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FHB IV- Endocrinology > Endocrinology 7 > Flashcards

Endocrinology 7 Flashcards

1
Q

Describe the anatomical location of the thyroid gland.

A

Located anterior to cricoid cartilage

Two symmetrical lobes fused by the isthmus

(Slide 6)

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2
Q

Describe the blood supply of the thyroid gland.

A

Blood Supply:
Superior (ext. carotid) and Inferior (thyrocervical trunk) thyroid arteries

Venous plexus on surface gives rise to superior, middle, and inferior thyroid veins — drain into internal jugular vein

Slide 7

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3
Q

How is the thyroid gland innervated?

A

Innervation:
Middle and inferior cervical ganglion (sympathetic NS)

Slide 7

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4
Q

From what is the thyroid gland derived?

How is the epithelium arranged?

A

Derived from branchial pouch endoderm.

Epithelium arranged in follicles that contain a large storage of thyroglobulin (colloid).

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5
Q

Describe shape of inactive follicles.

When/how do follicles become active? Describe their active form.

A

Inactive follicles have flattened, squamous epithelium.

Stimulated by TSH, follicles become active. Follicular cells transform to cuboidal epithelium.

Follicular cells are cuboidal when activated by TSH. Microvilli (Mv) extend
into the colloid to facilitate transport of thyroglobulin. The basement membrane
(BM) delineates the follicle. Note the parafollicular cells (“C”), which are located inside the basement membrane. They do not touch the colloid and contain many small granules.

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6
Q

Describe the cellular components of the thyroid gland.

Describe:
follicle
parafollicular cells
other cells

What is a colloid?

A 
Follicle: 
-epithelial cells surrounding lumen
- lumen filled with colloid – 30% of
thyroid mass,  thyroglobulin (TG) is major component) (The colloid is the extracellular storage site of T3/T4)
and thyrogloubulin.
-Cuboidal shape 
-Microvilli (Mv) extend into colloid
-Basement membrane – delineates follicle
-Close to fenestrated capillaries

Parafollicular cells (“C” cells)

  • produce calcitonin
  • other proteins that maintain follicle
  • Do not touch colloid
  • Many small granules

Other cells:
Epithelial cells, fibroblasts, lymphocytes, adipocytes

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7
Q

Describe iodide intake and turnover:

What are thyroid hormones?

What precursors are required?

What is the average US dietary intake? At what point does thyroid hormone deficiency occur?

What happens to excess precursor?

A

Thyroid hormones are iodothyronines

Requires two precursors: thyroglobulin (TG) and iodide

Iodide is critical component of thyroid hormones

US average dietary intake = 400 ug/day
less than 20 ug/day results in thyroid hormone deficiency

Most excess iodide is excreted in urine as iodine.

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8
Q

Explain the Wolf-Chaikoff effect.

How is this used clinically?

A

An intrathyroidal response that assures constancy of iodide storage in the face of changes in dietary iodide

Increases in iodide intake decrease gland transport and hormone synthesis (dashed line), and vice-versa

See graph slide 13

Clinically: very high iodide doses are used to rapidly shut down thyroid hormone production in hyperthyroid patients

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9
Q

What is the most preventable cause of mental retardation?

A

Thyroid hormone deficiency is the most preventable cause of mental retardation

World Health Organization campaign for all countries to have access to iodized salt (usually in the form of potassium iodide)

Slide 14

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10
Q

Describe the following thyroid hormones (and provide names)

T4
T3
rT3

Describe half life, how travels in blood, with what degree of affinity it binds to receptor…

Which is the primary active form?

A

Thyroxine = T4
Long half-life in plasma ~ 7-8 days
Tightly bound to transport proteins in blood
Binds to receptor with low affinity

Triiodothyronine = T3
Primary active form
Most is converted intracellulary from T4
Binds with high affinity, low capacity to receptor

Reverse triiodothyronine = rT3
Biologically inactive

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11
Q

Describe the HPT neuroendocrine axis and explain the factors that regulate this axis.

(Describe the negative feedback at each level)

A

Hypothalamus - PVN
Thyrotropin-Releasing Hormone (TRH)

Negative feedback by T4/T3 (synthesis)

Pituitary – Thyrotropes

Thyroid-Stimulating Hormone (TSH)

Negative feedback by intracellular T3 (release) “thyroid sensor”

Tonic inhibition by somatostatin, dopamine

TRH release from neurons in the PVN bind to G protein-coupled receptors on thyrotrope cells in the anterior pituitary and activate the DAG/IP3 signaling pathway. This
pathway stimulates the synthesis and release of TSH, which binds to receptors in the basolateral membrane of the follicular epithelial cells. TSH stimulates T4/T3 synthesis and release from the
thyroid follicle. T4 is peripherally deiodinated to T3 in the thyrotopes and brain by Type II
deiodinase, which acts as a thyroid hormone sensor. Intracellular T3 then acts by negative feedback to inhibit TRH and TSH. Dopamine and SS also inhibit TSH release.

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12
Q

Explain the significance of the follicular architecture for thyroid hormone synthesis.

A

THYROID FOLLICLE IS FUNCTIONALLY POLARIZED

Apical surface exposed to lumen (colloid)

  • Thyroid hormone synthesis
  • Iodination of TG

Basolateral surface exposed to blood

  • Iodine uptake “trap”
  • Thyroid hormone release
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13
Q

Describe the first two steps in the biosynthesis of thyroid hormone.

A

All steps TSH-mediated

  1. Iodide Trapping:
    TSH stimulates iodide (I-) trapping by increasing the activity of the NIS co-transporter in the basal membrane of the follicular epithelial cell.
  2. Transport:
    I- transported to follicular lumen and oxidized by thyroid peroxidase (TPO) to form iodine (I).

Thyroglobulin transported to lumen.

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14
Q

Describe the third and fourth steps in the biosynthesis of thyroid hormone.

A
  1. Iodination:
    Iodination of tyrosyl residues on thyroglobulin (“organification”).
  2. Conjugation:
    Conjugation of iodinated tyrosines to form T4 and T3-linked thyroglobulin
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15
Q

Describe the action of Carbimazole

A

Carbimazole – inhibits thyroid peroxidase (TPO)

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16
Q

What are MIT and DIT?

Describe the compositions of T3/T4.

A 
MIT = monoiodothyronine
DIT = diiodothyronine

Triiodothyronine = 1 MIT + 1 DIT

Thyroxine (T4) = 2 DIT

Slide 23

Thyroid hormone structure. T3 is formed from the coupling of one MIT and one DIT residue. Reverse
T3 is biologically inactive and is distinguished from the active form of T3 by the presence of two
iodinated residues on the outer ring, as opposed to the inner ring. T4 is formed from the coupling of two
DIT residues.

17
Q

Describe steps 5-7 in thyroid hormone synthesis.

A
  1. Endocytosis:
    Conjugated thyroglobulin with T4/T3 enters follicular epithelial cell.

Packaged in endosomes

  1. Proteolysis
    TG, MIT, DIT, T4, T3 released from vesicle
  2. Secretion
    T4/T3 secreted into circulation
18
Q

Explain how radioactive iodide uptake tests can be used to determine the physiological basis for thyroid hormone imbalance.

How can you distinguish between “cold” and “hot” nodules? Which is more predictive of malignancy?

A

Diagnostics: radioactive iodide uptake scan

Iodide uptake in thyroid epithelial cell

Iodide is transported by the sodium iodide symporter (NIS)

Radioactive iodide (131I, 123I) and anions like pertechnetate (TcO4) can be transported by NIS

Used to determine function of thyroid gland

Slide 26

“cold” nodule

More predictive of malignancy

“Hot nodule” = area of increased follicular
iodide uptake and thyroid hormone synthesis.
Usually benign.

“Cold nodule” = inactive/dysfunctional thyroid
follicle. Can be benign or malignant.

19
Q

List all steps in thyroid hormone synthesis.

A
  1. Iodide Trapping: TSH stimulates iodide (I-) trapping by increasing the activity of the NIS co-transporter in
    the basal membrane of the follicular epithelial cell.
  2. Transport:
    I- transported to follicular lumen and oxidized by thyroid peroxidase (TPO) to form iodine (I).
    Thyroglobulin transported to lumen.
  3. Iodination:
    Iodination of tyrosyl residues on thyroglobulin.
  4. Conjugation:
    Conjugation of iodinated tyrosines to form T4 and T3-linked thyroglobulin.
  5. Endocytosis:
    Conjugated thyroglobulin with T4/T3 enters follicular epithelial cell.
    Packaged in endosomes
  6. Proteolysis
    TG, MIT, DIT, T4, T3 released from vesicle
  7. Secretion
    T4/T3 secreted into circulation at basal membrane

All steps are stimulated by TSH

20
Q

Describe the normal uptake when using radioactive iodide uptake scan for diagnostics.

What indicates hyperthyroid? Hypothyroid

What is Graves Disease?
Describe Organification defect.

Illustrate on a graph.

A

Normal uptake is 25% after 24 hours

> 60% = hyperthyroid

21
Q

Describe Type I, II, and III Thyroid Hormone – Peripheral Conversion.

Describe ratio of T4/T3. What is the thyroid hormone sensor in the pituitary?

(Explain the significance of thyroid hormone conversion in extrathyroidal tissues and distinguish between different types of deiodinases.)

A

Type I
Outer and inner ring deiodinase
Liver, kidney, thyroid, skeletal muscle
Primary source of T3 in circulation

Type II
Outer ring deiodinase
Brain, pituitary, placenta, cardiac muscle

Type III
Inner ring deiodinase
Brain, placenta, skin

  • More T4 produced and stored in thyroid
  • 80% of T4 is peripherally deiodinated to T3
  • T4 has low receptor affinity
  • Reverse T3 has no biological activity
  • Type II deiodinase is the thyroid hormone “sensor” in the pituitary
22
Q

Describe the transport for thyroid hormones.

A

Thyroid Hormone – Transport
**More than 99% bound in circulation

Transport proteins:
Thyroxine-binding globulin (TBG) (70%)
Transthyretin (TTR) (10%)
Albumin (15 – 25%)
T4 tightly bound = longer half-life approx. 7 days; T3 approx. 1 day
23
Q

Describe the Thyroxine Binding Globulin (TBG)
Transthyretin (TTR).

What family?
Protease inhibitor?

T4 or T3 has higher affinity for TBG?

What can increase TBG levels?

What can decrease TBG levels?

A
  • 394 AA glycoprotein made in the liver
  • T4 highest affinity for TBG, but TBG is lowest concentration
  • 99.9% T4 and T3 are bound “total thyroid hormone”
  • Estrogen, hepatitis increase TBG; nephrotic syndrome, steroids decrease TBG = no net change in “free” T4/T3.
  • Unique: TBG can reversibly release T4 to target tissues
24
Q

Describe the receptor for thyroid hormones.

Where are these receptors expressed?

Describe affinity/capacity for T4/T3.

A

Nuclear receptor family
- same as steroid hormones
- forms heterodimers with
retinoic acid receptor (RXR)

Expressed in nearly every cell type

High affinity, low capacity for T3

Low affinity for T4 – very little biological activity at physiological concentrations

25
Q

Explain the physiological basis for the metabolic, cardiovascular, and CNS effects of T3.

A

Increases Basal Metabolic Rate (BMR)

  • Stimulates hepatic gluconeogenesis
  • Stimulates proteolysis
  • Stimulates lipolysis
  • Overall increased energy/oxygen consumption, increased thermogenesis

Promotes Brain (CNS) Maturation

Increases beta-adrenergic receptors: heart, skeletal muscle, adipose tissue

26
Q

Describe PHYSIOLOGICAL EFFECTS: METABOLISM for Hypothyroid and Hyperthyroid.

BMR
Carbohydrate metabolism
Protein metabolism
Lipid metabolism
Thermogenesis
A

Slide 38

27
Q

How does T3 affect oxygen consumption and heat production?

A

T3 increases cellular oxygen consumption and heat production by increasing mitochondrial activity

28
Q

Which is heat/cold intolerant between hypo/hyperthyroidism?

A

cold intolerant-hypothyroid

heat intolerant-hyperthyroid

29
Q

Describe the physiological effects of thyroid hormone on CNS.

A

T3 is critical for normal brain development
Neuronal cell migration/differentiation
Myelination
Synaptic transmission

30
Q

What is Cretinism?

A 
Cretinism:
Iodine deficiency during development
Short stature/impaired bone formation
Mental retardation
Delayed motor development
31
Q

Describe the physiological effects of thyroid hormone on the heart. (Indirect and direct)

What can lead to arrythmias? Why?

A

T3 increases cardiac output

Resting heart rate and stroke volume increase

Hyperthyroidism can cause arrhythmias due to increased beta-adrenergic receptors

Indirect:

  • increased heat production and CO2 in tissues
  • decreased peripheral vascular resistance
  • decreased diastolic bp
  • reflex increase adernergic stimulation

Direct:

  • increase cardiac muscle myosin heavy chain alpha/beta ratio Na, K, ATPase, SR Ca-ATPase, beta-adernergic signaling, G protein stimulatory/inhibitory ratio
  • increase ventricular contractility and function
  • decrease peripheral vascular resistance

overall, increase cardiac rate and output
increase blood volume

32
Q

Which thyroid hormone increases cardiac output?

A

T3

33
Q

Explain the consequences of over/under production of thyroid hormone and describe why either condition will cause enlargement of the thyroid gland.

A

?

34
Q

Why does the thyroid gland enlarge without iodine?

A

Goiter = enlarged thyroid
Cancer – 3:1 women:men

Hyperthyroid – Grave’s disease

Hypothyroid – Hashimoto’s thyroiditis, iodine deficiency

35
Q

Describe Graves Disease. What are clinical manifestations?

Describe the histology of thyroid gland from a patient with Graves Disease.

A

Autoimmune – antibodies (Long-acting thyroid stimulator - LATS)
stimulate TSH receptor
- Elevated T4/T3
- Diffuse symmetrical goiters with hyperthyroid symptoms: tachycardia,
opthalmopathy, irritability, hyperactivity, heat intolerance, weight loss,
nervousness, muscle wasting

Histology of thyroid gland from patient with Graves Disease. Note:
scant colloid, tall columnar activated follicular cells, and infiltration of
lymphocytes.

36
Q

Describe Hashimotos Thyroiditis.

A
  • Autoimmune destruction of thyroid follicles
  • Antibodies against TPO, TG
  • Diffuse goiter with hypothyroid symptoms: lethargy, fatigue, hair loss, cold intolerance,
    brittle nails decreased appetite, weight gain
37
Q

Describe thyroid storm. Include symptoms and treatment.

A

Emergency life threatening situation
Hyperthyroid coupled with severe acute illness

Symptoms:
High fever
Tachycardia
Altered mental status
Severe nausea, vomiting, diarrhea
Severe circulatory collapse ----- resulting in death

Treatment:
Propylthiouracil (PTU – only acute treatment)
Carbimazole (methimazole)
Beta blockers to restore normal heart function

FHB IV- Endocrinology (17 decks)

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