PATHO - Endocrine System Flashcards
The 5 general functions of the endocrine system
1) Differentiation of reproductive system and CNS in developing fetus
2) Stimulation of growth and development during childhood and adolescence
3) Coordination of the male and female reproductive systems (allowing sex reproduction)
4) Maintenance of internal environment
5) Initiating corrective/adaptative responses to emergency demands of body
Autocrine vs Paracrine vs Endocrine action
all are mechanisms of communication and control via hormones
Autocrine: hormones acting within a cell (i.e. on the cell that produced the hormone)
Paracrine: hormones acting on nearby cells
Endocrine: hormones acting on cells around the body via the circulatory system
Major Endocrine organs (9)
1) pineal gland
2) pituitary gland
3) parathyroid gland (on posterior surface of the thyroid gland)
4) thymus
5) thyroid gland
6) adrenal gland
7) pancreas
8) ovary
9) testis
All hormones share certain general characteristics, which include:
1) have specific rates & rhythms of secretion
- diurnal: during the day
- pulsatile and cyclic
- depending on level of circulating substrates
2) operate within feedback systems - negative or positive - for homeostasis
3) affect only target cells with specific receptors for the hormone and then act on these cells to initiate specific cell functions or activities
4) Excretion/inactivation
- steroid hormones - excreted via kidneys or metabolized by liver (inactives them and makes them more water soluble for renal excretion)
- peptide hormones - catabolized by circulating enzymes and eliminated in feces/urine
What are the different ways hormones can be classified?
structure
gland of origin
effects
chemical composition
Why do hormones get released (i.e. what happens in the body that would regulate the release of hormones)?
What mechanisms control this release?
Why they get released:
- 1) released to responsd to an altered cellular environment
- 2) released to maintain the level of another hormone/substance
Mechanisms regulating hormone release:
- 1) chemical factors (ex. blood glucose cause insulin release, calcium levels)
- 2) endocrine factors (ex. hormones from hypothalamus controlling pituitary hormones)
- 3) neural control (ex. ANS directly stimualting beta cells to release glucose)
Negative vs positive feedback
Negative feedback: when changes to chemical, neural or endocrine response to a stimulus DECREASE the synthesis/secretion of a hormone - maintains homeostasis/original steady state; most common
Positive feedback: when changes to chemical, neural or endocrine response to a stimulus INCREASES the synthesis/secretion of a hormone - moves system FURTHER away from original status
Describe the feedback loop between hypothalamus-pituitary axis (HPA) and the thyroid gland when T4 and T3 levels decrease, and whether this is a positive or negative feedback loop.
Negative feedback loop
1) ↓ serum levels of thyroxine (T4) and triiodothyronine (T3) stimulate secreation of thyrotropin-releasing hormone (TRH) from hypothalamus
2) TRH stimulates secreation of thyroid-stimualting hormone (TSH) from anterior pituitary
3) TSH stimulates synthesis and secretion of T3 and T4
4) T3 and T4 levels are now ↑ and generate negative feedback on the pituitary and hypothalamus to inhibit TSH and TRH synthesis
Negative feedback loops are possible at three levels, which are:
1) target organ - ultra short feedback loop
2) anterior pituitary - short feedback loop
3) hypothalamus - long feedback loop
Describe the feedback loop within the female reproductive cycle when estradiol levels increase, and whether this is a positive or negative feedback loop.
positive feedback loop
1) ↑ estadiol levels act on hypothalamus to release Gonadotropin Releasing Hormone (GnRH)
2) GnRH stimualtes release of follice-stimulating hormone (FSH) from anterior pituitary
3) FSH (and LH) cause ovaries to produce more estrogen, leading to ovulation
Water-soluble hormones vs lipid-soluble hormones
Describe how they are transported in the circulatory system and their half lie.
Water-soluble hormones:
- aka peptide hormones (protein hormones, catecholamines)
- circulate in free (unbound) forms - only these can signal a target cell (if they are bound to a carrier protein like lipid soluble hormones, they cannot)
- high MW, cannot diffuse across cell membrane - bind with receptors on or in cell membrane
- half-life typically seconds to minutes because they are catabolized by circulating enzymes
- ex. insulin
Lipid-soluble hormones:
- transported bound to a water-soluble carrier or transport protein
- can pass freely across plasma and nuclear membranes (via simple diffusion) & bind with cystolic or nuclear receptors (vit. D, retinoice acid, and thyroid hormones can also do this)
- hormone-receptor complex binds to a specific region in the DNA and stimulates specific gene exprsesion
- can remain in blood for hours to days
- ex. cortisol & adrenal androgens
What are target cells and what are the two main functions of the hormone receptors of the target cell?
Target cells: cells with appropriate receptors for THAT specific hormone
Two main functions:
- 1) to recognize and bind specifically and with high affinity to their particular hormones
- 2) to initiate a signal to appropriate intracellular effectors
Upregulation vs downregulation
Upregulation: low concentrations of hormones increase the number or affinity of receptors per cell
Downregulation: high concentrations of hormone decrease the number or affinity of receptors per cell
Cells are able to adjust their sensitivity to the concentration of a signaling hormone. How do they do this and what factors/phsyiochemical conditions may influence this sensitivity?
- sensitivity of the target cell to a specific hormone depends on # of receptors and/or their affinity for the receptors
- receptors are continuously synthesized and degraded, so their numbers on the cell surface can frequently change as well
- factors that affect their ability to do this:
- fluidity and structure of plasma membrane
- pH
- temperature
- Ion concentration
- Diet
- Presence of other chemicals (like drugs)
Describe how the regulation of hormone receptors on cells for glucose uptake is affected in NIDDM/Type 2 Diabetes.
In NIDDM, there is a decrease in insulin receptor sensitivity and hyperglycemia (so they need to be able to quickly increase their numbers of receptors to pick up as much insulin as possible to deal with the high sugar levels)
Direct effect vs Permissive Effect
ways in which hormones affect target cells
-
Direct effect: obvious changes in cell function that are specifically a result from stimulation by a particular hormone
- ex. insulin directly affects skeletal muscle via insulin receptors to increase glucose uptake
-
Permissive effect: less obvious hormone-induced changes that facilitate max response/functioning of a cell
- ex. insulin’s effect on mammary cells - facilitates response of mammary cells to prolactin
Where are the two locations that hormone receptors can be found?
a) in the plasma membrane
b) in intracellular compartment of the target cell
First messenger vs Second messenger
First messenger: the hormone that binds to the receptor on the plasma membrane that initiates a cascade of intracellular effects
- intiates signal transduction: the transmission of molecular signals from a cell’s exterior to its interior
Secondary messenger: intracellular molecules that relay signals received at receptors on the cell surface to the cytoplasm & nucleus of the cell and mediates effects of the hormone on the cell
Second messengers include:
- cyclic adenosine monophosphate (cAMP)
- cyclic guanosine monophosphate (cGMP)
- calcium
- inositol triphosphate (IP3)
- tyrosine kinase system
What first messengers activate/increase cAMP levels to cause cell signaling?
adrenocorticotropic hormone (ACTH)
thyroid-stimulating hormone (TSH)
both^ cause cAMP levels to increase, which then activate protein kinases leading to phosphorylation of cellular proteins (which then either activates/deactivates intracellular enzymes and causing specific functions)
What first messengers result in the production of IP3. Describe the cellular cascade as a result of the first messengers triggering IP3.
First messengers: Angiotensin II, ADH
Cellular cascade: first messengers generate IP3 which then triggers a release of intracellular calcium ⇒ forms a calcium-calmodulin complex ⇒ mediates effects of calcium on intracellular activities that are crucial for cell metabolism and growth
Insulin, GH, and prolactin are first messengers that bind to surface receptors and activate which second messenger(s)?
second messengers of the tyrosine kinase family:
Janus family of tyrosine kinases (JAK)
signal transducers and activators of transcription (STAT)
With the exception of thyroid hormones, lipid-soluble hormones are synthesized from ___________________. These lipid-soluble hormones include:
cholesterol (i.e. hormones with “steroid” in the name)
androgens, estrogens, progestins, glucocorticoids, mineralcorticoids, vitamind D, retinoid
Describe the steroid hormone mechanism causing an effect on its target cell.
1) Lipid-soluble steroid hormone molecules detach from carrier protein & pass through plasma membrane
2) Hormone molecules then diffuse into the nucleus where they bind to a receptor to form a hormone-receptor complex
3) Hormone-receptor complex then binds to a specific site on DNA molecule
4) Triggers transcription of genetic information encoded there
5) Resulting mRNA molecule moves to the cytosol where it associates with a ribosome and initiate synthesis of a new protein
6) new protein now produces specific effects on the target cell
The ______________ forms the structural and functional basis for central integration of the neurological and endocrine systems, creating the neuroendocrine system.
hypothalamic-pituitary axis (HPA)
Hypothalamus - Structure and function
Structure: at the base of the brain, connected to the pituitary gland by the pituitary stalk
- connected to the anterior pituitary through hypophysial portal blood vessels
- connected to the posterior pituitary via nerve tract, hypothalamohypophysial tract
Function:
- contains special neurosecretory cells that synthesize and secrete hypothalamic-releasing hormones that regulate the release of hormones from anterior pituitary
- ^ cells also synthesize ADH and oxytocin that are released from posterior pituitary gland
Structure of Pituitary gland
Structure: located in the sella turcica (saddle-shaped depression of the sphenoid bone at the base of the skull)
- weights ~0.5g except during pregnancy (weight ↑ ~30%)
- composed of two distinct lobes (different emrbyonic origins, cell types, function)
- 1) anterior pituitary: aka adenohypophysis
- 2) posterior pituitary: aka neurohypophysis
Structure of anterior pituitary - how much does it weigh and what are the 3 regions that make up the anterior pituitary
- accounts for 75% of total weight of pituitary gland
- 3 regions:
- 1) pars distalis - major component, source of anterior pituitary hormones
- 2) pars tuberalis - thin layer of cells on anterior and lateral portions of pituitary stalk
- 3) pars intermedia - lies between those two^ and secretes melanocyte-stimulating hormone in fetus ; disappears in the adult and cells are distributing through pars distalis and pars nervosa of posterior pituitary
What are the two main cell types that make up the anterior pituitary?
1) Chromophobes: nonsecretory
2) Chromophils: secretory cells, subdivided into 7 cell types - each secretes a specific hormone(s)
Anterior pituitary hormones are regulated by what?
1) secretion of hypothalamic peptide hormones or releasing factors
2) feedback effects of hormones secreted by target glands
3) direct effects of other mediating NTs
What are tropic hormones?
hormones that are released to target another endocrine gland; typically secreted by anterior pituitary
Tropic hormones released by the anterior pituitary
1) Melanocyte-stimulating hormone (MSH)
2) Follicle-stimulating Hormone (FSH) and Luteinizing hormone (LH)
3) Adrenocorticotropic hormone (ACTH)
4) Thyroid-stimulating hormone (TSH)
5) Growth Hormone (GH)
6) Prolactin
Melanocyte-stimulating hormone (MSH)
Secreted by which gland
Target Organ
Function
Secreted by: anterior pituitary
Target organ: anterior pituitary
Function: promote secretion of melanin and lipotropin by anterior pituitary; makes skin darker
Adrenocorticotropic Hormone (ACTH)
Secreted by which gland
Target Organ
Function
Secreted by which gland: anterior pituitary (corticotropic cell type)
Target Organ: adrenal cortex
Function: regulates cortisol and androgenic hormones release from the adrenal cortex (increased steroidogenesis); helps maintain adrenal gland
Growth Hormone
Secreted by which gland
Target Organ
Function
Secreted by which gland: anterior pituitary (somatotropic cell type)
Target Organ: muscle, bone, liver
Function: normal tissue growth and maturation; impacts aging, sleep, nutritional status, stress, and reproductive hormones
Prolactin
Secreted by which gland
Target Organ
Function
Secreted by which gland: Anterior pituitary (lactotropic cell type)
Target Organ: Breast
Function: Milk production during pregnancy and lactation. Some immune stimulatory effects & modulates immune and inflammatory responses
Thyroid-stimulating hormone (TSH)
Secreted by which gland
Target Organ
Function
Secreted by which gland: anterior pituitary (thyrotropic)
Target Organ: thyroid gland
Function: increase production and secretion of thyroid hormone; increased iodide uptake, promotes hypertrophy and hyperplasia of thymocytes (immune cells in thymus)
Lutenizing Hormone (LH)
Secreted by which gland
Target Organ
Function
Secreted by which gland: anterior pituitary (gonadotropic cell type)
Target Organ: in women - granulosa cells; in men - Leydig cells
Function:
- women: ovulation, progesterone production
- men: testicular growth, testosterone production
Follicle-stimulating hromone (FSH)
Secreted by which gland
Target Organ
Function
Secreted by which gland: anterior pituitary (gonadotropic cell type)
Target Organ: in women - granulosa cells; in men - Sertoli cells
Function:
- women: Follicle maturation, estrogen production
- men: spermatogenesis
IGF regulation of Growth Hormone
IGF-1: most biologically active, binds to IGF-1 receptors to mediate anabolic effects of GH & to insulin receptors on skeletal muscle
IGF-2: fetal growth but suppresses GH in the adult
Somatotropic hormones secreted by anterior pituitary
GH, prolactin
Glycoprotein hormones
TSH
LH
FSH
β-Lipotropin
β-Endorphins
β-Lipotropin
Secreted by which gland
Target organ
Function
Secreted by which gland: anterior pituitary (corticotropic cell type)
Target organ: Adipose cells
Function: fat breakdown and release of fatty acids
β-Endorphins
Secreted by which gland
Target organ
Function
Secreted by which gland: anterior pituitary (corticotropic cell type_
Target organ: adipose cells; brain opioid receptors
Function: analgesia; may regulate body temp, food and water intake
Structure of posterior pituitary
Structure: derived from hypothalamus, made up of 3 parts:
- Median eminence: at base of hypothalamus; mostly nerve endings of axons from hypothalamus and contains 10+ hypothalamic-releasing hormones & NTs (dopamine, NE, 5HT, ACh, histamine)
- Pituitary stalk: contains nerve axons coming from supraoptic and paraventricular nuclei of hypothalamus, connects pituitary gland to the brain
- Infundibular process (pars nervosa/neural lobe): where the hypothalamus axons terminate & where posterior pituitary hormones are secreted
What are the two hormones that are secreted by the posterior pituitary? Where are they synthesized?
Hormones:
- Antidiuretic hormone (ADH) aka arginine vasopressin
- oxytocin ‘
Synthesis: made in the supraoptic and paraventricular nuclei of the hypothalamus, packaged in secretory vesicle and moved down the axons of the pituitary stalk to the pars nervosa for storage
Function and regulation of ADH
Function: controls plasma osmolality; increases the permability of distal renal tubules and collecting ducts which leads to increased water reabsorption into the blood, concentrating urine and reducing serum osmolality
Regulation:
Increases:
- secretion regulated by osmoreceptors in hypothalamus (stimulated when plasma osmolality ↑ which causes increase in ADH secretion, more water reabsorption by kidney, plasma diluted back to baseline)
- secretion also regulated by intravascular volume changes (via baroreceptors in LA, carotid arteries, aortic arches) - decrease in volume causes increased ADH secretion
- ADH has no direct effect on electrolytes (but water reabsoprtion will dilute and cause their concentration to decrease)
- ADH secretion can also be increased via stress, trauma, pain, exercise, nausea, nicotine, heat exposure and drugs like morphine
- Decreases:*
- ADH secretion decreases with decreased osmolality, increased intravascular volume, hypertension, alcohol ingestion (alcohol inhibits the secretion of ADH), increase in estrogen, progesterone or angiotensin II levels.
Function and Regulation of oxytocin
Function: contraction of uterus, milk ejection in lactating women, may affect sperm motility in men. Has an antidiuretic effect similar to ADH.
- enhances effectiveness of contractions, promotes placental deivery, stimulates postpartum uterine contractions to prevent excessive bleeding
Regulation:
- In women: secreted in response to suckling and mechanical distension of the female reproductive tract - binds to receptors in mammary tissues to cause contraction of myoepithelial cells, which increases intramammary pressure and milk expression (“let-down” reflex)
Describe the structure and function of Pineal Gland, and the regulation of hormone release from this gland.
Structure: made of photoreceptive cells, located near center of brain. Innervated by noradrenergic sympathetic nerve terminals controlled by pathways within hypothalamus
Function: secrete melatonin (synthesized from tryptophan, which is first converted to 5HT and then melatonin)
Regulation: stimulated by exposure to dark, inhibited by light exposure.
Function of melatonin
- regulates circardian rhythms and reproductive systems (onset of puberty, secretion of gonadotropic-releasing hormones)
- immune regulation
- involved in aging process
- increases nitric oxide release from blood vessels
- removing oxygen free radicals
- decreasing insulin secretion
Structure and Function of Thyroid Gland
Structure: located in neck below larynx and thyroid cartilage. Has two lobes, on either side of the trachea and is connected by the isthmus.
- Pyramidal lobe is superior to isthmus (just another lobe of the thyroid gland that sticks upwards)
- Follicular cells: gland consists of follicles that contain follicular cells surrounding colloid (viscous substance) - these cells synthesize and secrete thyroid hormones and can be directly affected by NTs Ach and catecholamines
- 2 month supply of thyroid hormone stored in the gland
- Parafollicular/C cells: secrete calcitonin (thyrocalcitonin)
Function: produces hormones that control rates of metabolic processes throughout body
Function and regulation of calcitonin
Function: lowers serum calcium levels by inhibiting bone-reabsorbing osteoclasts (which is the opposite function of PTH)
- lowers serum phosphate levels
- decreases calcium and phosphorous absroption in GI tract
Regulation:
- stimulated by high calcium levels (major), gastrin, calcium-rich foods, pregnancy
- release inhibited by lowered serum calcium level
Regulation of thyroid hormone (TH)
- regulated via a negative feedback loop
- initiated by thyrotropin-releasing hormone (TRH) which is synthesized and stored in hypothalamus
- TRH levels increase with cold exposure or stress, decreased thyroxine (T4)
- TRH released into hypothalamus-pituitary portal system, circulates to anterior pituitary which is then stimulates release of thyroid-stimulating hormone (TSH)
- TSH circulates and binds to receptors on thyroid follicular cells → immediate release of stored TH and increase in TH synthesis; also increases growth of gland by stimulating thymocyte hyperplasia & hypertrophy
- TH levels rise, negative feedback loop on the HPA to inhibit TRH and TSH release leading to decreased TH synthesis and secretion
- TH synthesis also controlled by iodide levels and deiodinases that inactivate thyroxine
How is thyroid hormone synthesized?
- Uniodinated thyroglobulin is produced by the ER of the thyroid follicular cells.
- Tyrosine is incorporated into the thyroglobulin as it is synthesized.
- Iodide (inorganic form of iodine) is actively pumped from the blood into the colloid by carrier proteins located in the outer membrane of the follicular cells (active transport system called the iodide trap)
- Iodide is oxidized and quickly attaches to tyrosine within the thyroglobulin molecule.
- Coupling of iodinated tyrosine forms thyroid hormones. Triiodothyronine (T3) is formed from coupling of monoiodotyrosine (one iodine atom and tyrosine) and diiodotyrosine (two iodine atoms and tyrosine). Tetraiodothyronine (T4/thyroxine) is formed from coupling of two diiodotyrosines.
- Thyroid hormones are stored attached to thyroglobulin within the colloid until they are released into the circulation.
Thyroid gland produces 90% T4 , 10% T3
Once released in the circulation how are T3 and T4 transported?
transported bound to thyroxine-binding globulin, some via thyroxine-binding prealbumin (transthyretin), albumin, or lipoproteins
when bound, acts like a reservoir while unbound form is active
in body tissues, most T4 converted to T3 which acts on target cell
Function of thyroid hormone (TH)
- ++effect on growth, maturation and function of cells/tissues
- needed for normal growth, neuro development
- affects metabolic, neurologic, CV, and resp functioning over lifespan
- required for metabolism (so causes increased heat production and oxygen consumption), blood cell function, normal muscle function
- required for integumentary integrity
- has permissive effects - i.e. it optimizes the actions of other hormones and NTs
Structure and Function of parathyroid glands
Structure: two pairs of glands behind the upper and lower poles of the thyroid gland, but can range from 2-6
Function: produce parathyroid hormone (PTH)
Regulation and function of parathryoid hormone (PTH)
Function: most important in the regulation of serum calcium concentration
- increases calcium levels and decreases phosphate levels in serum
- Acts directly on bone to release calcium via stimulating osteoclast activity
- also acts on kidney to increase calcium reabsorption & decrease phosphate reabsorption
Regulation: via Calcium - stimulated by decrease in serum-ionized calcium levels. Inhibited when serum calcium concentration increases
- via Phosphate - Increased phosphate levels decrease calcium levels, causing calcium phosphate preciptation in soft tissue and bones ⇒ PTH stimulated
- via Magnesium - Hypomagnesemia also mildly stimulates PTH
- Note: intermittent admin of low dose PTH stimulates bone formation (which is opposite of what it normally does) - used for osteoporosis tx (with vit D as a cofactor to promote calcium and phosphate absoprtion to enhance bone mineralization & control inflammation)
Structure and Function of pancreas
Structure: located behind the stomach, between spleen and duodenum
- contains islets of Langerhans, which has 4 types of hormone secreting cells:
- alpha cells: secrete glucagon
- beta cells: secrete insuiln and amylin
- delta cells: secrete gastrin and somatostatin
- F (or PP) cells: secrete pancreatic polypeptide
- Innervation: both sympathetic and parasympathetic
Function: considered both an endocrine (produces hormones) and exocrine gland (produces digestive enzymes)
Endocrine vs exocrine gland
Exocrine glands: glands that secrete substances onto an epithelial surface via a duct. Examples: sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, prostate and mucous.
Endocrine Glands: glands that secrete their products directly into the bloodstream.
What two organs are endocrine and exocrine glands?
The liver and pancreas are both exocrine and endocrine glands; they are exocrine glands because they secrete products—bile and pancreatic juices—into the GI tract through a series of ducts, and endocrine because they secrete other substances directly into the bloodstream
Function of insulin and what factors alter the sensitivity of insulin
Function:
- once bound to cell surface receptor, it promotes cellular glucose uptake via glucose transports (GLUT) - considered an anabolic hormone that promotes glucose uptake primarily in liver, muscle and adipose tissue (insulin not needed for glucose uptake in brain, RBCs, kidneys, and lens of eye)
- Increases synthesis of proteins, carbs, lipids, and nucleic acids
- facilitates intracellular transport of potassium, phosphate, and magnesium
- Net effect: stimulate protein and fat synthesis, decrease BGL
Factors affecting sensitivity (and thus maintenance of normal cell function):
- age, weight, abdominal fat, physical activity
- adipocytes release a number of hormones and cytokines that are altered in obesity which impact insulin sensitivity
- weight loss and exercise improves sensivity
Structure and zones of the adrenal cortex
- 80% of the weight of the gland, three zones:
- 1) Zona glomerulosa: outer layer, ~15% of the cortex and primarily produces mineralocorticoid aldosterone
- 2) Zona fasciculata: middle layer, ~78% of cortex and secretes glucocorticoids cortisol, cortisone, and corticosterone
- 3) Zona reticularis: inner layer, ~7% of the cortex and secretes mineralocorticoids (aldosterone), adrenal androgens and estrogrens, and glucocorticoids
- stimualted by adrenocorticotropic hormone (ACTH) from pituitary
- all hormones synthesized from adrenal cortex are made from cholesterol
Synthesis, function/effects, and regulation of aldosterone
Synthesis: initial stages occur in zona fasciculata and zona reticularis. Converted from corticosterone to aldosterone in zona glomerulosa
Function/effects: conserves sodium by increasing activity of sodium pump of epithelial cells. Maintains extracellular volume by acting on distal nephron epithelial cells to increase reabsorption of Na+ and excretion of K+ and H+
- CV-related effects: enhances cardiac muscle contraction, stimulates ectopic ventricular activity (secondary cardiac pacemakers), stiffens blood vessels with increased vascular resistance, decreased fibrinolysis
- Pathological elevation of aldosterone: leads to HF, HTN, insulin resistance, inflammation
Regulation: RAAS - activated by sodium and water depletion, increased potassium levels, and diminished effective blood volume
- primary stimulant: Angiotensin II; others: ACTH
Decreased hypothalamic function leads to decreased GnRH, TRH, CRH, PIF, and GHRH. Describe what effect each of these would have on their respective target hormones in the anterior pituitary.
↓GnRH: cessation of menstruation (women) and hypogonadism & impaired spermatogenesis (men)
↓TRH: hypothalamic hypothyroidism
↓CRH: decreased ACTH response to low serum cortisol levels
↓PIF (prolactin inhibitory factor like dopamine): no inhibitory control of prolactin secretion by dopamine leads to hyperprolactinemia
↓GHRH: GH deficiency and growth failure in children
Thyrotoxicosis/Hyperthyroidism
Definition, Cause, Clinical Manifestations, Dx/Tx
Definition: Thyrotoxicosis - condition resulting from any cause of ↑TH levels. Hyperthyroidism - form of thyrotoxicosis where excess amounts of TH are secreted from thyroid gland
Causes: for Primary hyperthyroidism - Graves disease, toxic nodular goiter, adenoma. for Secondary hyperthyroidism - TSH-secreting pituitary adenomas (less common). Others - ectopic thyroid tissue, excessive TH ingestion
Clinical Manifestations: increased metabolic rate with heat intolerance & increased tissue sensitivity to stimulation by the SNS. Enlargement of the thyroid gland (goiter).
- Thin hair, exophthalmos (bulging eyes(, heart failure, weight loss, diarrhea, warm skin, hyperreflexia, pretibial edema
Diagnostics: elevated T4 and T3 levels and suppressed TSH levels (primary hyperthyroidism). Increased TSH levels despite elevated TH (secondary hyperthyroidism)
Treatment: drug therapy, radioactive iodine therapy (absorbed by thyroid tissue to cause cell death) and surgery. Complication for all forms of tx is excessive ablation leading to _hypothyroidism._Resolving the TH increase underlying issue will allow TSH secretion normally to subside and the thyroid gland returns to its original size. Irreversible changes can occur in some follicular cells so these cells function autonomously and produce excessive amounts of TH. Others may cease to function.
Graves Disease
Definition: autoimmune disease leading to hyperthyroidism and reuslts from a type II hypsersensitivity. Causes 50-80% of hyperthyroidism cases but exact cause unknown. More common in women.
Pathophysiology: Type II hypersensitivity - stimulation of thyroid by autoantibodies (thyroid-stimulating immunoglobulins is TSIs) directed against the TSH receptor. Overrides normal regulatory mechanisms and causes hyperplasia (goiter) and increased TH synthesis. TSH production by pituitary is inhibited through -ve feedback loop.
Clinical Manifestations:
-
Ophthalmopathy:
- lag of eyeball on upward gaze and of upper lid on downward gaze (due to hyperactivity of sympathetic division)
- enlargement of ocular muscles and changes - connective tissue acummulates, inflammation, edema leading to exophthalmos, periorbital edema, and extraocular muscle weakness => all leads to diplopia
- irritation, pain, lacrimation, photoboia, blurred vision, lots of visual changes.
- Pretibial myxedema (Graves dermopathy): subQ swelling of anterior portions of legs, hardened and red skin (can also appear on hands with clubbing of fingers - this is due to thyrotropin receptor antigens and recruited T lymphocytes stimulating excessive hyaluronic acid production in dermis & subQ tissue
Congenital Hypothyroidism
Definition, Pathophysiology, Clinical Manifestations, Dx, Treatment
Definition: the absence of thyroid tissue during fetal development or defects in hormone synthesis. TH is essential for embryonic growth so a deficiency will lead to congenital disabilities.
Pathophysiology: Primary hypothyroidism - decreased TH and increased TSH and TRH secretion (most common cause is Hashimoto disease/autoimmune thyroiditis; thyroidal tissue loss 2’ to surgery/radioactive treatment for hyperthyroidism; post head/neck radiation therapy; meds like lithium & amiodarone; iodine deficiency).
Central hypothyroidism -pituitary fails to synthesize enough TSH or lacks TRH (due to compressing tumors, TBIs, aubarachnoid hemorrhages, pituitary infarction). Hypothalamic dysfunction also leads to low levels of TH, TSH, and TRH
Subclinical hypothyroidism - mild thyroid failure. Defined as elevated levels of TSH with normal circulating TH levels.
Clinical manifestations: gradual onset
- high birth weight, hypothermia, delay in passing meconium, neonatal jaundice.
- Infants: difficulty eating, hoarse cry, protruding tongue (due to myxedema or oral tissues and vocal cords), hypotonic muscles od abdomen w/ constipation, abdominal protrusion, umbilical hernia, subnormal temperature; lethargy; excessive sleeping; slow pulse rate; and cold, mottled skin. Stunted skeletal growth, nutrient malabsoprtion, lack of bone mineralization. Dwarf, short limbs & delayed teeth growing
- low heat production and metabolism, low BMR, cold intolerance, lethargy, lower body temp
- Myxedema: severely advanced hypothyroidism leading to changes in dermis and tissues (produces nonpitting, boddy edema esp around eyes, hands, feet, above clavicles). Also thick tongue and mucous membranes leading to slurred speech and hoarseness.
- Myxedema coma: decreased LOC with severe hypothyroidism - hypothermia with no shivering, hypoventilation, hypotension, hypoglycemia, lactic acidosis.
Dx: examine cord blood for T4 and TSH levels.
Treatment: hormonal replacement therapy (levothyroxine - Synthroid)
Type 1 Diabetes Mellitus (T1DM)
Definition: diabetes due to beta cell destruction in pancreas; most common pediatric chronic disease. Two types: idiopathic and autoimmune
Demographics: 10-13% have a first degree relative with type 1 diabetes. Usually diagnosed around 2 years of age.
Pathophysiology:
- Idiopathic: less common, has strong genetic component and occurs mostly in Asians & Africans.
- Autoimmune: slowly progressive autoimmune T-cell– mediated disease that destroys beta cells of the pancreas. Gene-environment interactions result in the formation of autoantigens that are expressed on the surface of pancreatic beta cells, which stimulate immunity and beta-cell destruction. Insulin synthesis declines and hyperglycemia develops over time.
- 80-90% of insulin-secreting beta cells of islets of Langerhands has to be destroyed for insulin production to decline enough to the point of hyperglycemia
- leads to increased glucagon secretion due to no insulin inhibiting it
- Glucose accumulates in the blood and appears in the urine once the kidneys are no longer able to filter it out. The osmotic pressure created from this causes the S&S of thirst, frequent urination, etc. Protein and fat breakdown occurs because of the lack of insulin resulting in weight loss. Inreased metabolism of fats and proteins leads to high levels of circulating ketones, leading to DKA.
- amylin (another beta cell hormone) also decreases which further does not allow suppression og glucagon secretion
Clinical Manifestations: gradual onset
- Polydipsia - due to intracellular dehydration with elevated BGLs, and stimulation of thirst
- Polyuria
- Polyphagia - cell stores of carbs, fats, and protein depleted which increases hunger
- Weight loss - due to fluid loss in urine
- Fatigue
- Recurrent infections - more sugar, more bacteria can feed on & prolonged wound healing
- Genital pruritis
- Visual changes - blurred vision, diabetic retinopathy
- Paresthesia
- CV symptoms (diabetes contributes to plaque formation)
Diagnosis: children dx when they show S/S of DKA. Polydipsia, polyuria, polyphagia, weight loss, hyperglycemia in fasting/postprandial states
Treatment: insulin therapy x meal planning x exercise
DKA
Serious complication related to a deficiency of insulin & an increase in the levels of insulin counterregulatory hormones. Characterized by hyperglycemia, acidosis, and ketonuria. Protein and fat breakdown occurs because of the lack of insulin resulting in weight loss. Inreased metabolism of fats and proteins leads to high levels of circulating ketones, leading to DKA.
- Much more common in type 1 diabetes because insulin is more deficient
- Acetone (ketones) is exhaled by hyperventilation and gives a sweet/fruity odor.
- S/S: metabolic acidosis so leads to Kussmaul respirations (hyperventilation), postural dizziness, CNS depression, ketouria, anorexia, nausea, abdo pain, thirst, polyuria
- Treatment: fluids, insulin, electrolyte replacement
Type 2 diabetes mellitus (T2DM)
Definition, Demographics, Cause, Pathophysiology
Definition: NIDDM. Ranges from insulin resistance with relative insulin deficiency to insulin secretory defect with insulin resistance
Demographics: prevalence highest in Indigenous. Increased prevalence in children especially obese ones
Cause: Gene x environmental interaction. Risk factors - age, obesity, hypertension, physical inactivity, and family history. Also genetic abnormalities
Pathophysiology: insulin resistance - suboptimal response of insulin-sensitive tissues (especially liver, muscle, and adipose tissue) to insulin, associated with obesity. Pathways affected: abnormalities in insulin molecule, high amounts of insulin antagonists, down regulation of insulin receptor, alteration of glucose transporter (GLUT) proteins
- Obesity is one of the most important contributors to insulin resistance and diabetes. Mechanisms:
- Adipokines: leptin and adiponectin produced in adipose tissue. Obesity results in increased leptin and decreased adiponectin levels which contribute to inflammation and decreased insulin sensitivty
- Elevated levels of free fatty aacids and triglycerides and cholesterol - change insulin signaling and causes decreased tissue responses to insulin
- Inflammatory cytokines: from adipocytes which induce insulin resistance and toxic to beta cells
- _Decreased insulin receptor density_
- __Compensatory hyperinsulinemia prevents the clinical appearance of diabetes for many years, but beta cell dysfunction eventually develops and leads to a relative deficiency of insulin activity. Beta cell weight and number go down and remaining cells are exhausted from insulin demand.
- Increased [glucagon] because pancreatic alpha cells become less responsive to glucose inhibition resulting in an increase in glucagon secretion which stimulates mechanisms to increase BGL
- Decreased amylin further increases glucagon levels. Amylin increases satiety and suppresses glucagon release from the alpha cells.
- Ghrelin is a peptide produced in the stomach and pancreatic islets that regulates food intake, energy balance and hormonal secretion. Decreased ghrelin is also associated with insulin resistance.
- Incretins: class of peptides that are released from GI tract in response to food intake and increase insulin secretion (beta cell’s response to these to make insulin is also reduced in T2DM)
- Kidneys reabsorb glucose and is an important controller of serum glucose levels.
Cushing Syndrome
Definition, Pathophysiology, Clinical Manifestations, Dx, Treatment
Definition: syndrome resulting form chronic exposure to excess cortisol regardless of cause (hypercortisolism)
- Cushing disease: refers to excess endogenous secretion of ACTH (more common in women but worse Sx in men)
- Cushing-like syndrome: due to side effect of LT admin of glucocorticoids
Pathophysiology: (1) loss of normal diurnal or circadian secretion patterns of ACTH and cortisol; (2) no increase in ACTH and cortisol secretion in response to a stressor
- in ACTH-dependent hypercortisolism: excess ACTH stimulates excess cortisol production and loss of feedback control of ACTH secretion. Secretion of cortisol and adrenal androgens increased, cortisol-releasing hormone inhibited.
- ACTH-independent hypercortisolism: due to tumors secreting cortisol
Clinical Manifestations: *weight gain* due to accumulation of adipose tissue in trunk, face, and cervical areas (truncal obesity, moon face, buffalo hump.
- Glucose intolerance due to cortisol-induced insulin resistance and increased gluconeogenesis and glycogen storage by liver
- Polyuria
- Protein wasting leading to muscle wasting and weakness
- osteoporosis (pathologic & compression fractures, bone and back pain, kyphosis, reduced height) & short stature in children
- weakened integumentary tissues (vessels susceptible to rupture leading to easy bruising); skin lesions, visible capillaries, purple striate in the trunk area
- Bronze or brownish hyperpigmentation of the skin, mucous membranes, and hair occurs when there are very high levels of ACTH.
- Increased hair growth, acne, oligomenorrhea (infrequent periods) in women, vasoconstriction and HTN, immune suppression, irritability and depression, disturbed sleep, schizophrenia like psychosis.
Diagnosis: lab exams show high BGL, glycosuria, hypokalemia, metabolic alkalosis; imaging for tumors
Treatment: specific to the cause of hypercortisol secretion. Surgery, medication, and radiation. If not treatment, 50% will die within 5 years of onset (due to infection, suicide, complications with arteriosclerosis, HTN disease)
Addison Disease
Definition, Prevalence/Cause, Pathophysiology, Clinical Manifestations, Diagnosis, Treatment
Definition: aka Primary Adrenal Insufficiency. Rare autoimmune disorder characterized by low cortisol secretion 2’ to destruction of cortical cells.
Prevalence/Cause: most often 30-60 y.o., more common in women. Most cases due to chronic infections (i.e. TB) in underdeveloped countries.
Pathophysiology: characterizied by inadequate corticosteroid and mineralocorticoid synthesis & elevated ACTH levels (no negative feedback). 90% or more of adrenocortical tissue must be destroyed before S/S of hypocorticolism appears.
- Idiopathic Addison disease (organ-specific autoimmune adrenalitis) - causes adrenal atrophy and hypofunction. May occur in childhood (type 1) or adulthood (type 2). Has 21-hydroxylase autoantibodies and autoreactive T cells that target the adrenal cortical cells
- In ^ condition, adrenal glands are smaller than normal and misshapen. Often associated with other autoimmune diseases
Clinical Manifestations: non-specific; primarily due to hypocortisolism and hypoaldosteronism.
- Mild/mod hypocortisolism: weakness, fatigue, hyperpigmentation, vitiligo (white patches on skin).
- Progresses to anorexia, N/V./D
- Severe: adrenal crisis (Addisonian crisis) - hypotension that leads to vascular collapse and shock
Diagnosis: low cortisol levels in serum/urine and elevated ACTH. Low glucose. Elevated eosinophil and lymphocytes. Hyperkalemia which may cause mild alkalosis.
Treatment: Lifetime glucocorticoid and mineralocorticoid replacement therapy, diet modifications (high sodium diet). correct underlying cause.
