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endocrinology 1 Flashcards

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1
Q

Endocrinology

A

study of the endocrine system, its diseases, and the hormones it
secretes

We will focus on the following endocrine glands in this section:
• Thyroid gland
• Parathyroid gland
• Adrenal gland
• Pituitary gland
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2
Q

Endocrine glands

A

ductless glands that secrete their products directly

into the blood.

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3
Q

Hormones

A

Hormones are chemical messengers released from endocrine glands into
the bloodstream to act on specific target cells.
• There are three major classes of hormones:
• Steroid
• Protein
• Amine ( amino acid derivatives)

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4
Q

steroid hormones

A

• Synthesized from cholesterol by adrenal glands, gonads, andplacenta
• Lipid soluble
- Need a carrier protein to circulate in blood
• Not stored (released immediately)

Free hormone binds to intracellular receptors forming a complex

Examples:
• Aldosterone
• Cortisol
• Estrogen, Estradiol
• Progesterone
• Testosterone
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5
Q

Protein Hormones

A

Synthesized as prohormones by anterior pituitary, parathyroid glands, pancreas and placenta
• Water soluble
- Do not need a carrier protein to circulate in blood
• Stored in secretory granules (vesicles) until needed

• Hormones interact with receptors on cell membrane, which activates a secondmessenger system and initiates cellular activity

Examples:
• FSH, LH
• TSH
• PTH
• hCG
• Insulin
• Growth Hormone
• Prolactin
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6
Q

Amine Hormones

A

Synthesized from amino acids( particularly tyrosine) by thyroid and adrenal glands
• Some are water soluble (epinephrine)
- Others require a carrier protein
• Stored until needed

  • Epinephrine and norepinephrine interact with receptor site on cell membrane.
  • Thyroid hormones: free hormone interacts with intracellular receptors
Examples:
• Epinephrine (Adrenaline)
• Norepinephrine
• Thyroxine (T4)
• Triiodothyronine (T3)
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7
Q

Hormone Measurement

A

• Methods to determine hormone concentrations must be sensitive.
- Low levels of hormones in circulation

Common methods used:
• Enzyme-multiplied immunoassay technique (EMIT)
• Fluorescent immunoassay (FIA)
• Fluorescent polarization immunoassay (FPIA)
• Chemiluminescent immunoassay (CLIA)
• High-performance liquid chromatography (HPLC)

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8
Q

Factors influencing hormone concentrations

A

Diurnal or circadian rhythms
• Cortisol concentrations can be 50% lower in the evening (8 pm) versus the morning (8 am)
• Other hormones showing diurnal variations: growth hormone,
ACTH, TSH, PTH, catecholamines

Protein-binding
• Only free or unbound hormone may be biologically active

Assay Specificity
• The antisera in some immunoassays may cross-react with other hormones in thespecimen and cause a falsely elevated result.

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9
Q

Thyroid and parathyroid location

A

Positioned in lower anterior neck and shaped like a butterfly.
• Made up of two lobes that rest on each side of the trachea.
• A band of tissue (isthmus) runs anterior to the trachea and bridges the
lobes.
• Parathyroid glands are located posterior to the thyroid and regulate
serum calcium levels.

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10
Q

thyroid anatomy

A

• Two types of cells are responsible for synthesizing hormones:
1 • Follicular cells synthesize thyroid hormones ( T4 & T3)
2 • Parafollicular (C cells) synthesize calcitonin

• The follicle is the basic unit of the thyroid gland.

  • In the center of the follicle is the lacuna containing colloid.
  • The colloid is predominately composed of thyroglobulin (Tg).
  • A basal lamina is located outside the follicularcells.
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11
Q

thyroid development

A

By 11 weeks gestation, the thyroid gland produces thyroid hormone

Congenital hypothyroidism occurs in 1 in 4,000 live births.
• Mother’s thyroid hormone crosses placenta during development.
• Postpartum, infant needs to be given thyroid hormone

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12
Q

iodine importance

A

Iodine is an essential component of thyroid hormone.
• Found in seafood, dairy products, breads, vitamins
• Intake of < 50 μg/day leads to hypothyroidism. (RDI = 150 μg/day)
- can lead to Mental retardation, stunted growth

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13
Q

Thyroid Hormone Synthesis

A

Follicles*
• Site of thyroid hormone synthesis
• Spheres of thyroid cells surrounding a fluid core called colloid*

Glycoprotein thyroglobulin* is a major component of colloid.
• Produced by follicular cells
• Rich in tyrosine

• Inside the thyroid cells, iodide is oxidized and bound with tyrosine
residues on thyroglobulin to form thyroid hormone.

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14
Q

Thyroid Hormones

A

thyroid gland secretes the following thyroid hormones:
• Thyroxine T4
• Triiodothyronine T3

• Small amounts of:
    Reverse T3 (  rT3 )

• Minute quantities of precursors if T3 & T4:
Monoiodotyrosine MIT
Diiodotyrosine DIT

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15
Q

thyroid hormone steps

A
  1. Iodide is transported into the thyroid cell by the Na+/I- symporter.
  2. Iodide diffuses to the apical side of the cell and is transported into the colloid.
  3. Iodide is oxidized to iodine and incorporated into tyrosine residues (MIT & DIT) within thyroglobulin molecules.
4. The enzyme thyroid peroxidase (TPO) helps combine two diiodothyronine (DIT) molecules to form tetraiodothyronine (T4)
 OR
monoiodothyronine (MIT) and diiodothyronine to form triiodothyronine (T3).
  1. TSH signals the follicular cell to ingest a droplet of colloid (containing thyroglobulin) by endocytosis. Droplets are digested by intracellular lysosomes into T4, T3
  2. Tg is degraded in a secondary lysosome, releasing T4 and T3 into circulation
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16
Q

what does Thyroid stimulating hormone control

A

Synthesis is regulated by thyroid-stimulating hormone (TSH) from the pituitary.
• TSH is also known as thyrotropin

  • TSH stimulates:
  • The iodine pump
  • Thyroglobulin (Tg) synthesis
  • Colloidal uptake by follicular cells
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17
Q

Goiter

A

Goiter is caused by prolonged TSH stimulation which leads to increased vascularity and eventual hypertrophic enlargement of the thyroid gland

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18
Q

thyroid gland produces two hormones

A
  1. Thyroid Hormone
    • Critical in regulating body metabolism, neurologic development, and other body functions
  2. Calcitonin
    • Involved in calcium homeostasis

Conditions affecting thyroid hormone levels are much more common than those affecting calcitonin.

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19
Q

Activity of Thyroid Hormones

A

Depends on the location and number of iodine atoms

  • Approx. 80% of T4 is metabolized into either T3 (35%) or rT3 (45%).
  • T3 is 3-8 times more metabolically active than T4.

Forms of Thyroid Hormone:
• Triiodothyronine (T3) - main active form

• Tetraiodothyronine (T4) - main form secreted
- also called thyroxine

• Reverse T3 (rT3) - inactive form

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20
Q

Iodo-derivatives of Tyrosine

A

In the liver, T4 undergoes peripheral deiodination of the outer ring to form T3 and rT3

  • This deiodination is a rapid response control mechanism for thyroid hormone balance.
  • Formation of rT3 is favored in acute or chronic stress or illness.
  • Some medications can shift the deiodination towards rT3 as well.
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21
Q

Protein Binding of Thyroid Hormone

A

Only 0.04% of T4 and 0.4% of T3 are free and available for hormonal activity.

Three major binding proteins:
• Thyroxine-binding globulin (TBG) ** MAIN ONE
• Thyroxine-binding prealbumin or thransthyretin (TTR)
• Albumin

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22
Q

blood distribution

A

Plasma Distribution:
• 97% T4
• 2% T3
• <1% rT3

  • Concentrations of free hormone in plasma are low
  • FT4:T4 = 1:3000
  • FT3:T3 = 1:300

only free form are biologically active

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23
Q

hypothalamic-pituitary-thyroid axis

A

hypothalamic-pituitary-thyroid axis regulates thyroid hormone production.

Controlled by a negative feedback loop involving:
• Thyrotropin-releasing hormone (TRH) from hypothalamus
• TSH from pituitary
• Thyroid hormones from the follicular cells of the thyroid gland

Thyrotropin-releasing hormone (TRH)
• Synthesized by neurons in the hypothalamus
• When secreted, stimulates cells in the anterior pituitary gland to manufacture and
release thyroid-stimulating hormone (TSH).

Thyroid-stimulating hormone (TSH)
• Circulates to the thyroid gland and increases production and release of thyroid hormone

24
Q

hypothalamic-pituitary-thyroid axis steps

A
  1. Thyrotropin-releasing hormone (TRH) stimulates the production and release of TSH.
  2. TSH stimulates the thyroid gland to synthesize and secrete thyroid hormone.
  3. T4 that is released by the thyroid gland is converted to T3 in the liver (and kidney).
  4. T3 & T4 feedback inhibit TSH release through action at the pituitary and by ↓TRH release from hypothalamus.
25
Q

Control of Thyroid Function

A

• Synthesis of TSH is regulated by a negative feedback loop.

• When levels of thyroid hormone in circulation are too low:
- TRH and TSH secretion increases, stimulating thyroid hormone production.

• When levels of thyroid hormone in circulation are too high:
- TRH and TSH release will be inhibited, leading to lower thyroid hormone production.

  • When TSH binds to a thyroid-stimulating hormone receptor (TSHR) it places the receptor in the “on” conformation which stimulates the thyroid gland.
  • In the TSH-stimulated thyroid follicular cell the following activities occur:
    • The activity of the Na-I symporter increases
    • Synthesis of thyroglobulin (Tg) and TPO increases
    • Release of T4 and T3 increases
26
Q

Actions of Thyroid Hormones

A
  • After being released by the thyroid gland, thyroid hormone circulates in the bloodstream.
  • Free T4 and T3 cross the cell membrane and T4 is deiodinated into T3 (mainly in the liver).

• When T3 combines with hormone-responsive genes, messenger RNA are produced.
- This leads to production of proteins that influence metabolism and development.

27
Q

Effects of Thyroid Hormone

A
  • Tissue growth
  • Brain maturation
  • Increased heat production
  • Increased oxygen consumption
  • Increased basal metabolic rate
28
Q

Blood Tests for Thyroid Function

A
  • Thyroid-Stimulating Hormone (TSH)
  • Total thyroid hormones (T3 and T4)
  • Free thyroid hormones (FT3 and FT4)
  • Thyroxine-binding globulin (TBG)
  • Thyroglobulin (Tg)
  • Thyroid Autoantibodies
29
Q

what is Most useful for assessing thyroid function

A

Three generations of assays:
• 1st generation - capable of diagnosing primary hypothyroidism with elevated levels of TSH (thyroid gland disease leading to low thyroid hormone production)

• 2nd generation - screen for hyperthyroidism (detection limit of 0.1 mU/L)

  • 3rd generation - chemiluminometric assays
  • Increased sensitivity (detection limit of 0.01 mU/L)
  • Can detect subclinical disease (mild degree of thyroid dysfunction)
30
Q

what are 3rd generation assays are preferred for

A

3rd generation assays are preferred for:
• Monitoring and adjusting thyroid hormone replacement therapy.
• Screening for abnormal thyroid hormone production in the clinical
setting.

Subclinical Hypothyroidism
• TSH - slight ↑
• FT4 - normal

Subclinical Hyperthyroidism
• TSH - ↓
• FT4 - normal

31
Q

Thyroid-Stimulating Hormone - Specimen Collection

A

Serum or plasma
• Stable 5 days at 2-8oC, 1 month frozen

• Diurnal secretion:

  • Peak concentrations between 0200 and 0400
  • Lowest concentrations between 1700 and 1800
  • Most labs use two-site “sandwich” heterogeneous immunoassays using one of the following labels:
    • Enzyme
    • Fluorometric substrate
    • Chemiluminescent
  • The high-dose hook effect generally does not occur with TSH immunoassays
  • Reference Range: 0.4 - 4.5 mIU/L
32
Q

Total Thyroxine (T4)

A
  • Main hormone secreted by the thyroid
  • Amount in circulation is controlled by TSH
  • Highly protein bound (>99.9%)
    • Bound fraction is biologically inactive
33
Q

Total Thyroxine (T4) specimen

A

Specimen:
• Serum preferred
- Plasma EDTA or heparin can be used
• Stable up to 7 days @ RT or 30 days frozen

34
Q

measuring Total Thyroxine (T4)

A

• Clinical labs use an automated competitive immunoassay

  • Uses polyclonal antibodies against and albumin-T4 conjugate
    - Highly specific with minimal cross-reactivity with T3

• Chemiluminescent Microparticle Immunoassay (CMIA) used locally Abbott T4 Reagent

Interferences:
• T4 autoantibodies can produce falsely decreased or increased results with some assays
• Because T4 mostly reflects the inactive hormone, FT4 measurements are preferred.

35
Q

Total Triiodothyronine (T3)

A

• Main active thyroid hormone
• 20% secreted by thyroid gland, remainder produced by deiodination of T4 in
peripheral tissues
• Highly protein-bound ( >99.7%)
• Bound fraction is biologically inactive
• Less tightly bound than T4

36
Q

Total Triiodothyronine (T3)

A

Specimen:
• Serum preferred
• Plasma EDTA or heparin can be used
• Stable for 24 hours @ RT or 30 days frozen
• Centrifuge turbid samples before testing

37
Q

measuring Total Triiodothyronine (T3)

A

• Immunoassays are method of choice.
- Many commercial systems use enzyme labels (peroxidase or ALP) conjugated to T3 or anti-T3
antibodies.
• Enzyme activity can be determined using one of the following substrates:
- Photometric
- Fluorescent
- Chemiluminescent

• Poorer analytical performance compared to T4 because:

  • Lower concentration of T3 in serum
  • Greater antibody cross-reactivity
  • Protein interferences
38
Q

methods for measuring Free Thyroid Hormones (FT3, FT4)

A
  • Methods include:
    • Direct assays - reference method
    • Indirect assays
  • Indirect methods
    • One-step and two-step immunoassays (preferred)
    • Estimate free hormone concentration using antibody extraction techniques
    • Abbott FT4 Assay
39
Q

Thyroxine-Binding Globulin (TBG)

A

protein that the hormones can bind to

  • just know details, just that there is different methods for measuring TBG

• Competitive, heterogeneous method
- Measures competition between endogenous TBG and labeled TBG for binding sites on an immobilized anti-TBG antibody

Solid-phase second antibody method
• Bound conjugate is measured by chemiluminescence after addition of Luminol
and hydrogen peroxide

Enhanced microparticle turbidimetry
• Anti-TBG antibody inhibits cross-linking of Ag-microparticle complexes, reducing
the turbidity of the reaction mixture.

40
Q

Thyroglobulin

A

• Protein synthesized and secreted by thyroid follicular cells.

• Ideal tumor marker for thyroid cancer patients***
- Successfully treated patients should have undetectable thyroglobulin levels.

Three methods currently used:
• Competitive immunoassays
- Lower sensitivity, labor intensive
- Robust to antibody interference

  • Immunometric assays
    • Very sensitive, able to automate
    • Prone to antibody interference
    • Should be reported with anti-Tg results

• Peptide mass spectrometric assays

41
Q

Thyroid Antibodies

A

• Found in a variety of thyroid disorders, autoimmune diseases and certain malignancies.

  • Antibodies can be found against:
    • Thyroglobulin (TgAb)
    • Thyroid peroxidase antibody (TPOAb)
    • TSH receptor (TRAb)
    • TSH
    • T4
    • T3

• TPOAb is the antibody most often tested to evaluate thyroid autoimmune disease
- one we use the most

42
Q

Thyroid Autoimmunity

A

• In autoimmune thyroid disease antibodies are directed at thyroid tissue.
- attacking its own tissue

• Grave’s Disease (form of hyperthyroidism)
- Detected by testing for TSHR-stimulating antibodies

• Hashimoto’s thyroiditis (form of hypothyroidism)
- Test to detect thyroid peroxidase (TPO) antibodies

43
Q

Other Tools for Thyroid Evaluation

A

• Nuclear Medicine Evaluation
- Use of radioactive iodine to assess metabolic activity of thyroid tissue

• Thyroid Ultrasound
- Can detect small thyroid nodules

• Fine-Needle Aspiration
- Allows prompt identification and treatment of thyroid malignancies

44
Q

Disorders of the Thyroid - Hypothyroidism

A

• One of the most common disorders of the thyroid gland.
- Occurs in 5-15% of women >65 years old

Lab Results:

  • ↓ Free T4
  • N or ↑ TSH

• May have:

  • ↓ Na+ - increased urine sodium excretion
  • ↑ CK
  • Hyperlipidemia (50% of patients)
  • Anemia
45
Q

Symptoms of Hypothyroidism

A
  • Cold intolerance
  • Depression
  • Fatigue
  • Dry skin
  • Edema
  • Constipation
  • Hoarseness
  • Dyspnea on exertion
  • Cognitive dysfunction
  • Hair loss
  • Weight gain
46
Q

Hypothyroidism

A

• Can be divided into primary, secondary, or tertiary disease.

• Primary
- Thyroid gland dysfunction

• Secondary
- Pituitary gland dysfunction ( interfere w/TSH release)

• Tertiary

  • Hypothalamus dysfunction ( more rare)
  • TRH release
47
Q

Causes of Hypothyroidism

A

• Cretinism

  • Hypothyroidism occurring in infancy
  • Impaired musculoskeletal and nervous system development
  • Less common now due to newborn screening and addition of iodine to food

• Myxedema
- Symptoms of hypothyroidism
- Severely advanced hypothyroidism (refers to the deposition of mucopolysaccharides in the skin)
- Coma can occur in severe cases
• Hypotension, bradycardia, hypothermia, respiratory depression

• Hashimoto’s thyroiditis (Lymphocytic thyroiditis)

  • Most common cause in developed countries
  • Most common among middle-aged women
  • Autoimmune disease targeting thyroid gland
• Lab findings:
  -  Antibodies against:
       • Thyroglobulin
       • Thyroid peroxidase (TPOAb) - present in 80-99% of cases
       • TSH receptors
       • Iodine receptors
  • Other causes:
    • Iodine deficiency
    • Thyroid surgery
    • Radioactive iodine treatment

Lab findings:
• Overt hypothyroidism:
- ↑ TSH, ↓ FT4

• Subclinical hypothyroidism:
- ↑ TSH, normal FT4

• Treatment: thyroid hormone replacement therapy (Levothyroxine)

48
Q

Hyperthyroidism

A

Thyrotoxicosis
• An excess of thyroid hormone in peripheral tissues

  • Possible causes:
    • Excessive thyroid hormone ingestion (medication)
    • Leakage of stored thyroid hormone from thyroid follicles
    • Excessive thyroid hormone production from thyroid gland
49
Q

Symptoms of Hyperthyroidism

A
  • Heat intolerance
  • Anxiety
  • Emotional lability
  • Weakness
  • Tremor
  • Palpitations
  • Fatigue, weakness, decreased exercise tolerance
  • Increased perspiration
  • Weight loss despite normal appetite
  • Menstrual changes
  • Prominence of eyes
50
Q

Graves’ Disease

A
  • Most common cause of thyrotoxicosis
  • Autoimmune disease in which antibodies are produced that activate TSH receptor on thyroid cells, stimulating the production of thyroid hormones
  • Features:
    • Thyrotoxicosis
    • Goiter
    • Ophthalmopathy (eye changes)
    • Dermopathy (orange peel texture to skin)

• Strong familial disposition: 15% of patients will have a close relative with the condition

51
Q

Graves disease lab results & treatment

A 
Lab Results:
• ↑ FT3/FT4
• ↓ TSH
• Presence of TSHR-stimulating antibodies (TRAb)
• Presence of TPO Abs

Treatment:
• Medication
• Radioactive iodine
• Surgery

52
Q

Hyperthyroidism

A

Subclinical hyperthyroidism:
• Low TSH
• Normal T4 and T3

T3 thyrotoxicosis:
• 2-4% of patients with hyperthyroidism
• Low TSH
• Increased FT3 or T3
• Normal FT4

Secondary hyperthyroidism
• Caused by pituitary adenoma
• Inappropriately normal or high TSH for elevated thyroid hormones concentration ( thyroid isnt the cause )

53
Q

Toxic Adenoma and Multinodular Goiter

A

• Two other common causes of hyperthyroidism.

  • Caused by autonomously functioning thyroid tissue.
  • Thyroid hormone is being produced and secreted without stimulation from TSH
  • Toxic Adenomas
  • Symptoms of hyperthyroidism
  • Sometimes palpable nodule
  • Toxic Multinodular Goiter
  • Multiple areas of thyroid gland producing hormone autonomously
  • Treatment: Surgery, radioactive iodine, or medication
54
Q

Thyroid Disorders in Pregnancy

A
  • T3 and T4 concentrations increase during pregnancy due to an increase in TBG concentration.
  • Increased estrogen levels increase hepatic synthesis and reduce metabolism early in pregnancy resulting in the increase in TBG.

• TBG stays elevated throughout pregnancy.

• Placental hCG and TSH share the same α subunit but have different β subunits.
• hCG binds to TSH receptors on the thyroid gland, stimulating secretion of T4 and T3
• Increased thyroid hormones will inhibit TSH secretion and TSH concentration will fall.
• TSH decreases in 1st trimester, then rises in 2nd and 3rd trimesters as hCG concentrations
decrease.

• 1st trimester: ↓ TSH, ↑ FT4
2nd & 3rd trimesters: TSH increases, FT4 falls

55
Q

Points to Remember

A

• Produced by the pituitary:
TSH - thyroid-stimulating hormone

• Produced by the thyroid gland:
T3
T4
Thyroglobulin - protein

• TSH is the primary serum test to screen for thyroid disease.

Chemistry 2 (30 decks)

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