Patozone

Introduction

 

Endocrinology - The study of intra and extracellular communication by messenger molecules called hormones.

Hormones - Produced in an organ, but acts upon a distant location.

- Secreted into the blood prior to use

- Making circulating levels indicative of endocrine gland activity and target organ exposure

Interact with receptors in/on the target cell

 

 

Polypeptides / proteins

 

Synthesized and stored

Released into the bloodstream when needed by the body

Water soluble

Circulate unbound to carrier proteins or bound to them

Short half life

Examples, LH, FSH, TSH

 

 

Steroids

 

Produced by adrenals, gonads, & placenta

Synthesized by cholesterol but not stored by the body

Lipid-soluble

Circulate via carrier proteins and in the free form

Longer half-life

Free form is biologically active

Examples: estrogen, testosterone, progesterone, aldosterone

 

 

 

Amines

 

Have properties of steroids and polypeptides

Half-lives differ from very short to very long

Examples, epinephrine, norepinephrine, thyroxine

 

 

Components of endocrine system

 

Hypothalamus –

Produces stimulating & inhibiting hormones

Modifies & controls secretion of hormones from anterior pituitary

Occur in small quantities, therefore are measured by  the response  by the anterior and posterior pituitary

 

Pineal gland –

Produces melatonin

Controls circadian rhythms

 

Pituitary

Anterior – adenohypophysis

 - Produces tropic hormones that regulate target glands

 

Posterior – neurohypophysis

 - Releases hormones in response to suckling or changes in serum osmolality

Target gland or target cell

 

 

Disorder classification

 

Primary

Outside stimulating agents respond as expected

Hypo or hyper secretion of hormone from gland by its own volition

Glandular problem

 

Secondary

Target gland is functioning properly

Outside stimulating agents are in excess causing hypersecretion of the target gland hormone, OR

Outside stimulating agents are deficient causing hyposecretion of the target gland hormone

 

Tertiary

Problem at the hypothalmic level

Parathyroid Endocrinology

 

Role of the gland:

Regulate calcium levels

 

Chief Cells

-Most abundant

- Secretes parathyroid hormone (PTH)

 

Oxyphil cells

- Old chief cells

- Affinity for acidic dyes

 

 

Synthesized as a preprohormone (115 Amino a's)

 

Stored as prohormone (90 amino a's)

 

Released as an 84 amino acid molecule

- circulates with a half-life of 30 minutes

- Known as the intact molecule

 

Liver & kidneys produce two fragments from the intact molecule

 

Type of Parathyroid Hormone (PTH)

 

1) Intact PTH – circulating form

- All 84 amino acids

- Biologically active form

 

2) N-terminal

- Amino terminal end of the molecule

- 1 through 34 amino acids

- Biologically active

 

3) C-terminal

- Carboxyl end of the molecule

- 35 through 84 amino acids

- Biologically inactive

 

Mech: Regulates the amount of Ca in blood

- Normal: 8.8 – 10.4 mg/dL (2.2-2.6 mmol/L)

 

Regulates the amount of Ca in bone

- Controls bone density

 

Can live with ½ of a gland if necessary

 

More common to have more hormone from a hyperparathyroid gland

 

Hypoparathyroidism is less common

 

 

Calcium in bone

 

Ca combines with PO4 and forms hydroxyapatite

- Helps to form bone through osteoblastic activity

 

Osteoclastic activity releases bone Ca

 

Bone resorption results in ↑ Ca in blood

 

PTH directly causes Ca to be released from the bone into the blood

 

 

Calcium in serum

 

Controls normal conduction of electrical currents along nerves

 Controls how nerves talk to one another

 Controls muscle contraction

- Tingling sensations – low Ca

Controls normal brain function

- Brain feels “foggy” or confused – low Ca

- Feel run down or sluggish – high Ca

 

 

Forms of Calcium in Serum

 

Protein-bound – 45%

Complexed – 5%

Free or ionized – 50%

 

Serum proteins play important role

 

 Adj Ca (mg/dL) = [Tot Ca (mg/dL ) - Albumin (g/dL)] + 4

 

Alterations in serum proteins will affect interpretation of results

Protein binding is pH dependent

Body requires more Ca during pregnancy

- Physiologic growth

- Lactation

 

 

Effects of pH on Calcium binding

 

Acid/base status causes fluctuations in ionized Ca levels

 

Acidosis

- H+ bind to albumin

- Less sites for Ca to bind

 

Alkalosis

- Fewer H+ to bind to albumin

- More Ca binds to protein

- Less free Ca in serum

 

Regulation

 

Ionized Ca concentrations control the synthesis and secretion of PTH

↓ Ca+ stimulate PTH secretion

↑ Ca+ inhibit PTH secretion

 

Additional factors:

Sudden ↓ Mg stimulate PTH secretion

↑ PO4 → ↓Ca → stimulate PTH

This is an INDIRECT cause of PTH secretion

 

 

Actions on target organs

 

Bone

Direct influence

Activates & ↑ osteoclastic cells

↑ mobilization of Ca

↑ resorption of  Ca & PO4

↑ bone turnover rate

 

Kidney

Direct influence

↑ Ca reabsorption by distal renal tubules

↑ PO4 excretion

 (↓ in serum)

↑ Renal α-hydroxylase activity

↑ conversion of

 25-hydroxy Vitamin D    to

 1,25-dihyroxy Vitamin D

 

Vitamin D

Essential for maintenance of serum Ca

Absorbed thru the intestines

Formed in the skin by UV radiation

Becomes biologically active

Through metabolism

Cholecalciferol→25-OH-D3→1,25-(OH)2-D3

Liver→circulation→converted in kidney→active form

 

Intestine

Indirect influence

Increased levels of 1,25-dyhydroxy Vitamin D

-Enhances absorption of Ca in the intestine

- Stimulates osteoclastic cells in the bone

- Reabsorption of Ca in renal tubules

 

 

Calcitonin

 

Secreted by the “C” cells in the thyroid

Counteracts PTH

Lowers serum calcium

Inhibits osteoclastic activity

Inhibits renal tubule reabsorption

Increases excretion of Ca in urine

High levels of ionized Ca simulates release of calcitonin

 

 

Methodologies

 

PTH

2-site immunoradiometric (IRMA) assay

Measures the intact molecule

Very specific

No cross-reaction with PTH related peptide (PTHr)

 

Ca

Atomic absorption

Color-complex formation

Ion selective electrodes

 

Ionized Ca

Ion selective electrode

Requires collection on ice to reduce elevations in blood pH

 

 

Parathyroid Disorders

 

Associated with Hypocalcemia:

Ca levels fall below 8.5 mg/dL (2.25 mmol/L)

Tetany

CNS involvement

 

Hypoparathyroidism – rare

Accidental removal of the gland during thyroid surgery

Production of physiologically inactive PTH

Gland absent from birth

 

Pseudohypoparathyroidism – Ca remains low

Target organ resistance to PTH

PTH is elevated

 

Vitamin D deficiency - ↓ amounts of Vitamin D

Inadequate dietary intake

Malabsorption

Inadequate exposure to UV light

Rickets in children, osteomalacia in adults

 

Chronic renal failure – secondary hyperparathyroidism

Decreased synthesis of 1,25 (OH)2 D3

↓ Ca → ↑ PTH

Left untreated can lead to bone disease

Associated with diabetes

 

 

Associated with Hypercalcemia:

Ca levels are above 10.5 mg/dL (2.6 mmol/L)

Symptoms begin when Ca > 12mg/dL

Weakness, nausea, constipation, impaired mental concentration

Rehydration or drugs to ↑ renal excretion

 

Primary Hyperparathyroidism

Asymptomatic

80% are due to benign adenomas

PTH secretion is independent of negative feedback system

PTH is ↑ and Ca is ↑

Diagnosis is based on several serum Ca levels

 

Malignancy

Tumor directly invades the bone tissue

Some tumors produce PTHr

Causes osteoclasts to release bone Ca

PTH is inhibited

 

Toxicity

Example of too much of a good thing

Overconsumption of antacids

Excessive ingestion of Vitamin D

 

 

 

 

 

 

 

 

 

Thyroid Endocrinology

 

Synthesis of thyroid hormone

 

1. Active uptake of I- in exchange for Na+

 

2. Iodide may be discharged from the follicular cell by competing ions.

 

3. Iodide uptake is stimulated by TSH

 

4. Oxidation of iodide by H2O2 to form active iodine. - Thyroid peroxidase (TPO) catalyzes this reaction.

 

5. Active transport of iodine across cell membrane occurs.

 

 

Once thyroid hormone is released:

 

Binds to carrier proteins

TBG – thyroid binding globulin

- Binds T4 & T3

Transthryetin – pre-albumin

- Binds T4

 

TBA – thyroid binding albumin

- Binds T3

 

Circulate as free and bound forms

 

Dynamic equilibrium exists resulting in euthyroid status

 

T3 is the more potent and active of the thyroid hormone.

 

REMEMBER: Abnormal concentrations of binding proteins can result in abnormal total hormone concentration. ***** Remember this!

 

 

Mechanisms:

Regulates carbohydrate, lipid, & protein metabolism

Activates central nervous system

Stimulates heart & cardiovascular system

Regulates GI tract functions

Growth & development

Sexual maturation

 

 

Pregnency alterations of thyroid hormone by trimester

 

First trimester

Placenta produces large quantities of HCG

HCG stimulates thyroid gland to produce thyroid hormone (TSH-like effect)

Pituitary TSH decreases

Binding proteins increase

 

Second trimester

Binding proteins become saturated with thyroid hormone

HCG declines and pituitary TSH will begin to increase

Free hormone increases

 

Third trimester

When the binding capacity of the proteins is > hormone production from HCG stimulation

- Free hormone decreases

- Pituitary TSH increases

 

 

HCG – causes TSH-like effects

 

Binding proteins increase

 

Refer to the chart for comparison of T4, FT4, TSH, & TBG levels

 

Compare hormone levels by trimester

 

Explain the mechanism for hormone levels

 

 

Hypothyroidism

 

Fatigue

Slow mental performance

Cold intolerance

Impaired memory

Change in personality

Hoarseness

High cholesterol, LDL, Apo A & B, and increased risk for CAD*****

 

Primary Hypothyroidism disorders:

Myxedema – common symptoms worsen

 

Cretinism (congenital hypothyroidism)

 

Hashimoto’s disease (MC primary disorder)

 

Nodular thyroid disease – often benign

 

Subclinical – no apparent symptoms

 

 

 

Hyperthyroidism

 

Increased appetite with sudden weight loss

Fast heart beats/palpatations/tachycardia

Increased sensitivity to heat

Warm and clammy

Tremors

Increased anxiety and nervousness

Diffusely enlarged thyroid gland

 

 

Primary Hyperthyroidism disorders:

Thyroidtoxicosis – excessive thyroid hormones in circulation

 

Thyroid storm – life-threatening condition

 

Graves disease (MC primary disorder)

 

Thyroiditis

- Acute – usually caused by bacteria or parasite in an abscess

- Subacute – viral agent damages follicular cells

- Silent – autoimmune

 

 

Mechanistic differences:

Hypo results in low thyroid hormone levels, hyper results in elevated levels

 

Hashimoto’s – a result of antibodies attacking follicular cells

 

Graves’ – a result of activated B cells attaching to TSH receptors on follicular cells

 

Thyroid Function Tests

 

TSH

 

Plays central role in thyroid’s economy

Inversely related to FT4

2-fold change in FT4 causes a 50-fold change in TSH

Earliest hormone to respond to thyroid gland function - *** best first test to get !!!***

Affected by many physiological states & drug interactions

 

Assay sensitivity essential to differentiating between hyperthyroid and euthyroid patients

Assay of choice is 4th generation

- 3rd generation assays detect 0.01-0.05 mU/L

- 4th generation detects to 0.001 mU/L

 

Interferences include:

Prior exposure of patient to mouse monoclonal antibodies

Presence of pituitary tumors – causes ↑ TSH but not because thyroid has stopped producing hormone

 

TRH Stimulation

 

Used mostly for identification of TSH secreting pituitary tumor or Thyroid hormone resistance syndrome

 

TSH measurements are taken prior to TRH administration for baseline level, followed by timed intervals

 

Normal response

- Rise in TSH, peaks 15-20 min, returns to base in 60 min

- Associated rise in T4 & T3

 

Free T4

 

Olden Days

- Critical step

-- Separation of free hormone from bound

- Gold standard method

-- Equilibrium dialysis

- Dilutions

-- NOT recommended

 

Immunoassay advantage

- Not affected by varying concentrations of binding proteins

 

Total T4

 

Serum levels are dependent on:

Rate of synthesis

Rate of release

Concentration of binding proteins

Peripheral conversion of T4 to T3

 

Methodologies

- Immunoassays

 

 

T3 Uptake

 

Assesses whether alterations in Total T4 are due to alterations of binding protein concentration or alterations of thyroid function

 

Resin uptake ratio (RUR)

 

RUR is inversely proportional to TBG, directly proportional to T3 present

RUR < 1, when BP is ↑

RUR > 1, when BP is ↓

 

RUR with TT4 to calculate FTI

 

 

Free Thyroxine Index (FTI)

 

Indirect measure of free hormone concentration

 

FT4I = T4 x T3U ratio

- Example: RR for T4 = 4 to 10 ug/dL

T4 = 12 ug/dL

T3 uptake = 25% (normal reference = 30%)

RUR = 25/30 = 0.83

FTI = 12 x 0.83 = 10 ug/dL

 

Compare the two results:

12 ug/dL without BP correction – outside of RR

10 ug/dL with BP correction – within RR

 

 

Total T3 and Free T3

 

TT3 most useful for confirming hyperthyroidism

 

Primarily reflects the hormone stores in the blood

 

Most useful for confirming early hyperthyroidism in patient with altered binding proteins

 

Free T3 assays have become better but still not widely used

 

 

Thyroid Antibodies

 

TSI – Thyroid stimulating Ig’s

TSH receptor Ab

Anti-TR

TRAbs

 

Anti-TPO

Thyroid peroxidase Ab

Formerly known as Anti-Thyroid microsomal Ab

 

Bind to follicular microsomal membrane

Fixes complement

Destroys tissue

Decrease in Thyroid hormone

Seen in 95% of patients with Hashimoto’s disease

 

 

Anti-Tg

Anti thyroglobulin Ab

TgAB

 

 

TRAbs (TSI)

 

Abs bind to cell membrane near/at TSH receptor site

Feedback system no longer works

Increased levels of thyroid hormone

Seen in 85% of patients with Graves disease

 

 

How Abs work

How TSI works

Anti-TPO