Endocrine Flashcards
1
Q
What does the posterior pituitary secrete?
A
Oxytocin
ADH
2
Q
What does the anterior pituitary secrete?
A
- GH
- FSH
- LH
- TSH
- ACTH
- Prolactin
3
Q
What’s the difference between inactive and active thyroid cells?
A
Inactive: more colloid, flatter cells, epithelial cells
Active: less colloid, fatter cells, cuboidal cells, reabsorbed lacunae
4
Q
What are the steps for thyroid hormone production and synthesis?
A
- Iodine trapping: IoDide is moved into the cell via NaI transport (iodine pump) –> Iodine in the cell
Enzyme responsible: thyroid peroxidase
- Mediated by TSH - Organification: Thyroid peroxidase oxidizes iodine –> adds tyrosine molecule
- Coupling: thyroid peroxidase catalyzes coupling
- Add 1 molecule = MIT
- Add 2 molecules = DIT - Hormone synthesis: mostly T4 released
5
Q
What’s the most biologically active thyroid hormone?
A
T3
6
Q
What’s the fastest form of thyroid?
A
T3
7
Q
What enzyme catalyzes the deionidation of T4–> T3 in peripheral tissues?
A
Iodothyronine dioidinase
8
Q
What would you expect to see in a euthyroid sick dog? (TT4, fT4, TSH)
A
TT4: low
fT4: normal/high
TSH: normal
9
Q
What would you expect to see in a dog with a functional thyroid tumor (TSH, TT4, fT4)?
A
TT4: high
fT4: high
TSH: normal
10
Q
What’s the most common cause of hyperthyroidism in cats?
A
Adenomatous hyperplasia - usually bilateral (70%)
11
Q
What is the TSH in hyperthyroidism?
A
Low
12
Q
What’s the gold standard for diagnosing hyperthyroidism? What result would be normal/what would you see with hyperthyroidism?
A
T3 suppression test
4 day test
1. Day 1 - measure T3 and T4
2. Day 2-3 - give oral T3
3. Day 4: 2-4h after the 7th dose: measure T3 and T4
Normal: high T3, low T4
Hyperthyroid: high T3 and T4
13
Q
What’s the MOA of methimazole?
A
Inhibits thyroid peroxidase
-Prevent iodine incorporation into thyroid groups
-Prevent coupling of MIT + DIT –> T3+T4
-May interact with thyroglobulin molecule
14
Q
What’s the 1/2 life of the thyroid?
A
8 days
15
Q
What’s the most common cause of hypothyroidism in dogs?
A
Lymphocytic thyroiditis - immune mediated
16
Q
What type of hypersensitivity rxn will we see from canine hypothyroidism?
A
Type II - like most immune mediated diseases
17
Q
What breeds are predisposed to hypothyroidism?
A
Goldens – increase antibodies for thyroglobulin
Doberman
Fox, rat, tender field terrier
Irish setter
Boxer
Weiner dog
Cockers
18
Q
What drug incudes hypothyroidism? HOW?
A
TMS - inhibits thyroid peroxidase activity + thyroid hormone synthesis
Would see low TT4 + FT4
19
Q
What is a cause of 2ry hypothyroidism? Predisposed breed?
A
Cysts in rathe’s pouch - GSD
20
Q
Gold standard for dx canine hypothyroidism
A
TSH stimulation
Hypothyroid: blunted response
Normal: high T4 to TSH
21
Q
What would alkalosis do to iCa? Acidosis?
A
Acidosis = higher iCa
Alkalosis = lower iCa
22
Q
If a sample if stored, how would that change pH?
A
Stored = pH increases = iCa lowers
23
Q
PTH
Source
Site of action
Function
A
Source: chief cells of parathyroid gland
Site of action: renal tubule (DCT), duodenum, bone
Function: increase Ca, decrease phos
24
Q
Vitamin D
Source
Site of action
Function
A
Source: Diet
Site of action: GIT, bone
Function: increase Ca, increase phos
25
Calcitonin
Source
Site of action
Function
Source: C-cells thyroid gland
Site of action: bone
Function: decrease Ca (inhibits osteoclasts)
26
What enzyme catalyzes the hhydroxilation of 25, OD-D (calcidiol) to 1,25-(OH)2-D (calcitriol)
Alpha 1 dehydroxylase
27
MOA of thiazide
Inhibit NaCL cotransporter in DCT
28
How is calcium filtered/absorbed in the kidney?
99% reabsorbed
-60%: PCT
-35-30%" ascending LOH
-4-9%: DCT
29
Major regulators of PTH
Ca (when plasma calcium is low --> PTH increases)
Hyperphosphatemia increases PTH secretion
Mg is required for normal PTH secretion
30
What the difference between osteoblast and osteoclas
Osteoclast- breakdown of bone
Osteoblast- growing, proliferating bone
31
Is vitamin D slow or fast acting? Why
SLOW - steroid hormone
32
What's the active form of vitaminD
1, 25- dihydroxycholecalciferol (calcitriol)
33
Describe conversion of 25-hydroxycholecalciferol and where it happens
Cholecalciferol --> converted to 25-hydroxycholecalciferol by p540 enzyme in LIVER
Converted to 1,25-dehydroxycholecalciferol in the PCT of kidney
34
1/2 life of 25, hydroxycholecalciferol
weeks
35
1/2 life of 1, 25-dihydroxycholecalciferol
hours
36
What are the actions of calcitriol?
Intestine:
-Calcitriol forms a family. of calcium-binding proteins (calbindin-D) in the intestinal epithelial. cells --> calbindin D levels correlate with Ca transport . Also increases phosphorous absorption in the intestine
-Bone: works w/PTH to move Ca and phos from bone
-Kidney: promotes reabsorption of Ca + phos from kidney
37
What's the major site of action of calcitriol?
Intestine
38
What's the regulation mechanism of calcitriol?
Major site of regulation is formation of 1,25-dehydroxycholecalciferol in kidney by *1 alpha hydroxylate*
- Increased with HYPOcalcemia + HYPOphosphatemia and PTH
39
What are the major differences between PTH and 1, 25-dehydroxycholecalceferol?
PTH
- Fast acting (polypeptide)
- Increases Ca and decreases Phos
-Cell surface receptors
-Minute to minute regulation
-Acts primarily on bone and kidney
Calcitriol
- Slow acting (steroid)
- Increases Ca and phos
-Nuclear. receptors
-Day to day regulation
-Acts primarily on GIT
40
What is calcitonin? Where is it synthesized?
Smal peptide
Parafollicular (C-cells) cells of thyroid gland
41
What the action of calcitonin?
Decrease Ca and Phos
42
Where does calcitonin act?
Bone: inhibits bone resorption via direct effect on osteoclasts
Kidney: increases calcium excretion
43
What is FGF23? Where does it act?
Fibroblast growth factor hormone ("phosphatonin") -- phosphate regulatory hormone
--Reduces serum phosphate levels by its suppressive effects on phosphate reabsorption: **suppresses expression of Na-phos cotransortes in brush border of proximal tubule and reduces calcitriol (by suppressing 25-hydroxylase**
Polypeptide
**Acts on Klotho - cell surface protein necessary for activity**
44
How does FGF23 suppress phosphate?
Suppresses effects of phosphate reabsorption -- suppresses expression of type 2a and 2C Na-Phosphate cotransporter in brush border of PROXIMAL TUBULES and reduces calcitriol
45
What is effect of FGF23 on calcitriol?
Reduces calcitriol by suppressing 25-hydroxylase and enhancing expression of 24-hydrolyxase
46
What is the job of PTHrp
Regulation of Ca in fetus, mammaru gland, lower animals
47
What would PTHrp be in hypercalcemia of malignancy?
Typically high,, but can also be normal
48
Describe the pathogenesis of renal 2ry hyperparathyroidism
Disease of phosphorous retention** --> controlling hyperphosphatemia can prevent onset and progression of renal 2ry hyperparathyroidism
Phos excretion decreases with decreasing GFR
1. Phos stimulates PTH production indirectly via suppressing vitamin D production, causing hypocalcemia
2. Initially the increased PTH restores phosphorous levels to normal
3. As GFR decreases more, the response becomes maladaptive --> further increase in PTH secretion can no longer normalize phosphorous excretion
Role of FGF23: decreases PTH secretion in early stages of CKD
Advanced stages: FGF23 --> decreased calcitriol --> indirectly promoting development of hyperparathyroidism bc of adequeate amounts of calcitriol are needed to INHIBIT PTH
Additionally: mechanism of increased PTH concentration is development of FGF23 resistance in parathyroid gland bc expression of Klotho cells is decreased
49
What's the role of FGF23. in CKD?
Decrease PTH secretion in early CKD
Advanced stages: FGF23 --> decreased calcitriol --> indirectly promotes hyperparathyroidism (adequate amounts of calctriol needed to inhibit PTH)
50
Name DDX for hypercalcemia
H: hyperparathyroidism
-PTH (inappropriately) normal in 75%
-Concurrent low/low-normal pohsphorous
A: Addison's
R: renal disease
-iCa usually normal or low
D: VitaminD tox
-Severe hyperphosphatemia
-Persist weeks-months
I: idiopathic (cats), inflammatory (especially granulomatous-fungal)
O: osteolysis
N: neoplasia (lymphoma, AGASACA, melanoma, thymoma, other round cells)
S: spurious
51
What % of dogs with primary hyperparathyroidism are azotemic
10%
52
Breeds predisposed to primary hyperparathyroidism
KEESHOND
53
Name DDX for hypocalcemia
Hypoparathyroidism (severely. hypocalcemic)
Malabsorption/hypovitaminosis D (PLE, EPI)
Renal disease
Pancreatitis
Puerperal tetany
Cheating agent (EG, citrated blood)
Phosphate enema tox
Eclampsia
Hypoalbuminemia
54
Fluid of choice for hyperlcalcemic patient
0.9% NaCl.
55
Name management of hypercalcemia
Fluids: 0.9%NaCl- natriuresis promotes calciuresis
Furosemide- natriuresis promotes calciuresis
Prednisone- promoted Ca loss in pee
Biphosphonates
-Alendronate: PO for cats
-Pamidronate: IV for acute tx
Calcitonin
56
MOA of alendronate/pamidronate
SE
Binds to bone hydroxyapatite --> inhibits osteoclast function --> reduces bone resorption
SE: GI signs
57
MOA and SE of calcitonin
MOA: osteoclast-inhibiting hormone -- reduced tubular absorption of Ca, phos, Na, Mg, K, Cl --> promotes renal excretion
Also increases jejunal secretion of H2O, Na, k, Cl
SE: GI, hypocalcemia
58
Most common signs in 1ry hyperparathyroidism
LUTD (50%)
59
Breeds predisposed to primary hypoparathyroidism
Poodles toy <3
Terriers (westies, jack russels)
Labs
Mini schnauzer
GSD
60
Clinical presentation primary hypoparathyroidism
Seizures
Facial rubbing
Hyperventination
Tetany, stiff gait, muscle fasciculations
Posterior lenticular cataract
61
Where are the catecholamines secreted from?
Medulla of adrenal gland
62
What catecholamine do cats normally secrete?
Norepi
While dogs -- epinephrine
63
What's the common precursor of catecholamines?
Tyrosine
64
How is norepinephrine synthesized?
Hydroxylation and decarboxylation of TYROSINE
65
How is epinephrine synthesized?
Methylation of NE
66
Which enzyme methylates epinephrine to NE?
PNMT - phenylethanolamine N-methyltransferase
- Induced by glucocorticoids
67
What's the 1/2 life of the catecholamines?
2 min
68
Enzyme that oxidizes/breakdown NE and Epi?
Monomine oxidase (MAO)
Also part of the methylation of metinephrine
69
Most specific test for screening for a pheo
Urine metanephrine
70
MOA and SE Phenoxybenzamine
MOA: non-competitive, non-selective alpha-adrenoreceptor blocker
Adverse effects: hypotension, weakness, dizziness, vomiting, miosis
71
Alpha receptors cause x of blood vessels
Constriction
72
Beta receptors cause x activity of smooth muscle and x of blood vessels
Decreased activity
Vasodilation
Exception: heart -- contraction
73
Name the different receptors in the body organs
74
Describe the anatomy of the adrenal glang
Adrenal cortex:
1. Zona glomerulosa: Mineralcorticoids (aldosterone) - 7% of adrenal mass
2. Zona fasciculata: glucocorticoids (steroids) -50% of adrenal mass
3. Zona reticularis: sex hormones - 7% adrenal mass
Adrenal medulla: catecholamines (epi and NE) - 28% adrenal mass
75
Adrenocortical hormones are synthesized from what?
Derivatives of cholesterol- like vitamin D, bile acids
Synthesized by various members of cytochrome p450 fam
76
MOA of trilostane
3-B-hydroxysteroid dehydrogenase
-NOT a cytochrome p450
-Converts prednenolone to progesterone
-Most active in zona fasciculata (steroids here)
77
What enzyme catalyzes the formation of free cholesterol to lipid droplets?
Cholesterol ester hydroxylate
78
What's the most imp rate limiting step in the steroid pathway?
Pregnenolone!
79
What enzyme converts cholesterol to prednenolone?
Cholesteroldesmolase
80
What enzyme does etomidate and metyrapone inhibit?
11-B-hydroxylase
-Not present in zona glomerulosa
81
What 2 enzymes does the zona glomerulosa lack?
11-b-hydroxylase + 17-a-hydroxylase
82
What does type I 11B hydroxysteroid dehydrogenase do?
Reduces cortisone (inert) to active cortisol --> activate glucocorticoid receptor
Also metabolizes prednisone (inactive) to prednisolone (active)
83
What does type 2 11B hydroxysteroid dehydrogenase do?
In aldosterone selective tissues -- oxidizes cortisol to cortisone (inactive) to prevent activation of mineralocorticoid receptor by cortisol
Inhibited by licorice --> activation of mineralocorticoid receptorW
84
MOA ketoconazole
Cytochrome p450 inhibitor
85
What are the actions of ACTH?
1. Bind to membrane receptor
2. Activate adenylul cyclase via Proteins
3. Increase conversion of chol-->pregnenolone
4.Increases production of cytochrome p450 enzymes
86
What are the actions of AgII in the adrenal gland?
At1 receptor
Increases conversion of cholesterol-->prednenolone
Facilitates aldosterone synthesis
87
Bound steroids are physiologically (inactive/active)
INACTIVE
88
Plasma 1/2 life of cortisol
60-90min
89
Aldosterone 1/2 life
20min
90
What enzyme converts cortisol to cortisone?
11-HSD
91
What do these cells in the Islet of Langerhans secrete?
alpha: glucagon
beta: insulin
delta: somatostatin
F-cells: pancreatic polypeptide
92
What comprises an insulin molecule?
alpha chain, beta chain, C-peptide. joined by disulfide bond
93
What's the clinical use of C peptide?
Can measure endogenous pancreatic function and insulin secretion
94
What 2 insulin species are identical?
Porcine and canine
95
How do bovine and feline insulin defer?
Differ by one AA only
96
Name the long acting insulin
glargine and detemir
97
AA added to each of these
-Glargine
-Detemir
-Lispro
-Aspart
-Glargine: Glycine
-Detemir: Lysine-->Fatty acid binds to albumin, then slowly dissociates from albumin
-Lispro: Lys + Pro
-Aspart: Asp
98
Which insulins use U-40
Vetsulin and Prozinc
99
Insulins classified according to what
Species of origin, formulation, strength
100
How much of the glucose absorbed from the gut is stored in the liver as glycogen?
2/3
101
The insulin receptor is a xxx receptor
Enzyme-linked
102
What enzyme splits glycogen to glucose? Where does this occur
Liver phosphorylase
103
Insulin enhances uptake of glucose from the blood by liver by increasing what enzyme?
Glucokinase
104
What happens when the insulin coming into the liver is more that what can be stored as glycogen?
Insulin promotes conversion into FA --> packaged as triglycerides in VLDL --> transported in blood to adipose tissue --> FAT
105
Factors that lead to increase fatty acids in the liver
1. Increase glucose transport into liver cells by insulin (glucose-->pyruvate-->acetyl co-A (substrate to which FA are formed)
2. Excess citrate and isocitrate ions from when excess amount of glu is used for energy --> activate acetyl-con carboxylase--> carboxylate acetyl coA--> mallonyl Coa (1t stage of FA synthesis)
3. Most FA synthesized in liver and used to form trigs
106
What are the effects of insulin on fat storage
inhibits action of hormone-sensitive lipase
promote glucose transport through cell membrane -->fat cells
107
In the absence of insulin, which enzyme becomes strongly activated and leads to FA and glycerol being released into the blood?
hormone sensitive lipase
FFA become substrate for energy :(
108
Whars the sequelae to excess of fat during insulin deficiency
Ketosis and acidosis (insulin deficiency causes acetoacetic acid to be formed in liver cells)
Also have a decreased amount of usage. of acetoacetic acid in peripheral tissues
109
What makes up acetoacetic acid
Acetone (ketone bodie)s and beta hydroxybutiric acid
110
What enzyme phosphorylates glucose to glucose 6-phosphate?
Glucokinase
111
What's the rate limiting step for glucose metabolism in beta cells?
Phosphorylation of glucose
112
Describe the pathway of insulin secretion
1. Glucose is phosphorylated inside the cell by glucokinase enzyme to 6-glucose-phosphate
2. Glu-6-phosphate is oxydyzed to ATP
3. ATP inhibits the ATP sensitive K+ channels
4. CLOSURE of K+ channels --> depolarization of cell membrane
5. Opening of Ca-voltage gated channels
6. Influx. of Ca --> stimulates fusion of docked insulin-containing vesicles
7. Secretion of insulin via exocytosis
113
What transporter mediated glucose entering the cell?
GLUT2
114
How does the drug diazoxide work to increase insulin? SE?
Used in insulinomas
Works on the K-channel to keep them open
MOA: vasodilator of smooth muscle, stimulate beta-adrenergic system
Decreases bodys ability to decrease intracellular release of ionized Ca --> prevents release from beta cell insulin granules
SE: DM, pancreatitis, GI signs, hypersalivation
115
MOA and SE of glipizide
MOA: sulfonyurea antidiabetic agent (insulin secretagogue)
-Keeps K channels closed to increase insulin secretion
116
What causes increase insulin secretion?
1. High BG
2. High FFA
3. High AA
4. Intestinal hormones (Secretin, Insulin dependent peptide, glucagon like peptide 1, gastrin, CCK)
5. PS activation
6. Beta adrenergic stimulation
7. Xylitol dogs
117
What decreases insulin secretion?
1. Low BG, fasting
2. Somatostatin
3. Alpha adrenergic
4. Leptin
118
What are incretins?
Enzymes that enhance rate of insulin release from pancreatic bet cells in response to increase high plasma glucose
GLP-1 and GIP
119
What can glucagon do? Where is it secreted. from?
Alpha cells from islet of langerhans
Hyperglycemic drug -increases BG
High doses it can
-Increase heart strength
-increase blood flow to some tissues
-increase bile secretion
-inhibit gastric acid secretion
120
What are the inhibitory effects of somatostatin
-decrease secretion of insulin and gluconagon
-decrease motility of stomach, duodenum, GB
-decrease secretion and absorption in GIT
121
First choice of insulin for dog and cat
Dog: intermediate acting - vetsulin
Cat: long acting- glargine
122
Diabetogenic hormones
Glucagon
Glucocorticoids
Growth hormone
Catecholamines
123
What is hormone sensitive lipase? Where is it located? Function? Activation? Inhibition?
Hormone that promotes use of FFA for energy
Stored in adipocytes
Function: hydrolysis of reserve triglycerides
Activation: cathecholamines, glucagpn
Inhibition: insulin, prostaglandins
124
What are the counter regulatory insulin hormones?
Glucagon
Glucorticoids
Cathecholamines
GH
125
What are the catabolic effects of glucagon?
Increase gluconeogenes
Increase glycogenolysis
Increase lipolysis
Increase ketone body formation
126
PTH promotes osteoclasts or osteoblasts?
- PTH decreases osteoblast activity and increases osteoclast
127
What cells produce fibroblast growth factor 23 (FGF 23)?
Osteocytes
128
Where is cholecalciferol to 25 hydroxycholecalciferol made?
in liver
129
Where is 1,25 dihydroxycholecalciferol made?
Kidney
130
What's the effect of angiotensin II on aldosterone?
ANGIOTENSIN II increases aldosterone production
131
What enzyme oxidizes cortisol to cortisone in aldosterone responsive tissues?
11B-hydroxysteroid dehydrogenase type 2
132
What is the distribution of the GLUT 1-4 transporters and what's the function of each?
133
MOA of bexagliflozin? SE?
MOA: Na-glucose cotransporter 2 (SGLT2) inhibitor
-This transported is found in renal PCT--> absorbs renal glucose and lowers renal threshold for glucose-->increase urinary glucose excretion
-Also inhibit renal Na absorption--> delivers increased Na load to distal tubules (in humans this inhibits RAAS, increases GFR)
SE: diarrhea, glucosuria, polyuria, ketonuria, polyphagia, elevated BUN, USG, serum fPL, UTIs, ELEs, wt loss
134
What is the function of SGLT1?
Glucose absorption from distal intestinal lumen
135
What's the insulin regulated glucose transporter?
GLUT4
136
What's the function of SGLT2?
>90% of glucose reabsorption from glomerular ultrafiltrate
137
What GI hormones decrease hunger?
Letin, Adiponectin
138
What hormone stimulates appetite? Where is it produced? where does it act on?
Ghrelin
Produced in stomach cells
Acts on hypothalamus
139
What's the action of glucagon-like peptide? Where is it produced?
Produce in GIT by enteroendocrine L-cells and brainstem
Stimulates insulin secretion
140
Describe the mechanism for insulin resistance in obesity
Downregulatiion of GLUT4
Impaired binding to insulin receptor
Decreased leptin secretion
Decreased # of insulin receptors
141
What to treat first for DKA
0.9% NaCl
142
Most common cause of insulin resistance in cats
—high somatotrophin
143
What's the effect of insulin on LPL (lipoprotein lipase) and fat?
Stimulates FFA storage in adipocytes and liver
Inhibits hormone sensitive lipase, to keep triglycerides within the adipocyte.
144
How does insulin inhibit lipolysis?
Inhibiting hormone sensitive lipase (this enzyme breaks down FA)
145
Insuline is requires for glu entrance and use in most adipose and muscle cells via which transporter
GLUT4
146
What pro inflammatory cytokines can lead to insulin resistance?
TNFalpha IL6
147
Describe the metabolic effects of insulin deficiency
Metabolic shift from glycolysis to lipolysis, protein catabolic, glycogenolysis
148
Where are ketone bodies synthesized?
Liver from beta oxidation of FFAs
149
What enzyme reduces acetoacetate to Beta hydroxybutyrate?
NADH
150
What are the major ketone bodies? Which contribute to the acidosis?
Acetoacetate, beta-hydroxybutyrate - strong acids
Acetone - not acidic
151
What's the major ketone found in diabetics
Beta hydroxybutyrate
152
What ketone bodies does the urine dipstick read?
Acetoacetate and acetone
153
What ketone body is measured with serum ketone meters?
beta hydroxybutyrate
154
What's the most ketogenic of the counter regulatory hormones
Glucagon
155
Who activates hormone sensitive lipase in DKA
glucagon
156
What are the glucose counterregulatory hormones
glucagon, epinephrine, cortisol growth hormone
157
What would the total body K be in DKA, and why?
Can initially read low, high, normal
Total body deplition generally present bc of GI and renal losses and decrease intake
-Acidemia, relative insulin deficiency, hypertonicity--> pulls K from the ICF-->ECF = falsely elevated measure of serum K
Tx will result in K to move back into cells and serum K will decrease
158
What would the total body Na be in DKA, and why?
Total body depletion of Na due to renal losses (regardless of initial serum level)
As ICF is pulled into vascular space due to osmotic pull of hyperglycemia. --> plasma Na concentration will decrease
159
What would you expect the phosphorous to be in a DKA patient
Initial bloodwork - elevated because of dehydration and renal insufficiency
As it shifts into IC compartment with glucose when insulin is available --> severe decrease in levels
*Phos: major intracellular anion, source of ATP production intracellularly, cell membrane maintenance*
160
What can severe hypophosphatemia (<1mg/dL) cause?
Hemolytic anemia, lethargy, depression, D+
161
What do we need to look into if you have a DKA patient with refractory hypokalemia. despite appropriate potassium replacement therapy?
Magnesium deficiency
162
What would indicate "suppression" in a LDDST for HAC?
->50% less than baseline cortisol
-<1.4 ug/dL
