland
What is the primary function of thyroid hormones?
regulation of bm levels
control of hr and bp
regulation of body temp and metabolism
maintenance of fluid and electrolyte balance
= Regulation of body temperature and metabolism
Which hormone is responsible for stimulating the synthesis and secretion of thyroid hormones?
TSH, GF. FSH, ACTH, ADH?
=TSH
Which enzyme plays a crucial role in the conversion of thyroxine (T4) to triiodothyronine (T3)?
TSH receptor, Thyroid peroxidase, Thyroglobulin, Thyroid binding globulin, Thyroid stimulating hormone (TSH)
=Thyroid peroxidase
The most common cause of hypothyroidism in the United Kingdom is:
Graves disease
Hashimoto’s thyroiditis
Thyroid cancer
Iodine deficiency
None of the above
Hashimoto’s thyroiditis
The first-line treatment for hypothyroidism is:
Radioactive iodine therapy
Anti-thyroid medications
Thyroidectomy
Levothyroxine replacement therapy
None of the above
Levothyroxine replacement therapy
(Anti-thyroid meds is for Hyperthyroidism)
In hypothyroidism, if the dose of levothyroxine is too high, it may lead to:
Hyperthyroidism
Which of the following is a potential complication of untreated hyperthyroidism?
Thyroid storm
In the UK, primary care physicians generally refer patients with hyperthyroidism to:
Endocrinologists. Cardiologists, Gastroenterologists Rheumatologists, Dermatologists
Endocrinologists
After successful treatment of hyperthyroidism, patients may require lifelong:
Antidepressants, Vitamin D supplementation, Calcium channel blockers, Thyroid hormone replacement, Blood thinners
=Thyroid hormone replacement
