Endocrine Flashcards
What functions does the hypothalamic-pituitary axis regulate?
Regulates the functions of; thyroid, adrenal, osmoregulation, reproductive glands, growth and milk production and secretion
Describe the structure of the pituitary and what is the other name?
Hypophysis, consists of an anterior (adenohypophysis) and a posterior (neurohypophysis) lobe. The hypothalamus is connected to the pituitary by a thin stalk called infundibulum
What tissue makes up the posterior pituitary? What does this secrete and where do they act?
The neurohypophysis is made of neural tissue. The posterior pituitary is a collection of axons, whose bodies are in the hypothalamus. This secretes neuropeptides (as they are secreted from nerve cells) anti-diuretic hormone (acts on kidney and arterioles) and oxytocin (Brest and uterus).
What tissue makes up the posterior pituitary? What does this secrete and where do they act?
The neurohypophysis is made of neural tissue. The posterior pituitary is a collection of axons, whose bodies are in the hypothalamus. This secretes neuropeptides (as they are secreted from nerve cells) anti-diuretic hormone (acts on kidney and arterioles) and oxytocin (Brest and uterus).
Where are the cell bodies of the neurons which secrete ADH and oxytocin located ?
The cell bodies are located in the supraotic and paraventricular nuclei of the hypothalamus. The neuropeptide hormones are produced by both, but ADH is mainly secreted by supraoptic while oxytocin by the paraventricular nuclei
What is the adenohypophysis, what tissue is it made of and why?
It is the anterior pituitary and it is made of endocrine cells - the gland derives from the primitive foregut, hence the endocrine cells
What is the adenohypophysis, what tissue is it made of and why?
It is the anterior pituitary and it is made of endocrine cells - the gland derives from the primitive foregut, hence the endocrine cells
What 7 hormones does the anterior pituitary secrete?
1) thyroid stimulating hormone (tsh)
2) follicular stimulating hormone (fsh)
3) leutenising hormone (LH)
4) growth hormone
5) prolactin
6)adenocorticotroic hormone ACTH)
7) melanocyte stimulating hormone
How do the hypothalamus and anterior pituitary communicate ?
In both neuronal and endocrine manner. They are linked by the hypothalamic-hypophyseal portal blood vessels
Why does the hypothalamus have its own portal venous system?
The hypophyseal portal vessels allow the hypothalamus to communicate directly with the anterior pituitary. This allows it to;
1) release high concentrations of hypothalamic hormones that are delivered directly to the anterior pituitary
2) the hypothalamic hormones are isolated from the systemic circulation
What is the the TRH-TSH-thyroid system
thyroid releasing hormone (trh) is released from the hypothalamus-> secreted into the hypothalamic-hypophyseal portal vessels -> reaches anterior pituitary and stimulated thyroid stimulating hormone secretion (tsh) -> tsh enters systemic circulation and delivered to thyroid gland -> T3 released
Of the 6 anterior pituitary hormones, which are secreted by the same cell type? Which one is it?
What are the other cell types the secrete the other hormones ?
FSH and LH are both secreted by gonadotrophs
TSH - Thurotrophs
ACTH- corticotrophs
GH- somatotrophs
Prolactin - lactotrophs
What are pituitary hormone families ? Which ones are there
Hormones of the anterior lobe are organised in families based on their structural and functional homology.
1)TSH, FSH and LH family
2) acth family
3) GH and prolactin are a family
Define the structure of the FSH, LH and TSH family ?
They are composed of alpha and beta subunits. The alpha are all the same and transcribed from the same gene -> inactive component. The beta subunit is different and is the active unit . These are glycoproteins
What are POMC
Pro-opiomelanocortin; this is the common precursor for the hormones in the ACTH (anterior pituitary ) family
What hormones are included in the acth family ?
ACTH, Gama and beta lipoprotein, beta-endorphin, and melanocyte stimulating hormone
What is somatotropin ?
This is growth hormone. Growth hormone is synthesised by somatotrophs of the anterior pituitary
What signal is needed for the release of growth hormone?
Growth hormone releasing hormone (GHRH) is released from the hypothalamus (hypothalamic releasing hormone) which results in growth hormone release from the anterior pituitary
What is the pulsatile release of growth hormone and how does this change through life?
GH is released throughout life in pulses every 2 hours. The biggest pulse is 1h post falling asleep.
GH release increases in early childhood. There is a massive release in puberty, induced in females by oestrogen and in males by testosterone. These the decline throughout adult hood
What are potent physiological changes that inhibit of growth hormone release suppression ?
Hypoglycaemia and starvation
Draw the regulation of growth hormone secretion pathway
What controls release of growth hormone and how
The hypothalamus has two pathways which control release;
1) growth hormone releasing hormone (ghrh)
2) somatostatin
Ghrh acts on somatotrophs of the anterior pituitary and stimulate synthesis and secretion of GH
Somatostatin is released by the hypothalamus and acts on the anterior pituitary to inhibit growth hormone release
What negative feedback mechanism regulate growth hormone release ?
1)GHRH inhibits its own secretion via an ultrashort negative feedback loop
2) somatomedins (byproduct of GH action) on target tissue inhibit secretion of GH by the anterior pituitary
3) GH and somatomedins stimulate somatostatin release by the hypothalamus
What are the main effects of growth hormone metabolically and what are the key receptors?
Direct effect; skeletal muscle, adipose tissue, liver growth. These are mediated by tyrosine kinase-associated receptors
Indirect; mediated by somatomedins; main role is the production of IGF-1. IGF’s act through intrinsic tyrosine kinases
What are the main actions of growth hormone;
1) diabetogenic or anti-insulin effect-> increased gluconeogenesis in the liver. Lipolysis is also induced. Both increase BG
2)increased protein synthesis; stimulate DNA->RNA->PROT in nearly all organs
3) increased linear growth: alters cartilage metabolism, bone growth etc via protein synthesis
Define growth hormone deficiency;
Children; causes dwarfism, late puberty, mild obesity. Affects every downstream pathway
Adults;
Define growth hormone excess?
Acromegaly: growth hormone decreasing adenoma.
If before puberty-> giganteism due to excess linear growth at the physeal plate
After puberty-> once bone plates have closed and linear growth is not possible we see organomegally, tongue, hand and foot growth, insulin resistance and glucose intolerance
What is the role of prolactin and what concentration level is it found at
Development of breasts, inhibition of ovulation and stimulation of milk production. Low levels in males and non preganant females. Pregnancy causes a surge
Describe the synthesis of ADH and oxytocin
Neuropeptides produced in the posterior pituitary and are synthesised in the supraoptic (ADH neurons) and paraventricular nuclei (oxytocin) of the hypothalamus. Each produces the other hormone but to a lesser concentration. Synthesised as pre-prohormones, which are converted to progormones in the golgi in the hypothalamus. These are packed into vesicles that travel down the axons to the posterior pituitary where they are cleaved into the hormones
How are neuropeptides of the posterior pituitary secreted
When an action potential travels down the body to the axon in the posterior pituitary
What is the response of the posterior pituitary to an increase in serum osmolarity
Increased osmolarity (decreased water content) the anterior pituidary secretes and to diuretic hormone
What is the function of ADH?
ADH acts on the principal cells of the late distal tubule and collecting duct to increase water absorbtion, thus decreasing osmolarity
Also increases vascular tone by binding vascular V1 receptors
What is another name for ADH?
Vasopressin
What are the 9 stimulators factors for ADH?
1) Increased serum osmolarity
2) decreased ECF
3) angiotensin II
4) pain
5) Nausea
6) hypoglycaemia
7) Nicotine
8) Opiates
9) antineoplastic drugs
What are the 4 inhibitors of ADH ?
1) Decreased serum osmolarity
2) ethanol
3) alpha adrenergic agonist
4) ANP
How is ADH secreted in response to serum osmolarity?
Increased osmolarity -> sensed by baroreceptors in the anterior hypothalamus -> action potentials initiated in cell body of the ADH neurons -> depolarisation wave propagates down the nerves to the posterior pituitary-> posterior pituitary releases ADH
How is ADH released in response to hypovolemia or ECF volume contraction
Decrease of ECF by >10% results in BP drop sensed by baroreceptors of the left atrium, carotid artery and aortic arch->the vagus communicates this to the hypothalamus-> results in ADH increase
What are the actions of ADH?
1) increase in water permeability of the principal cells of the late distal tubules and collecting ducts
- ADH binds V2 receptor->adenylate cyclase (via Gs GPCR)->cAMP ->upregulated aquaporin 2 (AQP2) deposition in the membrane
2) contraction of vascular smooth muscle (hence name vasopressin).
- ADH-> V1 receptor-> phospholipase C (via Gq protein) -> IP/Ca2+ -> vascular smooth muscle contraction.
What are the actions of ADH?
1) increase in water permeability of the principal cells of the late distal tubules and collecting ducts
- ADH binds V2 receptor->adenylate cyclase (via Gs GPCR)->cAMP ->upregulated aquaporin 2 (AQP2) deposition in the membrane
2) contraction of vascular smooth muscle (hence name vasopressin).
- ADH-> V1 receptor-> phospholipase C (via Gq protein) -> IP/Ca2+ -> vascular smooth muscle contraction.
What are the main pathophysiologic changes associated with ADH?
- central diabetes insipidus; failure of the posterior pituitary to secrete ADH -> collecting ducts become impermeable and urine cannot be concentrated -> urine diluted and body fluids become concentrated (hyperNa and osmolarity). ADH levels are low
- nephrogenic diabetes insipidus; principal cells of the collecting duct do not respond to ADH due a defect in V2 recepto, Gs protein or adenylate cyclase. Same effect as above - however, ADH levels are elevated
-syndrome of inappropriate ADH (SIADH); excessive ADH is secreted from an autonomous site (eg Oat cell carcinoma of the lung). Excessive ADH causes excessive water reabsorbtion by collecting duct diluting body fluid (low osmolarity and low Na) and urine is inappropriately concentrated
What are the treatments for ADH pathologies
- central diabetes insipidus; treated with ADH analogue dDAVP
- nephrogenic diabetes insipidus; thiazide diuretics
- inhibit Na reabsorbiton in early distal tubule preventing urine dilution at this site
- decrease GFR (less water filtered, less excreted)
- increase Na excretion cause secondary ECf volume contraction
- SIADH; giving ADH antagonist Demeclocycline or water restriction
What stimulus’s stimulate oxytocin secretion and milk let down ?
Cervix dilation, suckling, smell/sight/sound of the infant,
What are inhibitors of oxytocin ?
Opioids (inc endorphins)
How does suckling result in oxytocin release ?
Sensory receptors in the nipples transmit signals to the spinal cord via afferent neurons. This ascends the spinothalamic tract to the brain stem, and up to the paraventricular nucleus of the hypothalamus
What are the effects of oxytocin release ?
- milk ejection;
Oxytocin ->contraction of the myoepithelial cells lining these ducts forcing the milk into the large duct - uterine contraction
At low concentrations it causes forceful contraction of smooth muscles of the uterus
What are the full names for T3 and T4
T3;triidothyronine
T4; tetraidothyridine or thyroxine
In what percentage is T3 and T4 excreted and which one is the metabolically active ?
90% of what is excreted is T4, although T3 is metabolically more active. The T4 is usually converted into the tissues into T3
What is rT3?
Reverse T3 and it has no biological activity
Describe the layout of the cells that produce the cells that produce thyroid hormones
Follicular epithelial cells of the thyroid gland are arranged in follicles. The cells have a basal membrane facing the blood and an apical membrane facing the follicular lumen. The lumen is full of colloid which is composed of newly synthesised thyroid hormones attached to thyroglobulin
What happens when the thyroid gland is stimulated ?
The colloidal hormone is absorbed into the lumen by endocytosis
What is the molecular structure of a hormone
Steroid + peptide+amine
what are the 3 clases of hormones?
What are they synthesized from?
which is the most common?
Peptides and protein hormones -> sysnthesised from amino acids
steroid hormones ->derived from cholesterole
Amine hormones -> derived from tyroside
Most hormones are peptide
what are the role of the nucleous, ribosomes, endoplasmic reticulum and golgi in peptide hormone synthesis?
Nucleous;
DNA->mRNA
Ribosomes
mRNA-> pre-prohormone
Endoplasmic reticulum
pre-prohormone->prohormone
Golgi
Pro-hormone-> homone (packed in secretory vescicles)
why, for medicine, has is it convinient that hormones are synthesised from DNA?
Because the gene on the DNA for most hormones have been cloned, and then inserted into cell cultures. This has allowed for the artificial synthesis of the hormones
what organs synthesise and secrete steroid hormones?
gonads, adrenal cortex, corpus luteum, placenta
which are the main steroid hormones?
Cortisol
Aldosterone
estradiol
estriol
progesterone
testosterone
1,25 dihydroxycholecalciferole
which are the main amine hormones
Thyroid homomes
Catecholamines (epinepherine, norepinepherine, dopamine)
What essential amminoacid is needed for the sysnthesis of amine hormones
Tyrosine - they are all derivatives of tyrosine
Examples of hormones that are protein bound in the circulation
What are the benefits of being protein bound?
Protein bound
- thyroid hormones
- steroid hormones
- insulin-like growth factors
Benefits;
1) creates a pool of hormones which are not currently active but ready for recruitment
2) stabilises free hormone levels
what is long loop, short loop and ultra-short loop feedback
Long loop -> hormone feeds all the way back to the beginning of the hypothalamic-pituitary axis
Short loop -> hormone feeds back to an intermediate step - e.g anterior pituitary -> hypothalamus
Ultra-short -> hormone inhibits its self (e.g. GHRH inhibits GHRH)
what are ways the body can downregulate a response to a hormone?
- negative feedback loops -> hormone concentration feedback to the synthetising pathway downregulation it
- dose-dependent receptor response -> magnitude of the response is dependent on the concentration of the hormone
- downregulation -> hormone decreases the number or affinity of its receptors in response to a target tissue
what are the two activities that G proteins can have and what is the designated for each
Inhibitory (Gi) or stimulatory (Gs)
which hormones use tyrosine kineases as a mechanism of action?
Insulin like growth factors (IGF1)
Insulin
Growth hormone
Prolactin
Which homones use guanylate cyclase mechanism?
Atrial nutrietic peptide
Nitric oxide
Which homones use IP3 pathways?
GnRH
TRH
GHRH
Angiotensin II
ADH (V1)
Oxytocin
alpha 1 receptors
(most releasing hormones)
which hormones use cAMP as an activation mechanims
ACTH
LH
FSH
TSH
ADH (V2)
HCG
MSH
CRH
Calcitonin
PTH
Glucagon
ß1 and ß2 receptors
(most stimulating hormones )
what are examples of hormones catalytic receptors?
Guanyl-cyclase (through cGMP)
Serine/theorine kinases (CaMK and MAPKs)
tyrosine kinases (JAK and STAT)
How do peptide and amine hormones activate secondary messages ? how does this differ from steroid?
How does this effect the time it takes them to activate
Peptide amine -> fucntion via cAMP, phospholipase C or tyrosine kinases (minutes to act)
Steoroid homrones diffuse through the nuclear membrane and bind to nuclear receptors that initiate DNA transcription and protein production (this is why they are slow acting (>hours)
what is the difference from the long and short portal hypophyseal system
These are both portal systems ;
Long; superior hypophyseal artery delivers blood to the hypothalamus -> forms the primary capillary plexus in the hypothalamus - > the long hypophyseal portal vessels take blood from the hypothalamus with hormones and delivery it to the pituitary
Short - > parallel to the long, but this found at the level of the infundibulum where it delivers blood to the anterior pituitary
What are the 2 important physiological implications of the portal blood supply to the anterior lobe of the pituitary ?
1) hypothalamic hormones can be delivered to the anterior pituitary directly and in high concentration
2) the hypothalamic hormones do not appear in the systemic circulation so they do not have effect while in the portal system
Where is growth hormone synthesised and by what cell type?
Somatotroph cells in the anterior pituitary
What are other names for growth hormone?
Somatropin or somatotropic hormone
why are growth hormone and prolactin in the same hormone family?
because they are made by the same gene and structurally similar (GH is a 191aa straight chain with 2 disulfide bridges) and prolacting 198aa straight chain with 3 disulphide bridges. These have 98% homology
what mess anger does the pituitary need for the production of growth hormone?
Growth hormone releasing hormone (GHRH)
what receptor and secondary messaging system is used by growth hormone?
GHRH from the hypothalamus binds GHRH-receptor on the somatotrophs of the anterior pituitary -> Gs activation -> alpha+GTP -> phospholipase C AND Protein kinase A-> IP3 AND cAMP
What hypothalamic molecule binds to somatotrophs, preventing GHRH from binding its receptor and resulting in somatotrophin release? How does it do this?
SomatotATITN - binds to its own receptro coupled with Gi protein which inhibits cAMP. Remember somatoTROPHIN IS Grouwth Hormone (GH). It also inhibits Ca channels which are modulated by IP3
what are the 3 feedback loops for GH, and state if they are short, ultrashort or long
1) GHRH inhibits its own secretion from the hypothalamus via ultrashort feedback
2) somatoMENDINGS, which are byproducts of GH action on target cells downregulate the anterior pituitary and hypothalamus (Long and short)
3) GH and somatoMENDIN stimulate secretion of somatoSTATIN from the hypothalamus. Short .
How does GH have a diabetogenic effect?
GH causes insulin resistance resulting in hyperglycaemia, increased gluconeogenesis in the liver and decrease glucose uptake by target cells. Lipolysis is also increased. Blood insulin levels will be high
How does GH promote growth?
In virtually all organs it increases uptake of aminoacids and stimulates the synthesis of DNA, RNA and protein. This increases lean body mass and organ size
where is prolactin synthesised ?
By lactotrophs which make up 15% of the anterior pituitary
What increases prolactin production, and what decreases it? what do these effect in the prolactin pathway?
Dopamine inhibits the prolactin gene in lactotrophs while thyrotropin releasing hormone increases prolactin gene transcription. Both dopamine and TRH are secreted by the hypothalamus.
what is meant by tonic inhibition of prolactin ?
In non-pregnant people, prolactin secretion is tonically inhibited by dopamine (prolactin inhibiting factor PIF) from the hypothalamus. In other words, the inhibitory effect of dopamine dominates, and overides the stimulatory effect of TRH,
what are the 3 main sources of dopamine which inhibit prolactin gene upregulation in lactortrophs? list the major one first
1) dopamine is produced by dopaminergic neurons in the HYPOTHALAMUS which secrete dopamine into the hypothalamic-hypophyseal portal system which then binds to receptors on lactotrophs in the anterior pituitary
2) dopamine released from non-lactotroph cells of the ANTERIOR PITUITARY (paracrine action)
3) Dopamine is released from dopaminergic neurons of the POSTERIOR pituitary
What are stimulatory factors for prolactin release?
pregnancy (oestrogen)
brest-feeding
sleep
stress
TRH
dopamaine antagonists (dopamine major inhibitor)
what are inhibitors of prolactin release?
Dopamine
Bromocriptine (dopamine agonists)
Somatostatin
Prolactin (negative feedback )
what are the effects of prolactin?
Lactogenesis -> prolactin stimulates milk production by inducing the synthesis of milk components inc lactose, casein, and lipids
Breast development -> in puberty prolactin + oestrogen + progesterone stimulate branching of the mammary ducts, and during pregnancy prolactin +progesterone stimulate growth and development of mammary alveoli
Inhibition of ovulation -> prolactin inhibits the synthesis and release of gonadrotropin-releasing hormone (GnRH). This inhibits ovulation .
what is a phantom pregnancy;
prolactin can stimulate lactogenesis in the abscence of pregnancy
Lactogenesis -> prolactin stimulates milk production by inducing the synthesis of milk components inc lactose, casein, and lipids
Does prolactin have any clinical implication in male fertility?
Little.
In cases of a prolactinoma (non cancerous pituitary tumour) can result in high prolactin levels which will inhibit spermatogenesis
When should bromocriptine be used and why?
When you want to inhit excess prolactone productions effects. This can only be used in hypothalamic destruction or prolactinoma as bromocriptine only inhibits prolactone secretion by the anterior pituitary
What conditions can cause failiure to produce prolactin and which ones cause excessive lprolacting production?
Prolactin deficiency; caused by ether destruction of the entire pituitary or selective lactotrophe destruction -> failure to lactate
PRolactin excess; caused by;
- destruction of the hypothalamus
- interruption of the hypothalamic hypophyseal tract
- prolactinomas
- loss of tonic inhibition of dopamine
Major symptoms are galactorea and infertility
what is prepropressophilin?
peptide precursor for antidiuretic hormone (preprohormone). it is composed of a signal peptide + ADH + neurophysin II + glycoprotein
what is prepro-oxyphysin?
it is the precursor to oxytocin(preprohormone). It is composed of a signal peptide + oxytocin + neurphisin I
what are the precursor molecules for ADH and oxytocin ?
ADH; Prepropressophilin
Oxytocin; prepro-oxyphilin
How is prepropressin converted to ADH ?
Prepropressophilin in the golgi is converted to pro-pressophillin via removal of the signal peptide (prohormone). This is then packaged into a secretory vesicles which travels down the axon of the neuron through the hypothalamic hypophyseal tract to the posterior pituitary. In the posterior pituitary neurophysin-II is cleaved leaving vasopressin
How is pre-prooxyphysin converted to oxytocin ?
pre-prooxyphysin in the golgi is converted to pre via removal of the signal peptide (prohormone). This is then packaged into a secretory vesicles which travels down the axon of the neuron through the hypothalamic hypophyseal tract to the posterior pituitary. In the posterior pituitary neurophysin-I is cleaved leaving oxytocin
how is ADH and oxytocin secreted into the circulation?
ADH and ocytocin + their neuorophins are contained within vesicles at the synapse. When an action potential reaches the synapse, Ca enters the neuron and the vesicles fuse with the synapse secreting their contents. The hormones cross the sypatic space and porus wall of the blood vessels to enter the circulation
What are the two most potent drivers of ADH secretion, and what pathways are used to upregulate this hormones release?
what are the other 7 drivers ?
1) increased plasma osmolarity -> detected by osmoreceptors in the hypothalamus -> action potentials -> secretion of ADH at the nerve terminal. Decreased osmolarity downregulates nerve firing
2) hypovolemia -> detected by baroreceptors in the aortic arch, carotid artery and left atrium -> vagus nerve conveys signal to the hypothalamus -> action potentilas -> release of ADH at the synapse
The other drivers are;
- angiotensin II
- Pain
- Nausea
- Hypoglycaemia
- Nicotine
- Opiats
- Antineoplastic drugs
once released into the blood stream, what are the roles of ADH?
1) increased H2O permeability of the late distal tubule and collecting duct. ADH -> V2 -> Gs -> PKA (via adenylate cyclase) -> cAMP -> upregulates AQP2 gene -> increased aquaporin 2 deposition in luminal membrane -> reuptake of H20 = correction of hypovolemia and hyperosmolarity + concentration of urine
2) contacting of vascular smooth muscle. ADH->V1->Qq->phospholipase C-> IP3 -> increased Ca entry -> smooth muscle contraction
In nephrogenic diabetes insipidus, where may there be a defect preventing ADH from having an effect?
mutation may be in the V2 receptor, adenylate cyclase, or Gs protein
What is nephrogenic diabetes insipidus, and why are thiazide diuretics used to treat nephrogenic diabetes insipidus?
Nephrogenic diabetes insipidus is the lack of response of the principal cells to respond to ADH (mutation in V2, Gs or Adenylate cyclase). Thiazides help by;
1) inhibit Na reabsorption in the early distal tubule -> prevents urine dilution at this site
2) Thiazides decrease GFR -> less water excreted, less urine dilation and increased osmolarity
3) increase Na secretion cause secondary ECF volume contraction. in response to volume contraction, proximal reabsorbtion of solutes in water is increased
you have a serum [Na] of 110mEq/L, osmolarity of 225mOsm/L and urine osmolarity of 650mOsm/L?
What is a key differential, what diagnostics should be performed and how can this be treated?
SIADH
- Chest imaging and if mass found biopsy (ddx inc oat cell carcinoma of the lung)
- Treat if clinical -> NaCl hypertonic infusion to raise serum osmolarity (want to increase ECF volume and increasing osmolarity will reduce H2O loss - Na needed to retain water). long term treatment with demeclocycline or water restriction. remove lung mass if possible
What is the main structural difference between T3 and T4?
one single atom of iodine
where are thyroid hormones synthesised
in the follicular epithelial cell of the thyroid
What is an essential element for thyroid hormone formation?
Are thyroid hormones synthesised at the time they are needed or are they stored?
What is the most active thyroid hormone and which one is more abundant ?
1) large volumes of iodine are needed and this must come from the diet
2) synthesis of thyroid hormones is partially intracellular and extracellular , with the complete hormone stored extracellulalrly in the follicular lumen until the thyroid is ready to secrete
3) T4, the more inactive form, is the major secretory unit, and require conversion to T3 post secretion
what are the steps involved in thyroid hormone synthesis ?
1) thyroglobulin (TG) is synthesised from tyrosine by the golgi of the follicular epithelial cell -> TG is incorporated into vesicles and excreted into the lumen of the thyroid gland
2) Na-I cotransport, or I-trap; I- is actively transported from blood -> follicular epithelial cells (against chemical and electrical gradient - pump activity is regulated by I- levels)
3) oxidation of I- to I2; thyroid peroxidase catalyses oxidation and the next two steps of organification of I2 into TG and the coupling reactions )
4) Organification of I2; at the apical membrane I2 combines with tyrosine moieties on TG, catlysed by thyroid peroxidase to form monoiodotyrosine (MIT) and Diiodotyroside (DIT). MIT and DIT remain attached to TG until secretion stimulus
5) coupling reaction; While attached to TG, two coupling reactions occur to DIT and MIT. 1) two molecules of DIT combine to form T4. 2) one DIT and one MIT combine to form T3. A portion of DIT and MIT do not couple and are left over
6) endocytosis of thyroglobulin; When thyroid gland is stimulated, iodinated-TG (with its attached T3, T4, MIT and DIT) is endocytosed into the follicular epithelial cells. Pseudopods are pinched off the apical membrane, engulf a portion of colloid and absorb it into the cell. Once inside TG is transported in the direction of the basal membrane by microtubules
7)hydrolysis of T4 and T3 from TG by lysosomal enzymes; TG droplets fuse with lysosomes. Lysosomal proteases hydrolysed peptide bonds to release T4, T3, MIT and DIT from TG. T4 and T3 are transported across basal membrane into the capillaries. MIT and DIT are recycled into the synthesis of new TG
8) deiodination of MIT and DIT; thyroid deiodinase removes I- from DIT and MIT. This is recycled.
why is T4 secreted at 10x the concentration of T3?
becuase the coupling of DIT+DIT (produces T4) is significantly faster that DIT+MIT (produces T3)
what is the wolff-chaikoff effect?
this is where high levels of I- inhibit organification (this is where I2 combines with tyrosine of TG to form DIT and MIT) `
How it works:
Iodine organification: The thyroid gland uses iodine to produce thyroid hormones (T3 and T4). Excess iodine inhibits the process of iodine organification, where iodine is incorporated into thyroid hormones.
Inhibition of thyroperoxidase (TPO): The mechanism involves the formation of iodopeptides that temporarily inhibit the activity of TPO, an enzyme crucial for thyroid hormone synthesis.
Downregulation of Na+/I- symporter (NIS): The Wolff-Chaikoff effect may also involve downregulation of NIS, a protein responsible for transporting iodine into thyroid cells.
What effect does the chemotherapeutic agent PTU (polyurcil) have on thyroid function?
What thyroid disease may this be treated for?
inhibits thyroid peroxidase blocking thyroid hormone synthesis.
PTU is an effective treatment of hyperthyroidism
How is T3 and T4 transported in the circulation?
Most is bound to thyroxine binding globulin (TBG) . A small amount of T4 will not not be bound to TG but is transported by albumin and pre-albumin. A smaller amount of T4 is still not bound at all and is free (fT4)
why is it important to distinguish total and free t4 on blood tests?
Total T4 is Free+TBG bound and is not metabolically active, while free T4 is metabolically active
Why is it beneficial to have both free T4 and TG bound T4?
Free T4 is metabolically active, while the TBG bound is not. The TBG bound acts as a T4 reservoir in the circulation
Give an example of when low total T4 may result in negative feedback inhibition of T4 synthesis?`
In advanced liver disease, Thyroxin binding globulin (TBG) decreases. This results in a transient increase in free T4. As a consequence, the increased fT4 negatively feedback inhibiting the formation of new thyroid hormone
What abnormalites may you see on a thyroid panel in a pregnant person
normal free T4 but increased total T4. This is physiologically euthyroid. this is because estrogen inhibits hepatic breakdown of TBG and thus increased TBG levels. The increased TBG will bind more free T4. This is detected as dected as decreased T4 and more is produced filling the fT4 gap. T3 is also increased as the thyroid is trying to replace the fT4.
what is a T3 resin uptake test?
measures binding of radioactive t3 to synthetic resin. The idea is that radioactive T3 preferentially binds TBG and that which is not will bind to resin. This can give an idea if TBG is decreased (hepatic failure) or when endogenous T3 is increased (endogenous hormone occupies the TGH) or when T3 is decreased in cases such as pregnancy
Most thyroid hormone which is secreted is the less active T4. How does the body convert this to the more active T3?
Target tissues (e.g. liver, kidney) use an enzyme called 5’-ionidase to convert T4 to T3 by removing one atom of I2 from the OUTER ring of T4
What is the small difference in conversion of T4 which can result in ether T3 or rT3 being produced?
Why is this important?
The 5’ ionidase produces T3 by removing one atom of I2 from the OUTER ring of T4. Conversely, 5’ionidase, produces rT3 by removing one atom of I2 from the INNER ring of T4.
Some rT3 is always produced, but this difference is what lets the cell determine how much active hormone is produced by the target tissue
during starvation (or fasting), what functional changes do we see in brain and other tissue 5’ iodinase function?
in non brain tissue, 5’ iodinase is inhibited, thus lowering O2 requirements and basal metabolic rate. However, in the brain, 5’-iodinase is not inhibited (there is a slightly different structure), protecting brain T3 levels
what is the main hormone that stimualtes thyroid hormone synthesis?
What pathological condition can imitate this pathway?
TSH
Thyroid stimulating immunoglobulins
increased thyroglobulin binding protein (e.g. pregnancy or autoimmune)
What factors inhibit thyroid hormone synthesis?
Iodine deficiency
Deodinase deficiency
excessive I- intake (Wolff chaikoff effect)
perchlorate thiocynate (inhibits Na-I cotransporter)
PRopylthiouracil (inhibits peroxidase enzyme)
Decreased TBG levs (e.g. liver failiure/disease)
what effect does PRopylthiouracil have on the thyroid?
inhibits peroxidase enzyme which converts thyroglobulin to TG+I2 and then TG+MIT+DIT and then TG +MIT+DIT+T3+T4
where is TRH secreted from?
paraventricular nucleous of the hypothalamus
where does TRH act on? what does it do?
Thyrotrophs of the anterior pituitary to upregulate TRH to stimulate transcription of TSH gene and secretion of TSH. TRH also regulates prolactin release
What is the role of TSH ? What controls the release TSH function?
secreted in response to TRH and has trophic effects (i.e. regulates thyroid growth).
1) TRH from the hypothalamus stimulates TSH
2) Thyroid hormones inhibit TSH by downregulation TRH receptor on thyrotrophes (free T3 regulates this - anterior lobe has thyroid deidinase
what actions does TSH have on the thyroid gland?
TSH -> TSH receptor -> Gs -> alpa-GTP -> PKA ->cAMP resulting in 2 actions;
1) upregulates every pathway in thyroid hormone synthesis (I- uptake, oxidation, lrganification of I2 into MIT&DIT, coupling of MIT&DIT to form T3/T4, proteolysis of TG and release of T4,T3.
2) TSH trophic effect -> hypertrophy of the gland after sustained exposure.
what are thyroid immunoglobulins and why are these important?
Part of the IgG plasma proteins. They bind to TSH receptors producing the same response as TSH -> hyperthyroidism + hypertrophy of the gland = Graves disease
if you have sings of hyperthyroidism, and run a thyroid profile, what changes would you see in a case of hyperthyroidism secondary to thyroid immunoglobulins?
Explain
HIGH T3, fT4 and tT4, but LOW TSH
You have hyperthyroid levels of thyroid hormones as the immunoglobulins are bound to TSH receptors, stimulating production and hypertrophy. But the anterior pituitary is detecting the high T3 and T4 and trying to compensate by supressing production TSH
whith what other homene do thyroid hormones act synergistically with to increase bone growth
GH
Once thyroid hormone reaches a target tissue, what is the first step that has to be undertaken for the hormone to have effect?
T4 conversion to T3 by 5’ ionidase, which removes an atom of I- from the outer ring of T4
how much T3 and rT3 is produced in the tissue ?
What would affect the ratio of T3 to rT3?
under NORMAL circumstances, T3 45%, rT3 55%.
The ratio would be affected by things like pregnancy, fasting, shunts, stress, hepatic and renal failiure etc
How does T3 affect protein production ?
T3 binds nuclear receptors on TRE’s (thyroid receptive elements) increasing DNA translation and protein synthesis. There are T3 receptors within the ribosomes to increase protein production
what effect does increased T3 levels have on cardiomyocytes at a molecular level?
- increased Na:K ATPase
- increased ß-1 receptor concentration
- increased Ca-ATPase concentration
-increases cardiomyocyte hypertrophy by increasing the number of Contractile units
how do thyroid hormones affect liver funciton?
- increase carbohydrate, fat and protein metabolism
how do thyroid hormones affect basal metabolic rate?
- increase O2 consumtyion by increasing the synthesis of Na:K ATPases = increase in temperature
Na:K ATPase is one of the receptors responsible for the largest use of O2 (need a lot of ATP)
What tissues are immune to thyroid homones increase in O2 consumption?
Brain, gonads and spleen
How do thyroid hormonws affect energy metabolism?
What about nutrient absorbtion?
What can thyroid hormones potentiate the effects of ?
increase protein, fat and carb metabolism
- increase glucose absorption by the GIT
- potentiate the effects of other hormones (catecholamines, glucagon, GH etc)
- increase gluconeogenesis, lipolysis and proteolysis (net effect is catabolic though)
why is infarction relatively uncommon in veterinary patients with hyperthyroidism
The increased thyroid hormone increases HR, ionotropy, NA:K-ATPase activity and Ca-ATPase activity resulting in increased O2 use. However, hyperthyroidism also increases ventilation and O2 delivery to the tissue
what effects does hyporthyroidism have on the CNS?
Oftem age dependent impacts.
- Perinatal; thyroid hormone essential for CNS development
with hypothyroidism resulting in mental retardation.
- Adults; listlessness, slowed movement, irritability, somnolence, impaired memory and decreased mental capacity
what are causes of hyperthyroidism?
- Thyroid adenoma or adenomatous hyperplasia is the most common cause of feline hyperthyroidism (70% of cases)
- Thyroid carcinoma, the primary cause of hyperthyroidism in dogs (rare in cats <3% of cases)
- Autoimmune (thyroid stimulating immunoglobulins - Graves)
-Other thyroid neoplasia - ## excessive TRH or TSH secretion (e.g. hypothalamic disorders)
what are differentials for decreased TSH in hyperthyroidism?
If non euthyroid, they are;
- Neoplasia of thyroid gland (adenoma cat, carcinoma dog)
- endogenous administration (overdosing)
what are differentials for hyperthyroidism with increased TSH or TRH ?
- disorders of the anterior pituitary or hypothalamus
How to treat hyperthyroidism?
Pros and cons of each
Gold standard I131
- can be given as first line
- can be given to IRIS 1 without other intervention
- beneficial for those with cardiovascular disease once euthyroid state is achieved medically
- 95% will be cured but supplementation
Thyroidectomy
- can be curative
- specialised skillset - invasive
- risk of damaging parathyroid gland
Methimazole
- control the symptoms - not a cure
- start low and titrate up to the dose needed to maintain T4 levels between 1.0 and 2.5 mcg/dL. Dosing of 1.25–2.5 mg every 24 hr for the first week of treatment, increasing to 2.5–5 mg every 12–24 hr, will help minimize side effects
Hyperthyroid diets with low iodine can help with medical management
If an owner elects to treat with hyperthyroidism with methimazole, what is the recommended treatment plan and schedule?
When do blood samples have to be taken?
- Start low and titrate up to the dose needed to maintain T4 levels between 1.0 and 2.5 mcg/dL. Dosing of 1.25–2.5 mg every 24 hr for the first week of treatment, increasing to 2.5–5 mg every 12–24 hr, will help minimize side effects
- T4 monitoring should occur every 2–4 wk until the goal levels are reached. Complete blood count, chemistry profiles, and urinalysis will provide information on potential bone
marrow dyscrasias, development or progression of azo-
temia, resolution of any liver enzyme changes, and any
other issues that may have been concealed by the hyper-
thyroid state. - Blood samples for T4 measurement may be taken at any
time during the day after methimazole administration. - once control is achieved, minimum database should be performed at least every 6 mo and more frequently if there are significant comorbidities
what are side effects of methimazole? when do they occur?
vomiting, bone marrow dyscrasias, and skin excoriations can occur up to several months after initiating therapy.
Once a dose of methimazole which is controlling the hyperthyroidism symptoms has been reached, is there need to change this?
Methimazole doses
will need to be adjusted over time because the drug does not
affect the growth of the adenomatous hyperplasia.
is. propylthiouracil used in cats with hyperthyroidism?
Not anymore, been replaced by carbimazole and then methimazole which have less side effects
Most common causes of hypothyroidism/
- autoimmune destruction (thyroiditis - antibodies ether block production of thyroid hormones or destroy the gland)
- prior surgical removal/I131
- hypothalamic or pituitary failure
- I- deficiency
- (rare) tissue resistance due to downregulation of thyroid receptors
How do you diagnose hypothyroidism
Have to have low fT4, tT4.
- IF TSH is low, then there is an issue with the hypothalamus, pituitary or hypothalamic-pituitary axis
- IF TSH is high, then there is a problem with the thyroid
(e.g. thyroiditis)
symptoms of hypothyroidism?
- decrease metabolic rate
- weight gain without increased caloric intake
- decreased heat production
- cold intollerance
- decreased HR
- slow movements
- slowed mentation
- lethargy
- Somnolence
- myxadema
what is goiter?
this is when hypothyroidism is caused by a defect in the thyroid gland by high circulating TSH.
when do you treat for hypothyroidism ?
have to demonstrate a T4 and elevated TSH. Cats with naturally occurring hypoT4 are more likely to be azotemic (not dogs).
Cats should be treated if clinical with multiple laboratory signs showing hypo T4
If the cat has concurrent disease, that should be treated first and then thyroid function re-evaluated. If hypothyroid <3-4months and not symptomatic monitor T4 for rebound. if >4 months and T4 is low, TSH elevated supplement with levothyroxine
If the cat is asymptomatic with no concurrent disease then monitor labs every 6 months, watch for clinical signs and azotemia. If goiter is present consider TSH testing.
If the cat is older than 2 and symptomatic then recheck T4 in 2-4 weeks, if still low, check TSH, and treat if hypo. If T4 is normal, then the cat is not hypothyroid
what is euthyroid sick syndrome?
Euthyroid sick
syndrome can decrease circulating thyroid hormone concentrations,
with preferential impact on TT4. In severe illness, fT4 is also
impacted. TSH may be subnormal or within the reference range.
Ideally, further thyroid testing should be delayed until clinical illness has resolved and the dog is clinically well
K9 breed predisposition for hypothyroidism>
begles, golden retrievers, Doberman pinschers, Great Danes)
if you have signs of hypothyroidism, or the patient is normal with high T4, what next step should be taken?
fT4 and TSH.
Although uncommon, circulating autoantibodies against
thyroxine (T4) can cross-react with the TT4 assay, caus-
ing an artificially high reported result. A free T4 by
equilibrium dialysis (fT4ed) or quantification of circu-
lating autoantibodies may be warranted
DOGS WITH CLASSICAL SIGNS OF HYPOTHYROIDISM AND A LOW TT4 - treatment approach?
Submit additional thyroid testing to document a subnormal fT4
and/or an elevated TSH concentration to confirm diagnosis
Initiate treatment with twice-daily levothyroxine supplementation
Monitor therapy based on clinical improvement and serial TT4 test-
ing. Assess a TT4 level 4–6 hr post morning pill 4 wk after starting
medication or after dose adjustments until control is achieved, then
every 6–12 mo as indicated.
why is it challenging to determine if the hypothyroidism is true in dogs?
Approximately 20–40% of dogs with hypothyroidism have a low
TT4 and low fT4 but a normal TSH concentration.However,
this scenario could also indicate nonthyroidal illness, so additionaltesting such as assessing for the presence of antithyroid autoantibo-
dies or a TSH response test can be run to help confirm diagnosis,
What are the 3 zones of the adrenal cortex and what do they secrete?
Glomerulosa =mineralocorticoids - ie aldostererone
Fasciculata = corticosteroids - ie cortisol
Reticularis = androgens
glucorticoid have a rhythmic secretion, when are they most prevalent and least?
circardian rhythm - peak in AM, low in PM
whar are the actions of glucocorticoids?
1) gluconeogenesis -> increased protein catabolism, increased lipolysis
2) anti-inflammatory -> increase liportin, decrease phospholipase 2, inhibit IL-2 production, decrease T cell proliferation, inhibit histamine (mast cells) and serotonin (platelet release)
3) suppress immune system; inhibit IL2 and T cells
4) Maintain vascular responsiveness to catecholamines -> increase alpha-1 receptors
what is the most important mineralocorticoid and what is its role?
Aldosterone.
Increases blood volume by retaining Na and therefore water. Increase K loss as Na is exchanged for K in the collecting duct. Acid is also excreted by the kidney by aldosterone.
Aldosterone also increases water absorption in the colon
There are two types of adrenocortical insufficiency. Which are these and what are defining characteristics ?
Primary; Addisons.
- Autoimmune destruction of adrenal cortex; Decreases cortisol + aldosterone and ACTH levesl as a result are increased. Lack of cortisol leads to hypoglycaemia and a decrease in ECF, leading to hypotension (in addition to loss of vascular tone). They are also hyperkalaemic due to the lack of aldosterone and have low Na and water retention. Additionally, due to the lack of aldosterone which does not pump out H+ and becuase they are hypoglycaemic leading to acidic ketone production they have a metabolic acidosis
Secondary; ACTH deficiency
- Same as primary but with NORMAL ALDOSTERONE levels
What are diseases of adrenal excess?
- adrenocortical excess = Cushings; increased cortisol and aldosterone -> hyperglycaemia, increased protein catabolism, central obesity, hypertension (too many alpha1), poor wound healing,
- hyperaldosteronism = Conns syndrome. Aldosterone secreting tumour = hypokalemia, hypertension (increased volume), metabolic alkylosis (more H+ excretion) and decreased Renin
- 21ß-hydroxylase deficiency; decreased cortisol and aldosterone but increased androgens
- 17alpha-hydroxylase deficiency = decreased androgens, decreased glucocorticoids and increased minearolocrticoids
what is the cellular organisation of the exocrine pancreas?
Alpha, ß, gamma cells, Delta and pp -> form islets of langherhans
What is the role of pancreatic alpha, beta and gamma cells?
are these cell types independent or not?
alpha; secrete glucagon
Beta; secrete insulin
Gamma; secrete somatostatin and gastrin
Alpha and beta are linked by gap junctions
what is the role of glucagon?
What does this cause when released ?
Prevents hypoglycaemia, by upregulating glucose production. Increases AA catabolism, and releases CCK and modulates the autonomic nervous system to help digerstion
Actions;
1) Liver and adipose tissue (via cAMP)
- increase gluconeogenesis, and glycogenolysis
- Lipolysis
- increased Urea production -> AA groups left over from gluconeogenesis form urea
What is the structure of insulin?
made of an alpha and beta chain linked by 2 disulfide bridges.
Pro-insulin - single chain peptide wchihc contains a C peptide. The C peptide is removed to form insulin
what is the role of insulin?
How is insulin secreted i?
Allows glucose to enter cells with GLUT4 insulin dependent receptors (skeletal and adipose tissue)
Glucose binds Glut2 receptors on ß cells -> enters cell (insulin indipendent receptir)-> glucose used to make ATP-> increased ATP induces K channels to close-> cause depolarisation of the cell-> leads to Ca channels to open -> insulin packed vesicles induced to fuse with membranel -> insulin secreted (2alpha and 2ß subunits)
once insulin is secreted, how does it interact with target cells and what does it cause?
insulin binds to insulin receptors which are tyrosine kinases.
This results in;
1) Increased glucose uptake (increase glucose transporters (GLUT4), increases glycogen formation, decreases gluconeogenesis, increases fructose 2,6 diphosphate
2) decrease fatty acid breakdown and ketoacid production - increases fat deposition, decrease lipolysis, inhibits keto acid production due to decreased acetyl-coa availability
3) decrease blood ammino acid levels -> anabolic protein synthesis
4) decrease K - increased cellular uptake no
what gastrointestinal hormone inhibits insulin ?
somatostatin
What proportion of Ca is protein bound?
40% of total calcium. 60% is ultrafiltatable and complexed to anions or free ionized
what are the main sources of Ca for the body?
GIT absorbtion
Bone reabsorbtion
where is Ca exreted ?
kidneys
how does the parathyroid respond to Ca levels?
Decreased [Ca] is detected by Ca Ca-sensing receptor on the chief cells of paratyroid, which produces PTH
Decreased Ca, decreased receptor binding, increased PTH
How do Mg levels affect PTH
Decreased Mg increases PTH. However, severe hypomagnesemia inhibits PTH, which can lead to hypoparathyroidism
what are the actions of PTH?
1) bone reabsorbtion of Ca and phosphate- P renally excreted hence Ca can increase as there is less P to bind it
2) PTH inhibits renal phosphate reabsorbtion in proximal tubule -> phosphaturia
3) Increased Ca reabsorbtion in the distal tubule
4) Increased intestinal Ca absorbition via 1, 25-dihydroxycholecalciferol
why do young animals have high P?
They have increased bone remodelling, which results in PTH increasing the release of Ca and phosphorous. Ca release is not significantly appreciated on blood test
What is the relationship between P and Ca
Calcium and phosphorus have an inverse relationship in the body; when levels of one increase, the levels of the other typically decrease.
as blood calcium levels rise, phosphate levels fall. This is because phosphate binds to calcium reducing the available free calcium within the bloodstream
What are pathological conditions which affect PTH levels?
1) primary hperparathyroidism -> parathyroid adenoma; Increased Ca, decreased P, phosphaturia, calcinuria, increased urinary cAMP, increased bone reabsorbtion
2) hypercalcaemia of malignancy-> PTH related peptide (PTH-rp) - > same side effects as primary
3) secondary hyperparathyroidism -> thyroid surgery or congenital; hypocalcemia, tetany, hyperphosphatemia, decreased urinary phosphate secretion
4) chronic renal failure -> decreased GFR, decreased 1, 25 dihydrocholecalciferol production= hyperphopshatemia, decreased free [Ca] which can result in secondary hyperparathyroidism (increased PTH and bone reabsorbtion)
what effects does vitamin D administration have on calcium levels?
Vit-D is active form of 1, 25 dihydrocholecalciferole -> increases serum [Ca]m serum PTH, and decrease serum [P]
Describe the pathway towards vitamin D production from the source and what functions vitamin D performed?
How is this pathway regulated?
Sources of Vitamin D such as UV rays and diet deliver vitamin D in their precursor forms, D2 and D3. These precursors then bind to the Vitamin D-binding protein (DBP) at the site of synthesis and form the DBP-D protein complex. Vitamin D is then carried in the DBP-D complex through the blood plasma to the liver. Precursors D2 and D3 are hydroxylated into inactive 25-hydroxvitamin D [25(OH)D] by 25-hydroxylase, coded by the cytochrome P2R1 (CYP2R1) gene. 25(OH)D is taken up into the kidney from the blood and activated via 1-α-hydroxylation by the CYP27B gene to the 1,25-dihydroxyvitamin D (1,25(OH)2D) activated state. An increase in parathyroid hormone (PTH), reductions in phosphorous and calcium upregulates CYP27B gene activity, while an increase in fibroblast growth factor (FGF-23) downregulates CYP27B gene activity.
what are the actions of vitamin D
1) increase serum Ca and phosphate
2) increased intestinal Ca absorption via calbindin (D-28K)
3) increase intestinal phosphate absorption
4) increase renal re-absorbtion of [Ca] and [phosphate]
5) increase bone resorbtion -> provides [Ca] and [phosphate] to make new bone
How do you treat hypercalcaemia?
How does the drug work
calcitonin.
Calcitonin lowers blood calcium levels by inhibiting the breakdown of bone (osteoclast activity) and increasing the excretion of calcium in the urine
What are the main structural differences between the adrenal cortex and medulla?
Medulla is an extension of the CNS -> epinephrine and norepinephrine
Cortex; endocrine
- Grlomerulosa -> Mineralocorticoids (ADH)
- Fasciulata -> corticosteroids (cortisol)
- Reticularis -> androgens
what all cortical hormones derived from and what is the rate limiting step in their synthesis?
All are steroid compounds derived from cholesterole. The adrenal cortex has receptors for LDL.
The rate-limiting step is the cleavage of the cholesterol side chain by the Cholesterol Side-Chain Cleavage Enzyme to form pregnenolone, which is the initial step in forming cortisol, aldosterone, and estriol.
This step is under control of PKA ->cAMP which is what allows enzyme activation to occur
Which is more potent: prednisone, methyprednisone, or dexamethasone?
prednisone > methyprednisone > dexamethasone
how is cholesterole trnasported in the body ?
bound to cholesterole binding protein or transcortin
which hormones have mineralocorticoid activity ?
90% of the activity is aldosterone. Glucocorticoids have mild mineralocorticoid activity too (deoxycorticosterone 3%). Cortisol has active but it is concerted by 11-ß-hydroxysteroid dehydrogenase to cortisone which doesn’t mind minerarolocorticoid receptors well
what are the sites of action of aldosterone?
Kidney
Colon
Sweat and salivary glands
where does aldosterone act and what does it do?
Increases the expression of Na and K channels on the luminal wall. Increase Na absorption increases water intake into the principal cell.
On the blood side, there is an increase in production of Na:K ATPase which secretes 3 Na into the blood (drawing water with it), importing 2K into the cell. This is why there is an increase in K channels on the luminal side, as the increased intracellular K is then pumped out into the urine. This is why hyperaldosteronemia results in mild hypernatremia (diluted out by water in ECF)), hypokalemia
Note; also see hypomagnesemia (cofactor) and urinary pH decrease and metabolic alkylosis)
which are the Na and K channel types which are upregulated on the tubular aspect of principal cells in response to aldosterone?
Na - eNak
K - romK
if the RAAS upregulates aldosterone, or if there is hyperaldosteronism, why may serum Na be normal ?
because this is diluted out by the increased water in the ECF. Mild hypernatremia are usually only seen with pathological hyperaldosteronism
what is the role of Mg in aldosterone function ?
Mg2+ acts as a cofactor for the Na+/K+ ATPase pump, which is essential for maintaining the electrochemical gradients of Na+ and K+ across cell membrane
what is aldosterone escape?
refers to two distinct phenomena:
(1) the kidneys’ ability to increase sodium and water excretion despite elevated aldosterone levels
(2) the failure of ACE inhibitors to reliably suppress aldosterone release in certain conditions
Describe how aldosterone escape affects the kidneys ability to increase Na and Water excretion?
In conditions like primary aldosteronism, where there’s excessive aldosterone, the kidneys initially retain sodium and water, but this effect is short-lived.
1) Renal Adaptation: The kidneys adapt to the excess aldosterone by increasing sodium excretion, preventing the development of edema (swelling) that might otherwise be expected.
2) Pressure Natriuresis: Increased renal perfusion pressure and volume expansion lead to increased sodium delivery to the distal nephron, overriding the aldosterone’s sodium-retaining effect.
3) Natriuretic Peptides: Volume expansion also increases levels of natriuretic peptides, inhibiting sodium reabsorption in the collecting duct.
why does increased aldosterone levels cause metabolic alkylosis and increased urine acidity?
H ions are excreted in the intercalated disks in exchange for Na
why would hypoaldosterolemia or excessive aldosterone blockade cause diarrhoea?
By blocking aldosterone we decrease Na, K and Cl absorption in the colon which decreases H2O reabsorbtion
How long does it take from aldosterone secretion to this having an effect, and why ?
45 min
Two pathways;
Major pathway
Increased Na and decreased blood volume detected by the kidneys -> upregulate RAAS -> AngII -> increase aldosterone
Minor pathway
acth pathway - less important
increased osmolarity detected by osmoreceptors in the hypothalamus-> CRH release which inteacts with corticotrophs -> release ACTH -> interacts with zona glomerulosa -> deoxycorticosterone is made and a precursor to aldosterone -> this is modified into aldosterone in the fasciculata
Both pathways;
aldosterone into blood -> aldosterone filters into the tubules by the kidneys where it travels to principal cells via the tubules -> enters the cytoplasm -> upregulate DNA transcription of genes for Na-KATPase and Na and K ion channels
How do increased glucocorticoid concentrations affect carb metabolism ?
What does this result in physically
increases it- increased glucocorticoids result in;
- increased gluconeogenesis -> increased glycogen
- Increases enzymes needed to convert AA in liver into glucose
- mobilised AA from muscle
- decreases cell glucose utilisation
All of this increases fat deposition and muscle loss.
what is the mechanism of action of glucocorticoids that results in decreased glucose utilisation?
not fully know. Thought to be due to depressed NADH oxidation to form NAD+. NADH must be oxidised during glycolysis
what is the difference in insulin sensitivity between pancreatic, pituitary and adrenal-dependent diabeters
Pancreatic; strongly insulin sensitive
Adrenal; moderately insulin sensitive
Pituitary; weakly insulin sensitive
What are the 3 endocrine forms of diabetes, and how do they differ in the way they respond to insulin?`
Pancreatic; strongly insulin sensitive
Adrenal; moderately insulin sensitive
Pituitary; weakly insulin sensitive
why does muscular weakness occur in hyperadronocorticoism?
there is increased AA mobilisation from the muscle, and decreased protein synthesis with increased protein catabolism (which forms glycogen and fat) weakening mucles
What shift in protein metabolism occurs between different cell populations in a Cushing’s patient?
What clinical exam features may this change in cause
Decreased extrahepatic protein metabolism (decreased transport of aminoacids into these cells), increased mobilisation of AA from muscle cells, and increased protein metabolism in the liver, which increases gluconeogenesis in the cells. One reason why you may get hepatomegaly and muscle loss
why do you see obesity in cushings?
1) increased glucose metabolism rsulting in glycogen and fat formation
2) polyphagia increases caloric intake
3) decreased metabolic energy demand
4) mobilisation of protein from muscle to form glycogen or fat if the glycogen stores are full
why does fat deposition occur during stress?
Excess cortisol mobilises AAs and FAs to form glucose for energy. However, if the energy is not needed the FA and the AA are concerted to fat.
Also, cortisol decreases glucose utilisation by most cell populations resulting in gluconeogenesis and lipogenesis.
What are cortisols’ anti-inflammatory effects?
- stabilise lisosome walls preventing leakage of enzymes
- Inhibit IL1 which reduces fever
- Inhibit T cell production
- decreases capillary leakiness
- decreases phagocytic activity of WBS
This is what allows cortisol to have protective effects during stress
what adrenal zones does ACTH affect?
Fasciculata and reticularis. The glomerolosa is not heavily affected (mostly affected by AngII - AKA RAAS)
what part of the hypothalamic-pituitary- adreanal axis is affected by stress?
stress increases CRH which is secreted by the hypothalamus and induces the pituitary to secrete ACTH ->thus cortisol
what are the secondary messengers ACTH induces when binding to receptors on the adrenal cortex
ACTH+receptor -> Gs ->apha-GTP->PKA (adenylate cyclease) -> cAMP ->activates proteins
why does cortisol have a protective effect during stress?
- stabilise lisosome walls preventing leakage of enzymes
- inhibit IL1, which reduces fever
- Inhibit T cell production
- decreases capillary leakiness
- decreases phagocytic activity of WBS
what cells secrete pancreatic polypeptide?
PP cells
what hormone inhibits both the secretion of insulin and glucagon?
What are the effects of insulin on glucagon?
Somatostatin inhibits both.
Insulin inhibits glucagon
what is somatostatin?
Somatostatin is a cyclic peptide well known for its strong regulatory effects throughout the body. Also known as growth hormone inhibiting hormone, it is produced in many locations, including the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS).
What is the half-life of insulin and glucagon?
5-10min
where is insulin and glucagon metabolised
First pass in the liver where 50% is metabolised, rest in the kidneys
what are pancreatic acini and what is their role?
Acinar cells are arranged in clusters called acini. Each acinus is composed of Acinar cells, cuboidal epithelial cells that synthesize and store digestive enzymes, and intercalated ducts that collect enzymes from the acinar cells.
Acinar cells produce and secrete digestive enzymes, including:
- Proteases (e.g., trypsin, chymotrypsin)
- Lipases (e.g., pancreatic lipase)
- Amylase (breaks down carbohydrates)
-Nucleases (e.g., DNase, RNase
what effect does insulin have on protein metabolism?
- stimulates uptake of AA to form proteins by the liver (and other cells).
- inhibits breakdown of existing proteins
how does insulin interact with cellular receptors?
Interacts with tyrosine kinases.
Insulin binds external alpha receptors -> changes conformation of the inner ßreceptor-> these become autophosphorylated which activates a protein kinase on the receptor -> protein kinase phosphorilates IRS (insulin response substrate) -> increases Glut4 and increases cell permeability to K, phosphate and AA
what is the largest cell population of the medulla and what are these analogous to?
what are they innervated by ?
chromaffin cells -> analogous ti sympathetic postganglionic neurons
Innervated by pre-ganglionic cholinergic neurons
what do chromaffin cells secrete?
catecholamines - epinepherine and norepinepherine
explain how chromaffin cells secrete catecholamines?
Preganglionic nerves secrete acetylcholine -> stimulates chromaffin cells -> secrete catecholamines
what are the steps in catecholamine synthesis?
L-tyrosine -> L-DOPA -> Dopamine -> norepinepherine -> epinepherine
Tyrosine hydroxilase which converts L-tyrosine to L-dopa
what is the rate limiting step in the formation of catecholamines
L-tyrosine conversion to L-DOPA by tyrosine hydroxilase
what enzyme converts dopamine to norepinepherine
Dopamine-beta-hydroxilase
what enzyme converts norepinepherine to epinepherine
PNMT
what is the ratio of epi:norepi ?
Species dependent but epinepherine is always more (e.g. dog 70:30)
why is the blood flow through the adrenal gland important in catecholamine production ?
Blood flow from the capsular artery dives through the cortex first and then into the medulla where it drains out of the medullary vein. This is important as cortisol regulates catecholamine production, so blood goes through the cortex fasciculata, picks up the cortisol and then takes this into the medulla where it can help upregulate catecholamine production
what do alpha 1 and alpha 2 receptors do?
Apha 1; vasocostriction, increase glycogenolysis and gluconeogenesis, incrase ciliary muscle contraction (pupil dilation)
Alpha 2; vasocostriction, decrease norepinepherien release, decrease release of insulin and glucagone, increase platelet aggregation
what do ß1 andß2 receptors do?
ß1; increase cardiac contractility and rate, increases renin secretion, increase nerve conduction velocity
ß2 vasodilation in skeletal muscles, bronchodilation, increase glycodenolysis and gluconeofenesis, increase insulin and glucagon
at low concentration what effect does epinepherine have?
What baout high?
Low->ß1
High->ß2
what is a phaechromocytoma?
neuroendocrine tumour of chromphin cells which secrete catecholamines
why do phaechromocytomas have a high
phaechromocytomas catecholamine secretion is highly variabe. Sometimes there is continuous release of catecholamines, other times it is pulsatile, other times a stimulus occurs which causes a large release of catecholamines and it depends if it is mostly norepinepherine or epinepherine
are phaeo usually epinepherine or norepinepherine secreting?
Despite most of the catecholamine being secreted by the normal cells being epinepherine, phaeos are usually norepinepherine.
However, it is possible for them to be epinepherine and in very rare cases they produce only dopamine. Rarely non secretory.
Not so much evidence in vet. Suspect primarily norepi in dogs
Are phaeos unilateral or bilateral? and do they occur in isolation?
90% unilateral, 10% bilateral. Can occur with other neoplasias of the adrenal or other adrenal conditions.
What determines the amount of catecholamine release?
variable but in humans there is a correlation on tumour size and increased secretion - these are highly vascular neoplasias so it is easy for the tissue to remain perfused and secrete more.
What is the growth rate of phaeos?
unpredictable and 50% are locally invasive
what are symptoms dependt on in phaeos?
Size of mass (bigger - more secretion
50% are localy invasive
13-25% are metastatic (lymph node, liver, lung, kidney, spleen, bone , heart)
Is secretion constant vs pulsative
is it primary Norepi or epi secreting.
Signalment for phaeo?
Dog; Older, with no breed or sex predilection
Cat; RARE (case reports).
what are the most common signs with phaeo;
Highly variable, can be continuous symptoms or episodic
Excess catecholamines; Panting, tachypnea, lethary, anorexia, pale mm, acute blindness, tachycardia/arrythmia, pacing, anxiety, disorientation
Tumour; abdominla enlargement, ascities, abdominal pain, hemoabdomen, collapse, hind limb edema, thrombi
Metastatic Dz; Depends on organ affected
what diagnostic changes do you see with phao; list CBC, CHEM and Urinalysis
highly variable
- CBC; stess leukogram, anaemia, high or low PLT most common
- Chem; elevated liver enzymes are the most common (unknown why - possibly due to hypertension and inflammatory cytokine), hypercholesterolemia (catecholamines can induce lipolisis), 20% will be mild-moderate hyperglycaemia (sometimes severe - rare DKA). Hypoalbuminimea.
Urine; proteinuria (suspect secondary to hypertension). Hyposthenuria and isosthenuria seen in ~50% of cases
Why may phaeos cause hyperglycaemia ?
Also, why do some phaes not cause hyperglycaemia?`
Depends on whether they are epinepherine or norepinepherine secreting and how much they secrete. Overall it is down to what adrenergic receptors are stimulated.
alpha 1; increase glucogenolysis and gluconeogenesis
Alpha2; decreases insulin and glucagon release, but this is counteracted by ß2 stimulation causing glycogenolysis and gluconeogenesis, plus these receptors increasing insulin and glucagon
are all phaeos hypertensive?
No, depends on secretory pattern. 50% of dogs with phae in one study had normal BP
Diagnostics for phaeo ?
- Advanced imaging- helps for met check and cardiopulmonary changes
- ultrasound - find mass
Biopsy - can bleed and cause massive catecholamine release so can be risky
cytology - can help identify cortical vs malignancy but not helpful for maligancy
Urine Metanepherine testing (metabolite of epinepherine)
Urine normetanepherine (diagnostic of choice)
What is COMT enzyme in phaes why is this important?
It breaks down norepinepherine into normetanepherine and epinepherine into metanepherine
Why do we test for metanepherine and not epinepherine?
metanepherine is more stable in the blood, while epinepherine has a short half life and secretion is more episodic. If you find a lot of the metabolite breakdown for epinepherine (ie metanepherine) then you can diagnose if epinepherine secretion is increased over time
why is urine noremetanepherine the diagnostic of choice over urine metanepherine?
Norepinenepherine is likely the most commonly secreted catecholamine in phaes (based off humans) and its metabolic breakdown product is noremetanepherine
Gold standard treatment for phaeo?
What can be given pre- gold standard treatment to improve outcomes
- adrenalectomy is treatment of choice.
Prior treatment with phenoyxebenzamine has been shown to improve outcomes
What is phenoxibenzamine?
binds alpha-1 and alpha-2 adrenegrgic receptors (more affinity for alpha-1) blocking them and it is used in the supression of hypertension of phaeo symptoms.
what beta receptors does phenoxybenzamine affect?
none
where does triloastane work and what is this?
Trilostane (vetoryl) is a synthetic steroid analogue that competitively inhibits the enzyme 3-β-hydroxysteroid dehydrogenase within the adrenal cortex.
Inhibition of this enzyme reduces synthesis of cortisol and, to a lesser extent, aldosterone and adrenal androgens
what is a rate limiting enzyme for aldosterone proction, only found in the glomerulosa?
Aldosterone synthase, otheriwse known as CYP11B2
what is another name for aldosterone synthase?
CYP11B2
what are the stimuli for aldosterone secretion ?
How?
- hyperkalaemia; high K stimulates aldosterone by depolarizing the membranes of the zona glomerulosa cells
- RAAS activation; Ang II acts on adrenal cortex to release aldosterone
what is CYP11B2
Aldosterone synthase
what is the role of aldosterone?
regulates blood pressure (vasocostriction and fluid retention) and regulaiton electrolyte (increase Na and Cl retention, K loss, Mg loss), acid base status (H+ lost - exchanged for Na) and intravascular fluid volume.
where does aldosterone act?
principal cells of the distal collecting tubules mainly. Also in the distal convoluted tubule
In primary hyperaldosteronism, what is the negative feedback loop that tries to lower aldosterone?
Renin is reduced in the atempt to stop RAAS
In seconary hyperaldosteronism, what happens to renin?
It is increased, as there is some other factor (heart disease, CKD, hypovolemia etc) which causes renin activation, thus raas activation and increased aldosterone production
what are the most common cause of primary aldosteronism?
Most commonly adrenocortical neoplasait, usually unilateral adenoma or carcinoma.
Adrenocortical hyperplasia may also happen
are tumours that are producing aldosterone also affecting cortisol or androgens?
Not well known. However, there are reoports, esp in cats, where alterations in progesterone secretion also affect cortisol levels as this part of the pathway is shared between the corticosteroids and mineralocorticoids (not androgens though)
Most common signalment for hyperaldosteronism?
Olders cats -no breed or sex predisposition.
Very rare in dogs and mostly documented in case reoports
Common clinical findings in patients with hyperaldosteronism?
Hypolalamia
- Weakness-> hypokalaemic polymyopathy (persistent and progressive and usually seen at K<3mb/dl)
- cervical ventroflexion
- Plantigrade stance at time
- ataxia / weakness
- rarely limb rigidity/dysphagia/collapse
Hypertension;
- blidness/eye colour change -> do fundic exam
-azotemia +/- Pu/Pd
Ie all signs of CKD
when should you test aldosterone levels?
In hypertensive hypokalaemic patients
what is the main differential for hyperaldosteronism
CKD - they also are azotemic, hypertensiove, often olf with Pu/Pd and hypokalaemic
what concurrent disease may you see with hyperaldosteronism?
diabetes melitius, ckd
hypokalaemia can cause nephrogenic diabetes insipidus via downregulation of acquaporin 2 channel or mineralocorticoid induced resistance to AVP
Aldosterone:renin -> high aldosterone low renin (uncommon test)
Aldosterone:creatinine ratio -> wide refernace range and not sensitive (uncommon test)
what diagnsotics should you perform for hyperaldosteronism
minimum database + T4 and BP
Mostly diagnosed on US. CT used for planing.
How do you medically treat hyperaldosteronism?
What is the gold standard tx though?
Big 3 medications;
- spironolactone
- Bp measurement (usually amlodipine - remeber renin is reduced so ACEi is not so useful
- K supplementation
Surgical removal of the adrenal tumour
Why is spironolactone given to cats with hyperaldosteronism?
It is an aldosterone receptor blocker, so it causes K retention and increased secretion of Na, Cl, P. Acts on the distal renal tubules luminal membrane
Why is amlodipine prefered over ACEi for the control of BP in hyperaldosteronism?
1) Renin is downregulated via negative feedback from increased aldoseterone levels. Thus there is little Ang I-> Ang II conversion so ACEi will be innefective at controlling BP
2) often these patients are azotemic and have an AKI from the hypertension
how does amolodipine affect blood pressure?
Dihydropiridine L-type Ca channel blocker in cardiac and vascular smooth muscle. The L-type though are more commonly found in afferent arterials and the vasculature in general. Thus is has a greater affect in dilating peripheral vessels
which drugs used can cause this
Amlodipine and cyclsporine cause gingival hyperplasia
what are the 5 cell types of the islets of langerhans?
Which ones are the acini?
1) alpha
2) beta
3) delta
4) gamma
5) epsilon
Tha acini are none of those. Those are exocrine pancreatic glandular cells while the islet cells are the endocrine pancreatic cells
what are the 3 roles of glucagon in response to low BG ?
1) Insulin antagonism
2) glycogenolysis -> break down glycogen into glucose
3) Gluconeogenesis -> make glucose from AA and FA
why are ketones produced when glucagon is excreted?
Fatty acids are oxidised to ketones as an energy sorce.
what are the 3 main ketones found in the body?
Acetone - breath ketones
Acetoacetate - urinary ketones
D-ß-hydroxybutyrate - blood ketone
what supresses glucagon secretion?
1) insulin
2) Amylin
3) glucagon like peptide 1 (GLP1)
what are tumours of alpha cells and what are the sings?
Glucagonoma
This is a rare type of cancer;
Clinical sings;
- Superfical necrolytic dermatitis
- Hyperglycaemia
- Small intestinal diarrhoea
what is a differential for this?
This is superficial necrolytic dermatitis which is a symptom seen in glucagonomas
what is the structure of insulin during formation by ß-cells?
Preproinsulin (signal sequence + proinsulin) -> proinsulin (A&B segments bound by disulfide bonds + C-peptide) -> Insulin (A&B only)
What physiological factors induce the synthesis and secretion of insulin
- increased [glucose]
- other nutrients (Fa’s and AA’s)
- incretins
- ACh
- xylotol
in what section of the cell is preproinsulin modified to insulin
Like other hormones;
Preproinsulin looses signal peptide in the endoplasmic reticulum leaving proinsulin
Proinsulin looses the c-peptide in the Golgi.
Insulin is packed into vescicles waiting for release
what is the carrier protein for insulin and why is this improtant?
it does not have one. That is why it has a short half life of 3-10 min
where is insulin degraded and how what is the half life?
Live and T1/2 is 3-10min
what are the main types of glucose transporters, where are they found, and what are special features of each?
Glut1; brain, RBC, fetal tissue-> insulin indipendent so glucose passively diffuses into the cell (except satiety center which is insulin dependent)
Glut2; ß-cells, liver, renal tubules, interstinal epithelium. These are insulin independent (glut 2 are the ones whcih depolarise the memrbase and allow insulin release from ß cells)
Glut 3; found in neurons and sperm and is also insulin indipendent
Glut4; skeletal muscle and adipose tissue -> INSULIN DEPENDENT
most of the brain has insulin indipendent glucose transporters. Which are these ?
and what is the secotion of brain that has insulin dependnt glucose transportters?
The brain has GLUT1 while the CNS has GLUT3 insulin indipendent transporters.
The one exception is the satiety center which has GLUT4 insulin dependent transporters
why are diabetics polyphagic?
The satiety center needs insulin to allow glucose into the cell, thus with the lack of insulin or resistance, the brain cannot detect that there is glucose and drives the patient to eat
what inhibits glut4
cortisol
How is insulin released from ß-cells
Glucose binds to GLUT2 allowing glucose to enter-> increased ATP -> increased [ATP] causes K channels to close -> depolarises the cell causing Ca voltage gated channels to open -> increased [Ca] causes the insulin storage granules to fuse with the cell membrane releasing insulin
how much insulin is primed for relase and how much is in reserve?
1% primed for release
99% in reserve
what are sulfonourea drugs?
What do they do and what is an example?
oral drugs for diabetics which bind to Kir subutin of the K ATP channel. This will cause closure of this channel inducing the cell to depolarise and release insulin.
An example is Glipizide
what is diazoxide?
It is a drug that binds to the Kir subunit of the K ATP sensitive channel on ß islets causing desensitization of the channel to ATP making it less likely to close with increased intracellular glucose concentration, and therefore, depolarize the cell. This reduces insulin release
what does insulin stimulate in the body?
1) Binds GLUT4 allowing glucose into skeletal musle and adipose tissue
2) Stimulates glycogenesis
3) stimulates lipogenesis
4) stimulates protein synthesis from amino acids in the blood stream (not by extracting them from muscle cells)
5) promotes cell K uptake
IT essential induces the formation and storage of all enegy sources
What does insulin inhibit in the body?
1) gluconeogenesis
2) glycogenolysis
3) hormone sensitive lipase
4) protein degradation (proteolisis)
5) ketogenesis
Essentially inhibits all energy storage form breakdown and alternative energy pathwyas
what are insulinomas?
predispositions and clinical findings?
tumours of ß cells that secrete insulin resulting in episodic hypoglycaemia
Most common in large breed dogs and pomeraneans.
Insulin concentrations are high, BG often low (which is the opposite of what it shoudl be) , ketones can be high.
Clinical signs are often chronic (1-3 months) and include seizures, collapse, weakness, muscle twitchin and ataxia
is you have a high insulin level and low BG what is a leading differential and why>
Insulinoma. Normally, low BG will have LOW insulin and HIGH glucagon, as insulin release is due to high glucose and promotes storage of energy sources. Insulinomas are insulin secreting tumours, so insulin is high and they force all of the glucose into the cell making BG low
How do you diagnose an insulinoma?
Bloodwork -> Low BG and HIGH insulin (key)
CT - most sensitive (90%)
what is the prefered imaging modality for insulinomas and why?
CT - most sensitive (90%)
Aus - not very sensitive (30-75%)
How do you differentiate an insulinoma from normal pancreatic tissue on a CT?
Insulinomas hyperattenuate on the arterial phase, while pancreatic tissue has normal attenuation
recommended treatment for insuloma?
Other available treatments
surgery recomended
Other;
- Steroids
- Octreotide (somatostatin analogue)
- diazoxide (inhibit insulin release by Katp dependnt channel inhibiton)
- Stroptozoxin (cytotoxic to ß cells)
- palladia
Is insulinoma malignant?
yes - 50% have metastasis based on a 2021 study
median survival with medical management for insulinoma?
What about with surgery ?
8 months for medical
20 months for surgery (OVERALL survival -most had regional mets, 15-20% had distant mets)
Unknown median with mets - Hz ratio 1.7 so more likely to die sooner but had better survival compared to medical alone.
Based on a 2021 study of 116 dogs with insulinoma.
What species similarities are there in the amino acid sequence for insulin
Cats most similar to cow (one aa difference to cow but 3 to dogs and 4 to human)
Dog/human most similar to pig (one aa difference)
what other hormon is secreted by ß cells with insulin and what does this do
they co-secrete amylin
Amylin decreases glucagon secretion, delays gastric emptying and suppresses appetite.
What toxicity can amylin cause and in what species?
In cats and primates, amylin can aggregate into amylin fibrils which are toxic to ß-cells
what do Delta cells secrete?
What does this do?
What other site secretes it?
Somatostatin, which inhibits other islet hormomes, decreases GI and gallbladder motility, decreases absorbiton and secretion in the GIT
It is also secreted by the GIT
what is the overall job of somatostation?
to shut down everything. Gallbladder secretion, GIT motility and islet secretions
what are somatostatinomas?
How common?
What do they cause ?
Extremely rare tumours of the delta cells of the pancreas which secrete somatostatin.
Somatostatin SHUTS it DOWN
- hyperglycaemia (decreased insulin secretion)
- Cholelithiasis (decreased bile and GB emptying)
- Small intestinal diarrhoea (decreased pancreatic enzyme and bicarb secretion
what role do delta cells have in foetal development and what tumour can occur in these cells becuase of this role?
What are the clinical consequences of this tumour?
They produce both somatostatin AND Gastrin during foetal develoment.
You can get gastrinomas in the pancrease which results in severe gastric acid hypersecretion -> Zollinger-Ellison Syndrome
what is Zollinger Ellison Syndrome?
Severe gastric acid hypersecretion caused by a gastrinoma in the pancreatic delta cells
what are ocretodide and pasireotide?
What are they used to treat?
these are somatostatin analogues
- Acromegaly -> inhibits GH
- Insulinoma -> inhibits insulin release
- Gastrinoma -> inhibits gastrin release
What are 3 diseases where we would use somatostatin analogues?
what are two somatostatin analogue drugs
- Acromegaly -> inhibits GH
- Insulinoma -> inhibits insulin release
- Gastrinoma -> inhibits gastrin release
Two analogues are OcretoTIDE and pasireoTIDE (the blocks the tide from coming in)
what do epsilon cells secrete and when?
What does this do?
Secretes Ghrelin in response to an empty stomach -> increases appetite (orexigenic), body weight, gastric motility and gastric secretion
It also supresses insulin release and decreases fat mobilisation
what are the major sources of Ghrelin synthesis in the body?
Stomach is the major source
Epsilon cells of the pancreas are a minor source
what inhibits ghrelin?
fatty meal or gastric dilation
what is orexigenic mean
stimulates hunger
what are PP cells of the pancreas?
what do these do?
AKA F-cells
Secrete pancreatic polypeptide in response to protein means and vagal stimulation.
This does the following;
major
- inhibits gallbladder contraction
- inhibits pancreatic enzyme and fluidsecretion
minor’
- stimulates glucocorticoid secretion
- modulates gastric acid secretion and GI motility
- Reduces appetite and food intake
what is another name for PP cells of the pancreas?
F cells
what is the role of progesterone in insulin function and what common disease can this cause?
Progesterone stimulates growth hormone release and GH is an insulin secretion inhibitor
During pregnancy (diestrus), progesterone spikes, this causes growth hormone to spike and can lead to gestational diabetes (in DOGS not humans- that is different)
How does cortisol cause diabetes (ie how can cushings cause diabetes)?
It inhibits GLUT4 translocation to the cell membrane resulting in insulin resistance. Additionally it promotes gluconeogenesis which increases BG
how can catecholamines cause diabetes
1) inhibit insulin release
2) cause glucogenolysis
3) cause gluconeogenesis
4) cause lipolysis
All of which increase BG
What are incretin hormones?
These increase insulin secretion and sensitivity.
These are Glucose-dependent Insulinotropoc Peptide (GIP) and Glucagone-like Peptide 1 (GLP1)
what do incretin hormones do and what are examples of these?
Examples are; Glucose-dependent Insulinotropic Peptide (GIP) and Glucagon-like Peptide 1 (GLP1)
These;
- Increase glucose dependent insulin secretion
- increase insulin biosynthesis
- decrease glucagon decretion (glucagon inhibits insulin)
- increases receptor sensitivity to glucose
- inhibit apoptosis and stimulate proliferation of ß-cells
where are GIP and GLP-1 secreted?
secreted in the endocrine cells of the small intestine
what is type 1 diabetes and is it reversible?
Type 1 is the charachterised by ß-cell destruction and results in an absolute insulin deficiency.
IT is not reversible as the cells have been destroyed
causes of type I in people
- 98% are autoimmune - infiltration of ß islets by lymphocytes and there are antibodies against islet cell antigens or insulin
In autoimmune type I diabetes, what are examples of antigens towards which antibodies are created?
- GADA (glutamate decarboxylase)
- IAA (insulin)
- IA-2 (islet antigen)
- ZnT8 (zinc transporter 8)
Dogs tend to develope which form of diabters?
Type I - not much evidence for autoimmunue. There are vacuolated cells, suggesting ß-destruction, but there is not usually evidnece of lymphocytic infiltration
Occasionally pancreatitis and pancreatic neoplasia can cause ßislet apoptosis
If you are not overweight, and have insulin resistance, why may you not have diabetes.
have to have 2 things for type II diabetes ;
- peripheral insulin resistance
- some degree of ß-cell destruction
If you are normal, with a healthy pancreas and have some degree of insulin resistnace, you will end up with a hypersecretion of insulin as the pancreas is trying to let that glucose into your skeletal muscle and adipose tissue. This is normal and how you overcome diabetes
But the type II cannot compensate so they must have some loss of ßcells
why do horses never become diabetic
They develope insulin resistance, however, they do not loose ß-cells so they are able to hyper-secrete insulin to overcome the resistance.
what is type II strongly associated with
Obesity
Fat inhibits insulin signaling and causes peripheral insulin resistance.
which form of diabetes is reversible?
And what stage must it be addressed to allow for reversal?
Type II insulin resistant (type I has ß cell destruction so it cannot be reversed).
It has to be treated early on in develoment before ß-cells are lost. If you do not treat it early you get glucotoxicity whereby the chronic hyperglycaemia causes ß-cell apoptosis
what are the components of glucotoxicity?
Chronic hyperglycaemia causes;
- impares insulin secretion
- downregulates insulin receptors
- impairs glucose transport
Additonally you get the formation of advanced glycation end products (AGE) which cuase glucose autoxidation, formation of glucosamine and increased oxidative phosphorilation which reads to the production of Reactive Oxigen Species (ROS)
what do you see on histo of the ß islets in cats?
islet amyloidosis
how is insulin sensitivity quantifiably associated with weight in cats?
For every 1Kg of weight gain, there is a 30% reduction in insulin sensitivity
what does islet amyloidosis look like in dogs?
Dogs do not get islet amyloidosis - only cats with type II diabetes
what form of diabtes causes islet amyloidosis and in what species?
type II - only in cats and primates
if you have islet amyloidisis in an old cat histo of ßcells, what type of diabetes would it have?
maybe type II - but old cats can develop this in the abscence of diabetes
is obesity a risk factor for diabetes in dogs?
what pecularities are there with diabetes and weight in dogs
Obesity is an increased risk factor
you will see insulin resistnace but most can appropriatelly compensate for this by hypersecreting insulin.
how common is hypersomatotropism in diabetic cats?
1 in 4 (25%)
What is hypersomatotrophisms and how is it associated with diabetes ?
pituitaty adenoma which secretes growth hormone. Growth hormone causes insulin resistance and the release of Insulin-like Growth Factor 1 (IGF-1)
why do acromegalic cats have large faces?
Acromegaly is secretion of growth hormone from a pituitary adenoma. GH increases the release of insulin-like Groth Factor 1 which causes overgrowth of bones, resulting in protrusion of the mandible and broadenign of the face
are hypersomatotrophism or acromegaly the same thing?
Hypersomatrophism is the increase release of growth hormone, however, it can occur in the abscence of clinical signs.
Acromegaly is hypersomatrophisms once we start seeing the sings of face broadening and mandible protrusion
What does excessive IGF-1 cuase?
Bone growth and broadening of the face and mandible protrusion
organomegally (hepati, pancreatic etc)
hypertrophic cardiomyopathy
If you have a diabetic cat, what test can you run to rule out hypersomatotrophism?
IGF-1. If this is normal then they are just diabetic, if high, hypersomatotorphic with the diabtes possibly being secondary to the hypersomatotrophism
when is the best time to check a cat for hypersomatotrophism? why?
at the time of the diagnosis of diabetes.
Once you start treating them IGF-1 can drift up and you can end up in a grey some where it overlaps with the diagnosis of acromegaly
If IGF-1 is high, which is the next step?
CT as this has a sensitivity of 94%
why can hypersomatotrophysim complicate the treatment for diabetes?
These cats may beed 10-20x the normal insulin dose due to resistance. This can be challenging to administer and expensive
what are the treatment options for hypersomatotrophism?
If the cat is diabetic, what changes do you expect?
- Surgery (gold)
- Radiation
50-85% of Diabetes cases should go into remission bit it can take weeks to months.
what percentage of cats treated for hypersomatorophysm will go into remission?
what is the timeline
50-85% of Diabetes cases should go into remission bit it can take weeks to months.
what changes do you expect in IGF-1 when hypersomatotrophism is successfully treated?
It often does not change - we do not know why
IF a cat which is successfully treated for hypersomatotrophysism, but its diabetes does not resolve, what changes in insulin requirements do you expect?
Pre treatment HST cats may need 10-20x the insulin dose. This dose requirement should improve post treatment
what changes do you expect in fructosamine levels post successful treatment of a hypersomatotrophic cat whose diabetes has not gone into remission?
The frutosamine levels usually improve
when treating hypersomatotrophism what should you warn owners about in regards to the diabetes management?
50-85% will go into remission, however, even those that do not, their diabetes should become more manageable through insulin dose reductions
what is pasireotide?
IT is a long acting somatostatin analogue which is give SQ once monthly in catrs with hypersomatotrophysm and diabetes. This causes IGF-1 reduction and reduced insulin requirement. In the trial 3/8 cats went into remssion. Diarrhoea was a common side effect.
It is prohibitively expensive (16,000$ per month)
what is cabergoline?
it is a dopamine agonist with a high affinity for dopamine receptor 2 which is in the pituitary of cats with hypersomatotrophysim and diabetes. 35% of cats achieved remission in 6 months. Given Po q48h and is affordable
Most cats had small pituitary tumours though (3-4mm RI 3m), but many with bigger ones did not responde
what is dostinex
carbergoline -> dopamine receptor 2 agonist for the treatment of hypersomatotrophism and diabetes
what percentage of dogs with hyper-A have diabetes?
14%
But many dogs treated with trilostane will have mildly elevated BG and giving them insulin reduces the risk of them going into diabetes
why are dogs with hyperadrenocorticocism more likely to develop diabetes?
Cotisol increases insulin resistance, and increased gluconeogenesis increasing BG which will result in increased insulin release and increased risk of glucotoxicity
what are key considerations when considering potency and duration of action of insulin?
more potent the shorter the duration of action
what is the potency and duration of action of the following;
- glargine
-prozinc (PZI)
- Vetinsulin
- Regular
- neutral protamine hagedorn (NPH)
- glargine -> long acting, low potency
-prozinc (PZI) -> medium acting and medium potency - Vetinsulin -> medium acting and medium potency
- Regular -> potent, short acting
- NPH -> intermediate portency and time of duration (dogs - very short in cats)
what is humilin?
onset and duration of action?
regular insulin
-IV, onset immediate, duration 1-4h, hence best given as a CRI
- IM, onset 45min, duration 3-8h
- SQ not given, unpredictable potency and duration
Higher potency = lower dose needed
Appart from regular insulin, which are appropriate for DKA treatment?
- Lispro; dog and cat
- Glargine; cats
- Aspart; dogs
what is the DKA glargine protocol
- protocol involves a combo of SQ and IM (initial is SQ, then 4h later start IM and give q4h IM and ontop SQ every 12h
what type of insulin of vetinsulin?
What are key charachteristics of note when administering this?
Porcine lente insulin - intermiediate acting U40 (not U100). mixed in supernate so has to be shaken and has biphasic peak in dogs due to the supernate
Start 0.25U/Kg q12h dogs
How do NPH and vetsulin compare in dogs?
If not responding to one do you switch to the other?
Similar
Both reach glycaemic control in 60-70% of patinets.
Nadir for NPH is 2-4h while vetinsulin is 4-6h.
Can try, should not make a difference.
how does accuracy compare between vet pen and syringe?
pens slightly underdose, although syringe commonly overdose, especially at high doses
Pens are more precise at low dose (esp <1U) but higher dose the precision drops with these too and can become comparable to syringe
Protamine sinc insulin (PZI, proZinc) is used in what species and what characteristics need to be considered for administration?
It is for cats, and one of the top choices. Unpredictable in dogs.
Start at 1IU/Cat q12h.
ROLL to MIX
Glargine (lantus) is used in what species and what characteristics need to be considered for administration?
Long acting u100 recombinant insulin.
soluble at acidic pH and precipitates at a neutral pH (upon SQ injection) which allows for slow absorbtion. Has a long duration and a peakless effect
Start at 1U/cat q12h
No mixing needed
Top choice for cats. Highly variable in dogs (high risk for subclinical hypoglycaremia)
what changes are there in glargine compared to human insulin?
3 changes;
- Change of A21 asparagine -> glycine
- 2 extra arginines at B31 and B32
Insulines are named for their changes
Gl ->glycine
ARG -> arginine
=GL-ARGine
what is a risk of using glargine in dogs?
can cause sub-clinical hypoglycaemia at recomended dose
what is Toujeo?
How do you start this or transition this?
It is a U300 glargine for dogs- longer duration of action and less day to day variability. But it is less potent
New diabetics; start at 0.5U/Kg q24h
Transition from other; use current q12h insulin dose x1.33 to determine q24h dose
what is detemir?
Human recobinant u100 lysine. Forms a hexamere at the injection site and ireversibly binds to albumin prolonging duration of action.
Good for cats. Also an option for dogs if NPH and Vetinsulin does not work (or Torjeo). Can also cause subclinical hypoglycaemia in dogs
0.1U/kg for dogs so can be hard for small dogs
what is degludec
U100 and U200 insulin, also forms a hexamere, but very expensive so not used often
what are ultra-long acting insulins and what are their charachteristics in dogs and cats
These are recombinant fusion proteins of synthetic insulin and canine or feline FC. FC the fragment crystallizable region of immunoglobulins which allows for the extended half life allowing them to be once weekly injections.
what is bexagliflozin?
this is Bexacat, a tablet oral feline insulin. It is a SGLT2 inhibitor.
should not be used in cats that are already on insulin. There is a large list of contraindications
What are SGLT2 inhibitors?
(Bexacat -ie Bexagliflozin) these inhibit the SGL2 channel in the proximal tubule. The SGL2 channel is the one which re-absorbs glucose and these help prevent glucotoxicity
you have glucosuria while on a SGL2 inhibitor. What actions should you take?
Determine if they are type I or II diabetic?
If they are type I they should not be on SGL2.
Next, check BG. If normal do not worry. SGL2 inhibitors prevent glucose reabdorbtion in the proximal tubule (more lost in urine) to help prevent glucotoxicity
why should you not use bexagloflozin in type I diabetics or those which have had DKA
Because it will increase glucose loss in the urine. The cells cannot take in the glucose as there is no insulin, but they actually need the glucose.
Ketotic patients are producing ketones because they do not have enough glucose, and if we give Bexacat to them, we will decrease the amount of glucose available for them to uptake when they do get given insulin
waht are GLP-1 inhibitors
Incretins –> these increase insulin secretion and may reduce glycemic variability in cats
What is sulfonylurea (glipizide)
increase insulin secretion by closing the K-ATP channels allowing the ß cells to depolarise more promptly. However, these can cause disease progression (increase insulin exposure > desensitization) and amylosis in cats. Also risk for cholestasis, vomiting and hypoglucaemia
What is metformin?
Biguanides - inhibit glucose release/gluconeogesis and increase insulin secretion. They also reduce cholesterole, triglyceride and glucose concentration in dogs with hyper-A
what is arcarbose
drug that reduces glucose abdorbtion
why may vanadium and chromium be given in a diabetic patient
Increase insulin sensitivity
what are the priorities for diabetic dog nutritional management?
priority is to feed a balance diet 2x daily paired with insulin.
The formulated diets have a lot of fiber and complex carbs and they can lead to weight loss which is good in the overweight but not those which are thin - should be avoided in these patients
what are the priorities for diabetic cat nutritional management?
what macronutrient breakdown do you want the food to have?
weight loss and low carbohydrate diet is critical. Low carb diets are associated with remission and longer survival.
Carb 12% (most normal are 40%)
Protein 40%
Fat 48%
what is the key target for glycaemic control
prioritise clinical sign resolution over the curve, especially if you only have one day of data.
If the patient feels good and the curve has a massive BG drop, then you will need to address this even if the patient feels well.
If the curve looks great but the patient is clinical then keen treating until the clinical sings are gone.
what methods are there to determine the glucose curve?
In hospital day curve
Free style libre - great in stable
if you have a free style libre reading which is suggesting hyperglycaemia, how do you respond to this?
If the patient is asymptomatic then you do not need to address this. Could be just the innacuracy of the device, but they are also feeling well so we do not change
what is the most common complication of a libre in a cat?
cats knock them off or the sensor fails 40-80% of the time
how long do you aim to leave the freestyle on for?
hopefully 2 weeks
when comparing free style to pinna or other blood sumples, what are the benefits and cons of a freestyle?
Freestyle is more likely to catch nadirs and hypoglycaemic events as the in hosptial curves will miss these if they are outside of the hospitalised periods.
At which Bg do you start reducing insulin dose on a glucose curve if the patient is non clinical
50mmol/l
Can tollerate 50-60 if it is occasional and short lived
when is glucose the higher in dogs? why?
insulin is under circadian control - dogs tend to run a little higher overnight (1-6am on average)
what is fructosamine?
When should this be used?
product of irreversible glycosylation of plasma proteins. Reflects mean BG of the preceding 1-2 weeks. Individual trends are more improtant than lab reference range and only has moderate correlation with control .
Useful in cats to confirm diabetes and rule out stress hyperglycaemia
Being replaced by freestyle, but good in those where owner doesnt want to pursue libre / patient not tolleration / not much sq space so sensor doesn’t work well.
Used in those which you see infrequently, owners think they are doing ok or do not. If it comes back similar to prior, great, if singificantly higher then you have to curve
what factors can influence fructosamine?
- False results with low or high serum proteins (e.g. PLE/PLN etc)
- hyperthyroidism lowers fructosamine (increases protein turnover)
- positively correlated with body weight so massive changes can change results
- male cats run slightly higher than female
you have a high frusctosamine level in a cat, what does this tell you if it is a newly diagnosed and when it is a recheck>
Newly diagnosed -> can confirm diabetes and rule out the change being stress hyperglycaemia
Recheck - have to compare to prior. IF same, patient non clinical, then diabetes is controlled. If higher, diabetes is apparently controlled, you need to curve (owner maybe nonobservant or dumb). If clinical and high, doesnt matter what the fructosamine says, you need to treat to resolve clinical sings.
what is glycated haemoglobin A1C test?
what does it detect?
Similar to fructosamine test. Reflects average glucose over previous 2-3 months.
Glucose irreversibly binds to the amino-terminal group of haemoglobin HbA1c, thus can help detect chronic hyperglycaemia
what is the chance of a cat goning into diabetic remission and wht is the relapse rate and over what time frame?
25-50% go into remission
30% relapse over 9 months
what are positive predictors of diabetic remission?
- New diabetics (shorter duration)
- recent corticosteroid therapy (maybe partially iatrogenic - big thing)
- Older age
- Lower insulin dose
- lower mean glucose contration during treatment - ie doing well
what are negative predictors of diabetic remission?
- hypercholesterolemia
- diabetic neuropathy
how do IGF-1 levels and DKA predict likelyhood of remission
They do not predict anything
complications of diabetes?
Dogs;
- cateracts; 50% by 6m and 75% by 12m -can reduce with good glycaemic control
Dog and cat
- bacteruria; often subclinical
- proteinuria; no known clinical consequences
how does diabetes cause caterachts and why don’t we see chateracs in most diabetic cats?
what is a subpopulation of cats which will form cateracts?
It is rare.
Glucose is metabolised to sorbitol by aldose reductase in the lens. This is then converted to fructose. These pull water into the lens causing diabetes
Older cats >7yo are defficint in aldose reductase. You will as a reuslt only see caterachts in juvenile diabetes
if you find bacteruria in a diabetic animal when should you culture and treat?
How long do you treat for?
If non clinical you do not need to culture or treat.
If clinical culture, treat as per usual. You do NOT need to give a longer course
why is proteinuria common in dogs and cats with diabetes?
How do we treat this
membraneous glomerulonephropathy with fusion of the foot processed, glomerular and tubular basement membrane thickening, subendothelial deposits, fibrosis and sclerosis occur. This prevents re-absorption
We do not treat unless we think there is a glomerulonephropathy which is not associated with diabetes
Prognosis for diabetes?
Good.
Highest mortality in the first 6 months while trying to gain control
majority of total body calcium is found within the _____________ as ___________
bone as hydroxyapatite crystals
What percentage of total body calcium is found in…
- Extracellular fluid (ECF)
- Intracellular (ICF)
- Bone
Approximately 0.1% of calcium is in the extracellular fluid (ECF). 1% is in cellular organelles. 98.9% is stored within bone.
Amajority of total body phosphate is found within the _____________ as ___________
bone as hydroxyapatite crystals
What percentage of total body phosphate is found in…
Extracellular fluid (ECF)
Intracellular (ICF)
Bone
Extracellular fluid (ECF) - <1%
Intracellular (ICF) - 14-15%
Bone - 85%
What percentage of ECF calcium is found as…
- Ionized Ca
- Protein-Bound Ca
- Complexed Ca
Ionized Ca - 50%
Protein-Bound Ca - 40%
Complexed Ca - 10%
T/F: The terms “hypocalcemia” and “hypercalcemia” are reflective of intracellular calcium concentrations.
FALSE - these terms indicate relative concentrations of extracellular calcium.
hat changes in skeletal muscle and neuronal hyperexcitability can we expect with HYPOcalcemia? HYPERcalcemia? Why?
Hypocalcemia - INCREASED excitability producing clinical signs of facial pruritus (humans report tingling and numbness), tetany (twitching, tremoring), and seizures.
Hypercalcemia - DECREASED excitability producing clinical signs of PU/PD, weakness, hyporeflexia, depression, and constipation.
When calcium concentrations fall below normal, the neuronal permeability to Na ions increases. This allows the central nervous system and peripheral nerves to become easily excitable and fire an action potential.
why do you see uncontrolled tremmoring and/or facial priritis in hypocalcaemia?
When calcium concentrations fall below normal, the neuronal permeability to Na ions increases. This allows the central nervous system and peripheral nerves to become easily excitable and fire an action potential.
What changes would you expect to see in ionized calcium Ca+2 concentration in acidemia? Alkalemia?
Albumin has a set number of binding sites for positively charged cations (H+ and Ca+2). Therefore, if you have excessive H+, more of the sites will be taken up by H+.
Therefore, acidemia causes shifting of the protein-bound to ionized-form. In acidemia, you will have an INCREASED ionized calcium.
In alkalemia, you will have a DECREASED ionized calcium because you have a deficit of H+ in the blood and more of those binding sites will be available for calcium to bind.
Calcium and phosphorus are both absorbed from the __________ and excreted in the __________.
gut and urine
What percentage of calcium and phosphorus are absorbed from the gut?
Phosphorus is actually absorbed well - nearly 100% of dietary phosphorus is absorbed by the gut.
Calcium is absorbed poorly through the gut. Only 35% is absorbed, rest lost in the faces
how is calcium absorbed in the gut? how effictive is this pathway?
Calcium is absorbed poorly through the gut. Vitamin D promotes calcium absorption via formation of calbindin by the intestinal brush epithelium. Even with calbindin binding calcium and enhancing facilitated diffusion, only 35% of dietary calcium is actually absorbed. The rest is excreted in the feces!
how much of the injested Ca is secreted by the kidneys in the urine and what component (Ica, protein bound or compexed Ca)?
10% of ingested Ca is excreted by the kidney, but only 1% of all calcium is lost
Plasma-protein bound calcium cannot be filtered through the glomerulus. The remainder of anion-bound and free, ionized forms are filtered into the tubular lumen.
where is Ca reabsorbed by in the kidney ?
90% proximal tubule and loops of henle
10% late distal tubule and collecting ducts
what hormone mediates renal re-absorbtion of Ca and in which segments of the kidney?
PTH
90% proximal tubule and loops of henle
10% late distal tubule and collecting ducts
How is phosphate secreted and re-absorbed ?
secreted by overlflow. If hypophosphatemia ensue then all P is reabsorbed
Calcium homeostasis is achieved through the actions of three hormones:
Parathyroid hormone
Vitamin D
Calcitonin
PTH is stimulated by _____________ in extracellular calcium.
Stimulated by decreases in extracellular calcium (hypocalcemia).
where does PTH act upon to increase Ca concentration in hypocalcaemia?
Bone (increase release of calcium salts from resevoid)
Gut (increase absorbtion)
Kidney (increased re-absorbtion_
How many parathyroid glands are there
4
how is hypocalcaemia detected and what occurs when this is?
Hypocalcemia is detected by the calcium sensing receptors (CaSR) within the parathyroid glands.
Chief cells within the parathyroid glands will produce parathyroid hormone (PTH) in response to hypocalcemia.
PTH has direct and indirect effect. Define these
Rapid Phase - Osteolysis (DIRECT)
- PTH binds to receptors on OSTEOBLASTS and OSTEOCYTES.
-These cells are connected cell-to-cell by long, filmy processes.(osteocytic membrane system).
- When PTH binds the receptors, it causes activation of osteocytic membrane pumps that shuttle soluble calcium ions from the bone fluid (intracellular fluid of the osteocytic membrane system) → extracellular fluid.
- This causes a rise in extracellular calcium within minutes to an hour!
Slow Phase - Osteolysis (INDIRECT)
- PTH binds to receptors on osteoblasts that release two molecules (Receptor Activator for Nuclear Factor kB Ligand - RANK L) and (Macrophage Colony-Stimulating Factor - MCS F) that bind to preosteoclastic cells and aid in their maturation / differentiation process.
- The mature osteoclasts then develop a ruffled border and release enzymes and acids that promote bone resorption.
during maintance phase (normocalcaemia) how does the body prevent excessive bone re-absorbtion?
How does PTH prevent this?
In normal “maintenance” phase of calcium homeostasis, osteoblasts send a signal to osteoclasts to decrease osteolytic activity. The name of this signaling molecule is Osteoprotegerin (OPG). It will bind to RANK L and prevent maturation / differentiation of osteoclasts. PTH prevents the secretion of OPG!
PTH will __________ the rate of tubular reabsorption of calcium, and __________ tubular excretion of phosphate.
INCREASE and INCREASE
what are the 2 forms of vitD in food?
where are these synthesisded from and which is more bioavailable
D2 and D3 which are Vit-D pro-hormones.
D2 (synthesized from ergocalciferol) - found in plant sources (ergot it a plant)
D3 (synthesized from cholecalciferol) - found in animal sources (fish oil, egg yolk, butter, liver, etc.)
D3 is generally more bioavailable compared to D2
Both Vitamin D2 and D3 are prohormones. In which organ are they first activated? By which enzyme class? What is the product?
what about the second organ, enxyme and what product
First
Vitamin D2 / D3 are hydroxylated at C25 in the liver by the cytochrome P450 family of enzymes.
The result is 25-hydroxyvitamin-D (25 (OH) D)
Second
25(OH) D is hydroxylated into the hormonally active 1,25(OH)2 D (calcitriol, 1,25 dihydroxyvitamin D) within the proximal tubule of the kidney.
The enzyme responsible for this enzymatic reaction is 1-alpha-hydroxylase.
What are mediators of 1-alpha hydroxylase activity? For example, what increases and decreases its activity?
- PTH - INCREASES activity
- FGF-23 - DECREASES activity
- 1,25 (OH)2 D3 - DECREASES activity (negative feedback loop)
Vitamin D Receptor (VDR) is present in most cells of the body. 1,25 (OH)2 D3 is a _________ hormone and therefore, the receptor is located __________ the cell.
Vitamin D Receptor (VDR) is present in most cells of the body. 1,25 (OH)2 D3 is a steroid hormone and therefore, the receptor is located within the cell (primarily the nuclei)!
Vitamin D receptors have two specific binding sites. What are these for?
Vitamine D is a steroid hormone, so it crosses into the nucleous where it binds the vitamin D receptor, while the second then binds DNA allowing fro gene transcription
where is calcitonin produced an what is the role of this?
Secreted by the thyroid gland, specifically the parafollicular (C-cells) in the interstitium between follicles.
Its overall effect is to respond to high levels of extracellular calcium, and decrease extracellular calcium.
which hormone antagonizes PTH
calcitonin as this decreases extracellular calcium
what is calcitriol?
tablet version of 1,25-dihydroxycholecalciferol
what are examples of CONGENITAL vitamin D disorders?
How are these inherited and how common?
Test available?
Very rare - case reports only
Due to enzymatic or receptor deficiency
Autosomal recessive inheritance
Not related to diet
Can be classified in three main types:
1) Vitamin D Dependent Rickets Type 1B-> affects CYP2R1 which results in a lack of 1-alpha-hydroxylkase (convers D3 ->25 (OH)D
2) Vitamin D Dependent Rickets Type 1A -> CYP2B1 defect which convers 25 (OH)D to 1,25 (OH)2D in the kidney
3) Vitamin D Resistant Rickets Type 2A ->Affects vitamin D receptor in the GIT and bones making this Vit-D resistant rickets
Genetic test available for pomeranian dogs
with vitamin D dependent rickets 1A, what abnormal biochem findins do you see?
Hypocalcemia
Hyperphosphatemia
PTH ↑
25 (OH) D Normal (deficiency blocks next enzyne
1,25 (OH)2 D ↓
with vitamin D dependent rickets 1B, what abnormal biochem findins do you see?
Hypocalcemia
Hyperphosphatemia
PTH ↑
25 (OH) D ↓
1,25 (OH)2 D ↓
with vitamin D dependent rickets 2A, what abnormal biochem findins do you see?
Hypocalcemia
Hyperphosphatemia
PTH ↑
25 (OH) D ↑
1,25 (OH)2 D ↑
Prognosis and treatment for the Vitamine D dependent congenital rickets diseases
1B = lifelong calcitriol, regular checks of iCa. Good prognosis
1A = lifelong calcitriol, regular checks of iCa. Good prognosis
2A = poor prognosis (very rare). can try to treat with calcium supplementation and calcitriol but rarely respond.
examples of aquired VitD disorders?
- poorly supplemented diet (home cooked diets)
- has been reported in dogs and cats with PLE, EPI, and acute pancreatitis.
what are clinical signs of aquired vitamin D deficiency ?
Clinical signs include osteomalacia (in adults) and rickets (in puppies and kittens), pain when long bones are palpated, lameness, and stiff gait.
where are Ca sensing receptors found ? what type of receptor are they?
G-protein, found in the parathyroid gland, kidneys, cartilage, and bone.
CaSR maintains Ca within normal range.
in hypoparathyroidism what changes do you seen on Ca and P blood work and what changes are there in absorbition and secretion in the kidney, GIT and bone
↓ PTH → INCREASE calcium and DECREASE phosphate.
↓ resorption Ca from bone → ↓ Ca and phosphorus
↓ absorption Ca and phos from intestines
↓ resorption Ca and ↑ excretion phosphorus through renal tubules
PNS and CNS hyperexcitable
what do we give for the actue and chronic treatemtn of hypoparathyroidism?
Acute
Calcium gluconate IV (give slow and monitor EKG - bradycardia, PVCs, of QT) shortening
Chronic
- Calcitriol - initial dose for 2-4 days, then decrease
- Ergocalciferol - initial dose until Ca 8-9.5 mg/dL, then decrease (usually can be to EOD).
- PO calcium (Ca carbonate; others Ca gluconate and Ca lactate)
Usually taper and stop within 1 week of starting calcitriol
in hyperparathyroidism what changes do you seen on Ca and P blood work and what changes are there in absorbition and secretion in the kidney, GIT and bone
Inappropriate ↑ PTH → INCREASED calcium and DECREASED phosphate.
↑ osteoclastic activity in bones → ↑ Ca and phosphorus
- ↑ osteoblastic activity → secretion of ALP
- Risk of fractures due to weakened bones
↑ absorption Ca and phos from intestines
↑ resorption Ca and ↓ excretion phosphorus through renal tubules
PNS and CNS depression
what are the causes of primary and secondary hyperparathyroidism?
Primary Hyperparathyroidism
Usually 1 gland, but can be more
About 87% solitary adenoma, 8% hyperplasia, 5% carcinoma
Secondary Hyperparathyroidism
Usually hyperplasia of more than 1 gland
CKD or chronic dietary Ca deficiency
what clinical signs result due to hyperparathyroidism in dogs and cats?
PU/PD (Ca antagonizes effects of ADH in collecting ducts → HyperCa inhibits tubular uptake of Na and Cl → inhibits concentrating ability)
GI - inappetence, vomiting, constipation (secondary to Ca-induced smooth muscle hypoexcitability and dysmotility)
Urolith formation
Renal failure?
what are therapies, MOA and adverse effects for hyperparathyroid management of hypercalcaemia?
what is the phophaduric effect?
PTH inhibits phosphate re-absorbtion by the proximal tubule (phosphaturic effect). This excretion of P allows the serum iCa to increase
