Block 6 Flashcards
(104 cards)
1
Q
Define the HPA axis and what is released by each portion.
A
H - hypothalamus and it releases CRH (corticotropin releasing hormone)
P - (anterior) pituitary and it releases ACTH (adrenocorticotrophic hormone)
A - adrenal gland and it releases mineralocorticoids, glucocorticoids, androgens, and epinephrine
2
Q
What are the two regions of the adrenal glands and what is secreted from each section?
A
Cortex (outer “glandular” region) and it has three zones
- zona glomerulosa (outer zone that secretes aldosterone - mineralocorticoid)
- zona fasciculata (middle zone that secretes cortisol - glucocorticoid)
- zona reticularis (inner zone that secretes adrenal androgens)
Medulla (inner 20% of adrenal gland)
- secretes epinephrine/norepinephrine in response to sympathetic stimulation
3
Q
What protects the mineralocorticoid receptors from binding to cortisol?
A
11,beta-hydroxysteroid dehydrogenase - it converts cortisol to cortisone which cannot bind to it
4
Q
List a few examples of glucocorticoids
A
- Cortisol (accounts for ~95% of total glucocorticoid activity in body)
- Corticosterone (only accounts for ~4% of glucocorticoid activity)
- Cortisone (synthetic, almost as potent as cortisol but no MR activity)
- Prednisone (4x as potent as cortisol)
- Methylprednisone (5x)
- Dexamethasone (30x)
5
Q
How does aldosterone work? Describe its MOA.
A
- MOA: acts on renal tubular epithelial cells to increase sodium and water reabsorption
- it enters cytoplasm, binds to MR receptor, and moves to the nucleus
- once at the nucleus, it causes an increase in synthesis of ENaC and Na-K-ATPase
- ENaC faces the tubular lumen and reabsorbs sodium; Na-K-ATPase exchanges the sodium for potassium, which is then excreted out into urine
6
Q
What is the primary way aldosterone secretion is controlled?
A
It is controlled by ECF potassium concentration
- when potassium levels are too high, aldosterone secretion increases
- decreased sodium also has a direct stimulating effect on the adrenal cortex
7
Q
How does decreased blood volume/pressure affect the kidneys?
A
The kidneys will release renin, initiating a cascade that ultimately leads to angiotensin II production, which also causes increased secretion of aldosterone
8
Q
What effect does the heart have on the adrenal glands when there’s increased blood pressure/volume?
A
Atrial natriuretic peptide (ANP) is released from the heart, which then has an inhibitory effect on the zona glomerulosa (where aldosterone is secreted)
9
Q
How much aldosterone and cortisol is protein bound? What are their respective half-lives?
A
Aldosterone - 60% and 20 min
Cortisol - 75% and 60-90 min
10
Q
Where are adrenocortical hormones metabolized and how are they excreted?
A
Metabolized in the liver and excreted by the kidneys
11
Q
An absence of aldosterone can lead to…
A
diarrhea and further loss of salt from the body
12
Q
Name the 4 ways aldosterone is secreted.
A
1 - potassium ion concentration of ECF
2 - increased activity of renin-angiotensin system
3 - sodium ion concentration of ECF
4 - ACTH secretion (increased ACTH secretion = increased aldosterone)
13
Q
List secondary effects of aldosterone
A
- Increased aldosterone can lead to increased hydrogen ion secretion, resulting in mild alkalosis
- Increased aldosterone may cause hypokalemia (low potassium) and muscle weakness
- Decreased aldosterone may cause severe NaCl wasting, mild acidosis, hyperkalemia, and cardiac toxicity (weak heart contractions, arrhythmias, and heart failure)
- Zero aldosterone secretion can lead to loss of salt and water via urine –> deceased NaCl in the ECF and decreased ECF volume –> low blood volume –> circulatory shock
14
Q
What is Conn’s syndrome?
A
Primary HYPERaldosteronism
- is caused by a small tumor of the adrenal gland, which secretes large amounts of aldosterone
15
Q
Describe the symptoms of Conn’s syndrome.
A
- low plasma levels of potassium (high levels of aldosterone)
- high levels of sodium (thus increased blood volume/pressure)
- low plasma levels of hydrogen (mild metabolic alkalosis)
16
Q
What is Addison’s Disease?
A
Hyposecretion of both glucocorticoids and mineralocorticoids.
17
Q
Describe what occurs with Addison’s disease.
A
Results in decreased sodium and water reabsorption, increased blood potassium, low blood volume, hypotension, and dehydration. This is caused by the decrease in aldosterone secretion.
the decrease in cortisol secretion results in decreased blood glucose levels, particularly during periods of prolonged stress.
18
Q
Describe how cortisol secretion is regulated.
A
CRH is released by the hypothalamus, which stimulates the anterior pituitary to release ACTH. ACTH stimulates the release of cortisol from the zona fasciculata of the adrenal cortex.
Additionally, pain, stress, and hypoglycemia stimulate cortisol secretion.
Cortisol itself has negative feedback control on both CRH and ACTH. Some of the free (unbound) cortisol is physiologically active and enters target cells, the rest is used to induce negative feedback.
19
Q
How does the circadian rhythm affect glucocorticoid levels?
A
Secretory rates of CRH, ACTH, and cortisol are high in the morning and low in the evening.
20
Q
The normal concentration of calcium in the ECF is
A
9.4mg/dL
21
Q
Describe how changes in ECF calcium concentration has an impact on neurons.
A
Hypercalcemia –> progressive depression of the nervous system
Hypocalcemia –> nervous system excitation
22
Q
Which form of inorganic phosphate would be higher in an acidic ECF environment? Why?
A
Dihydrogen phosphate because there are more H ions present
23
Q
Why is vitamin D vital for calcium absorption?
A
Calcium is poorly absorbed from the intestines because of its divalent nature. Vitamin D works to promote absorption by causing the expression of calcium transporters on the intestinal membrane
24
Q
While most of the calcium that is excreted via the kidneys is absorbed in the proximal tubules, loops of Henle, and early distal tubules, what happens to the remaining calcium in the distal tubules?
A
The late distal tubules are under control of PTH (parathyroid hormone). Parathyroid works to increase blood calcium concentration.
- if PTH is high, reabsorption is increased and excretion is decreased
- if PTH is low, reabsorption is decreased and excretion is increased
25
How does phosphate excretion work?
Renal phosphate excretion is controlled by an overflow mechanism.
Critical plasma phosphate concentration is 1 mmol/L.
conc. < 1mmol/L - all filtered phosphate is reabsorbed
conc. > 1mmol/L - rate of loss is directly proportional to additional increase in phosphate
26
What controls phosphate excretion?
PTH levels. Increased parathyroid hormone = increased phosphate excretion.
27
Why does an increase in parathyroid levels cause an increase in phosphate excretion?
PTH also works to increase blood calcium levels through the activation of osteoclasts and the breakdown of bone. When this happens, it releases both calcium and phosphate from the bone. So, to counteract this unwanted increase in phosphate, excretion is also increased.
28
Which form of calcium dysfunction (hypo or hyper) is characterized by presence of tetany? Why?
Hypocalcemia. With hypocalcemia, there is less calcium available in the ECF, meaning there's less calcium around the VGSCs. This makes it easier for the sodium to influx and neurons supplying the peripheral skeletal muscles have increased excitability.
29
Other than tetany, what are some other complications that may occur with hypocalcemia?
Seizures/convulsions due to increased excitability in the brain.
Laryngeal spasms (voice changes)
Bronchospasms (difficulty breathing)
30
Describe some of the symptoms associated with hypercalcemia.
- Nervous system and muscle contractility is depressed
- constipation
- lack of appetite (because constipation)
- kidney stones
- confusion, memory loss, depression
31
Describe the composition of mature bone.
30% organic matrix (osteoid)
| 70% calcium salts (bone salts, hydroxyapatite crystals)
32
The majority of osteoid is made up of _______, which provides _______ strength. The remaining 5-10% is compounds of...
- Collagen fibers
- Tensile strength (the ability to resist twisting forces)
- Extracellular fluid and proteoglycans (especially chondroitin sulfate and hyaluronic acid) which help control the deposition of calcium salts
33
Bone salts provide the _____ strength of bone. Why do the hydroxyapatite crystals not precipitate in the ECF despite the high concentrations of calcium and phosphate ions?
Compressional strength
Inhibitors, such as pyrophosphate, are present in all tissues of the body and plasma to prevent the precipitation of hydroxyapatite crystals in locations other than bone
34
Osteogenesis is mediated by _________
| Osteolysis is mediated by _________
Osteoblasts
Osteoclasts
35
Why is plasma calcium concentration able to return to normal within 30-60 minutes after a large increase/decrease?
This is due to the exchangeable calcium in the bones that is in equilibrium with the calcium in the ECF.
- this calcium is deposited in the form of amorphous calcium phosphate salts that are readily mobilizable. Osteoblasts and osteocytes utilize the amorphous salts to quickly break/form storage of calcium, depending on what is needed to restore equilibrium.
36
Describe the process of bone absorption due to an osteoclast.
- Parathyroid hormone binds to an osteoblast, causing it to release OPGL (osteoprotegrin ligand)
- OPGL binds to an activates receptors on preosteoclasts, changing them to osteoclasts
- the osteoclast extends projections towards the bone and releases:
- -> proteolytic enzymes (from the lysosome) that digests the organic matrix of the bone
- -> acid (citric, lactic) to dissolve bone salts
- -----> then, phagocytoses minute particles of bone matrix and crystal
37
How do osteoblasts work to control the activation of osteoclasts?
Along with producing OPGL, osteoblasts produce OPG.
| --> OPG is a cytokine that inhibits bone resorption by binding to OPGL and preventing it from binding to preosteoclasts.
38
Describe how vitamin D, PTH, and estrogen affect the OPG-OPGL pathway.
PTH and (high) Vitamin D inhibit OPG and stimulate OPGL
Estrogen stimulates OPG
39
Which hormone is associated with high levels of ACTH and what effect does it cause in patients with hyperaldosteronism?
MSH (melanocyte stimulating hormone)
| - it stimulates the melanocytes to form melanin, leading to increased pigmentation of the skin
40
Does cortisol increase or decrease blood glucose levels?
Increase - hypoglycemia is one of the factors that induces (stimulates) cortisol secretion.
ALSO - cortisol decreases insulin sensitivity and increases gluconeogenesis
41
Name body responses that can stimulate cortisol release.
Pain
Hypoglycemia
Low cortisol levels (no negative feedback)
Stress
42
What is a potential consequence of high cortisol in regards to carbohydrate metabolism?
Adrenal Diabetes
- this may occur because the hyperglycemia brought about by increased gluconeogenesis will stimulate insulin secretion, furthering the decreased insulin sensitivity caused by cortisol in the first place
Note - the opposite effect is also true: decreased cortisol levels may lead to hypoglycemia
43
Cortisol has a ______ effect on protein metabolism.
Catabolic effect.
- decreased synthesis and increased breakdown
(the amino acids that are produced from the breakdown of protein are used for gluconeogenesis)
44
Describe how cortisol impacts fat metabolism.
Cortisol causes the mobilization of fatty acids from adipose tissue, as well as enhanced oxidation of fatty acids in the cells.
- this is done so that fatty acids will be used for energy instead of glucose
45
Buffalo-hump, rounded "moon-face", and truncal obesity are associated with
increased cortisol
| - it can lead to deposition of fat in the neck, head, and abdominal regions of the body
46
Cortisol induces the production of _______, which prevents the release of arachidonic acid from the membrane. What effect does this have?
Lipocortins.
Anti-inflammatory
47
Biological effects of glucocorticoids (cortisol):
- increased gluconeogenesis and _______ uptake of glucose by fat and muscle cells.
- decreased protein synthesis and ______ protein degradation
- __________ anti-inflammatory and immunosuppressive effects
- decreased
- increased
- increased
48
What is meant by the term "Addisonian Crisis"?
It is the critical need for extra glucocorticoids and associated muscle weakness in times of stress that individuals with Addison's disease experience
49
What is Cushing's syndrome?
Hyperactive adrenal cortex - excess excretion of cortisol
50
List possible causes of Cushing's syndrome and what they mean for cortisol and ACTH levels.
1 - tumor of the adrenal cortex (primary); increased levels of cortisol and decreased levels of ACTH.
2 - tumor of the anterior pituitary (secondary); increased cortisol AND increased ACTH
NOTE - because of the increased ACTH, there will also be increased androgens and MSH
For both causes, there will be slight mineralocorticoid effects from cortisol
51
A drug that blocks steroidogenesis is
ketoconazole
52
What is the key function of glucagon?
To release glucose from the liver and increase blood glucose levels
53
Somatostatin release is stimulated by
increased blood glucose
increased amino acid concentrations
increased fatty acid concentrations
increased secretions of GI hormones
54
What is the purpose of somatostatin?
to extend the time over which food nutrients are assimilated into the blood
55
somatostatin has a ________ effect on the secretion of glucagon and insulin
inhibitory
56
How does exercise impact glucose uptake?
Exercise causes insulin-independent glucose uptake by muscles because contraction of the muscles causes translocation of GLUT4 from its storage depots to the cell membrane.
57
Define diabetes mellitus.
Impaired carbohydrate, fat, and protein metabolism caused by lack of insulin secretion or insulin resistance.
58
Compare and contrast type 1 and type 2 diabetes mellitus.
Type 1
- caused by LACK of insulin
- early age of onset (~14)
- occurs due to destruction of beta cells
- treatment is insulin with glucose monitoring
Type 2
- caused by decreased sensitivity (aka RESISTANCE)
- onset is late (after 30)
- obesity is related
59
What do growth hormone and cortisol have in common?
- Both are excreted in response to hypoglycemia
- Both decrease glucose uptake
- Both increase blood glucose levels
60
Describe the two main types of tissues of the pancreas and the three major cell types.
Tissues:
- acini: exocrine portion containing digestive juices
- islets of langerhans - endocrine portion
Cell types:
- alpha: produce glucagon
- beta: produce insulin
- delta: produce somatostatin
61
Which cells of the pancreas act as the glucose sensors?
Beta cells
62
In addition to insulin, beta cells produce _______, which works to...
Amylin
inhibits glucagon secretion
63
Describe the process of insulin production.
- preproinsulin is made (it's a straight chain of SP-B-C-A chains)
- the SP chain is cleaved off of preproinsulin, then the protein folds and forms disulfide bonds, creating proinsulin
- then, two endopeptidases cleave proinsulin into two pieces (C peptide and insulin)
64
How is C peptide used?
Because C peptide is made in a 1:1 ratio with insulin, it can be used as a biomarker of insulin production/beta cell function.
65
What are the most important roles of insulin?
1 - maintaining blood glucose levels
| 2 - anabolic hormone: promotes the synthesis of glycogen, proteins, and triglycerides
66
What is GLUT? Describe the different forms.
GLUT = glucose transporters
GLUT-4: inducible transporter; translocation and activity is initiated by insulin; is found primarily on skeletal muscle and adipose tissue
GLUT-2: major transporter of glucose into pancreatic beta cells and liver cells; only acts in relatively high levels of glucose, such as after a meal
GLUT-1: present in all tissues; doesn't require insulin; important to the nervous system
67
What happens once glycogen storage capacity has been reached?
Excess glucose is converted to fat and stored in adipose tissue
68
Without glucose in the cells, what do they use for energy?
Fatty acids
69
Describe the effects of insulin (and lack of insulin) on the liver.
Main effects
1 - inhibits gluconeogenesis
2 - promotes glycogen synthesis
3 - inhibits glycogen breakdown
Lack leads to
1 - increased gluconeogenesis
2 - inhibition of glycogen synthesis
3 - promotion of glycogen breakdown (aka glycogenolysis)
70
Describe the impact of low blood glucose on the brain.
Because the brain normally only uses glucose, blood glucose levels must be maintained above 50mg/dL or hypoglycemic shock can develop.
71
How does insulin work in regards to fat synthesis and storage?
1 - Increases in utilization of glucose conserves fat
- promotes conversion of excess glucose to fatty acids in the liver, which are then transported to adipose tissue
- promotes conversion of glucose to glycerol (storage form of fat) in the adipocytes
2 - Prevents breakdown of fat (lipolysis)
- inhibits hormone-sensitive lipase
72
List the sequence of events that can occur with long term lack of insulin
decreased insulin --> increased lipolysis --> increased free fatty acids in the blood --> high concentrations of lipids in the blood --> atherosclerosis, heart attacks, cerebral strokes, and other vascular events
73
How does ketoacidosis occur?
Increased beta-oxidation of fatty acids (to use for energy) leads to an increase in concentrations of acetoacetic acid, beta-hydroxybutyric acid, and acetone.
74
Ketoacidosis is more common with which type of diabetes mellitus?
Type 1 because these patients have little to no insulin
75
What impacts does insulin have on protein synthesis and storage?
- causes active transport of amino acids into cells
- increases mRNA translation
- increases transcription of certain genes
- inhibits catabolism of proteins
- depresses the rate of gluconeogenesis in the liver
NOTE: insulin in synergistic with growth hormone, and a lack of insulin will result in protein depletion and increased plasma amino acid levels
76
Explain the mechanism of insulin release.
Release:
- glucose enters beta cell and is converted to glucose-6-phosphate
- ATP production is increased
- ATP then blocks the ATP-k channels and efflux of potassium halts (this causes a depolarization of the cell)
- calcium enters the cell
- insulin is released via exocytosis
77
What is the key purpose of glucagon?
To release glucose from the liver and maintain blood glucose levels between meals/during fasting
78
What results from glucagon release?
- increased blood glucose levels
- initiation of glycogenolysis
- stimulation of gluconeogenesis
- stimulation of hormone-sensitive lipase
79
release of insulin is promoted by increased levels of
- glucose
- amino acids
- free fatty acids
- GI hormones (incretins like GLP-1)
80
release of insulin is diminished by
- low blood glucose
- high levels of insulin
- somatostatin (because it inhibits release of all other hormones from the pancreas)
- PGE2
81
Describe the process by which vitamin D is produced.
1 - 7-dehydrocholesterol is irradiated into cholecalciferol in the skin
2 - the liver converts cholecalciferol into 25-hydroxycholecalciferol (this is the rate limiting step because of negative feedback)
3 - 25-hydroxycholecalciferol is converted to 1,25-dihydroxycholecalciferol (the active form) in the kidneys under PTH control
82
How does calcium concentration control the formation of the active form of vitamin D?
Increased calcium concentration inhibits PTH secretion, which is needed for the final step in vitamin D synthesis
83
If someone has little to no sun exposure, which steps in vitamin D synthesis are impacted?
```
All of them because sunlight is necessary for the first step, so levels of
- cholecalciferol
- 25-hydroxycholecalciferol
- 1,25-dihydroxycholecalciferol
will all be decreased
```
84
If someone has kidney disease, what impact will that have on the active form of vitamin D?
1,25-DHC levels will be low because that is where synthesis of the active form takes places (under PTH control)
85
Why would liver disease impact vitamin D synthesis?
Because the rate limiting step occurs in the liver, where cholecalciferol is turned into 25-hydroxycholecalciferol
86
Explain how vitamin D synthesis is a self-regulating process.
Vitamin D causes an increase in the number of calcium transporters present on the intestinal membrane.
Synthesis will be decreased once calcium levels have risen because calcium inhibits PTH release, which is needed for vitamin D synthesis.
87
Which protein is most important for intestinal absorption of calcium?
Calcium-binding protein
88
Along with calcium absorption, what else does vitamin D promote absorption of (in the intestine)?
Phosphate
89
What is the impact of vitamin D on phosphate and calcium reabsorption/excretion (in the kidneys)?
Vitamin D decreases BOTH renal calcium and phosphate excretion
- aka it increases reabsorption
90
How does the level of vitamin D impact it's effects on bone absorption/deposition?
In small quantities, vitamin D promotes bone calcification (calcium deposition into the bone)
In excess (greater than normal) quantities, vitamin D causes bone absorption because (at high levels) it increases levels of OPGL and decreases levels of OPG
91
Parathyroid hormone is a _______ hormone
Protein hormone
- receptors are on the cell surface
- no protein binding in the blood
- stored in secretory vesicles
- released via exocytosis
92
Almost all of the PTH is synthesized and secreted by the _________.
chief cells
93
Describe the effect PTH has on bone absorption, including the rapid phase and the slow phase.
Rapid Phase
- removal of amorphous calcium phosphate salts from bone matrix by osteoblasts/osteocytes --> PTH binds to receptors on them, activating calcium pumps
Slow Phase
- causes activation and proliferation of osteoclasts via the OPGL pathway (osteoblasts have increased secretion of it, and OPGL goes on to activate osteoclasts from preosteoclasts)
- the osteoclasts breakdown the hydroxyapatite crystals
94
What effects does PTH have on excretion and reabsorption in the kidneys?
Increases calcium reabsorption (aka decreases excretion)
Decreases phosphate reabsorption (aka increases excretion)
95
How does PTH increase calcium and phosphate absorption in the intestines?
indirectly -- because it helps in the synthesis of vitamin D and vitamin D directly causes this increase
96
What is the biggest determinant for PTH levels?
How is it detected?
Calcium concentration in the blood
The chief cells of the parathyroid gland has a calcium-sensing receptor. When levels are high, calcium will bind to the CaSR and inhibit chief cell release of PTH.
97
What physiologic conditions would demand an increase in PTH secretion and parathyroid gland size?
What would cause a decrease?
Increase - pregnancy and lactation
Decrease - increased dietary calcium, increased vitamin D in body, bone absorption caused by other factors (ex. bone disuse due to lack of exercise)
98
Where is calcitonin synthesized?
What is its purpose?
How is it stimulated?
Made by the parafollicular cells of the thyroid gland
Causes reduction in blood calcium concentration (is like the reverse of PTH but has weaker effects)
It's stimulated by high calcium concentrations in the blood
99
Control of plasma calcium levels is predominantly under the control of
PTH
100
Describe the immediate and prolonged effects of calcitonin.
Immediate:
- decrease absorptive activities of osteoclasts
- decreased osteolytic effects of osteocytes and osteoblasts
Prolonged
- prevents the formation of new osteoclasts
101
In terms of control of calcium concentration, what are the "first line" and "second line" of defense?
First:
- hyper = calcium goes into bone
- hypo = bone releases calcium
Second:
- PTH
- Calcitonin
102
Describe what's occurring with hypoparathyroidism.
- decreased secretion of PTH
- -> decreased osteocyte & osteoblast-mediated resorption of amorphous calcium phosphate salts
- -> osteoclasts become almost totally inactive (no reabsorption from bone so bones remain strong)
- -> hypocalcemia results
- ---> tetany can develop
Treatment:
- vitamin D up to 100 K units per day with 1-2 grams of calcium
103
Why would you not want to give the active form of vitamin D to treat hypoparathyroidism?
Because if you overdose the vitamin D, then you'll get bone absorption
--- vitamin D stimulates the OPGL pathway
104
Describe what occurs with hyperparathyroidism.
- increased secretion of PTH (usually due to a tumor of the parathyroid glands)
- -> causes increased osteoclast activity, resulting in:
- ---> bone degradation
- ---> hypercalcemia
- ---> decreased phosphate ions in ECF due to increased renal excretion of phosphate
Possible outcomes include:
- frequent fractures due to bone reabsorption
- hypercalcemia induced CNS depression, muscle weakness, constipation, lack of appetite
- formation of kidney stones
- parathyroid poisoning and metastatic calcification --> death
Treatment = surgical removal of parathyroid glands
