Endocrine Flashcards
What pharmacological agents are used to treat obesity?
What is their mode of action?
Phentermine (Duromine) - a sympathomimetic amine with anorexic activity and appetite suppression effect through the hypothalamus. Given as 3 month therapy.
Orlistat - lipase inhibitor that causes steatorrhoea (reversible long-acting gastrointestinal inhibitor of lipases, which are required for systemic absorption of dietary triglycerides)
Off label use of agents that also cause weight loss-
Non diabetics: Topiramate (monosaccharide antiepileptic med, also used in migraine. SE teratogenic)
Diabetics: Exenatide (GLP1 agonist), Liraglutide (Victoza / GLP1 analogue)
What are the neurotransmitters that cause:
- satiety
- hunger
Satiety caused by:
- (gut) - cholecystokinin, GLP-1, oxyntomodulin, PYY3-36
- (adipocytes) - leptin
- (pancreas) - insulin, amylin, pancreatic polypeptide
Hunger stimulated by grehlin (from stomach)
(PEP lecture)
What are the HbA1c targets for adult T2DM in:
1. General population
2. Newly diagnosed DM with no CV disease
3. Longer duration DM or those with CV disease
4. Recurrent severe hypoglycaemia or Hypoglycaemia unawareness
5. Patients with major comorbidities likely to limit life expectancy
- = Or
Where are Calcium sensing receptors found in the body and what do they do?
What disease process is affected by CaSR?
(PEP lecture)
CaSR’s are expressed in the:
- parathyroid gland
- renal tubules
- (less important) thyroid C cells, osteoblasts, osteoclasts, breast, intestine, brain
CaSR is a G-coupled membrane protein that responds to changes in serum calcium and Amino acid levels.
Function in
Parathyroids - regulates PTH secretion. Normally causes a tonic INHIBITORY action on PTH secretion. It prevents release of PTH when Ca is high.
(when Ca level falls, the parathyroid gland is “released from tonic inhibition” –> PTH secretion)
Renal tubules - promotes Calciuria when Ca is high.
In Prox tubule- inhibits phosphaturic action of PTH
In LoH- inhibits salt reabsorption
In Dist tubule- inhibits Ca reabsorption
In Coll tubule- inhibits ADH action
FAMILIAL HYPOCALCIURIC HYPERCALCEMIA occurs when there is an inactivating mutation of CaSR which renders it less sensitive to rises in Ca (raises set point to tolerate abnormally high levels of serum Ca)
How do you diagnose Familial Hypocalciuric Hypocalcaemia?
URINARY CALCIUM shows relative hypocalciuria!! Urine Ca is inappropriately normal in the context of Hypercalcaemia. (Inappropriate increase in renal tubular reabsorption of calcium, when it should be excreting it in the urine)
Other findings: Hypercalcaemia Normal PTH Normal PO4 Vit D / Calcitriol normal or elevated Mg normal or elevated Renal function normal
What is the mechanism behind Autosomal dominant Hypocalcaemia?
What are the biochemical findings?
Autosomal dominant Hypocalcaemia - lowers the “set point” and renders the CaSR more sensitive Ca.
Hypocalcaemia High Urine calcium PTH normal Mg normal Recurrent nephrolithiasis
What is the mechanism of Cinecalcet?
CINECALCET DECREASES PTH.
(“CINNA brings down PANEM in THE Hungergames!!” = CINNAcalcet brings down PTH)
Binds to CaSR and increases the sensitivity of the CaSR to calcium –> reduces PTH secretion –> reduces plasma PTH.
Used to treat primary and secondary hyperparathyroidism.
Side effects:
GI side effects
Hypocalcaemia (unlike Calcitriol) - easy to treat with CaPO4 or Calcitriol
What is the clinical profile of asymptomatic primary hyperparathyroidism?
Middle aged/ elderly Mild Hypercalcaemia Normal or mildly increased PTH Normal renal function, urine Ca Normal Vit D Normal BMD
DDx: thiazides, lithium, FHH
What is the best management for patients with asymptomatic primary hyperparathyroidism?
(PEP lecture)
Surgery may be appropriate in the majority of patients with asymptomatic primary hyperparathyroidism, due to:
- improvement in BMD (note BMD usually declines at 10 yrs, more significant in cortical bone in radius/NOF than trabecular bone in Lspine)
- reduction in fractures
- reduced frequency of kidney stones
- improvements in some Neuro-cognitive elements
Surgery appropriate if:
- Ca > 0.25 mmol/L above the upper limit of normal
- eGFR < 60
- Osteoporosis on BMD a (T score <2.5) or previous min trauma #
- age under 50
If patient does not qualify for surgery,
- Monitor closely with annual Ca and Creatinine
- Bisphosphonates/ antiresorptive therapy stabilises BMD a but does not cure Hypercalcaemia or lower PTH
- Calcimimetics decrease Ca but NO EFFECT ON BMD
- BMD every 1-2 years
What are the causes of PTHrP-related Hypercalcaemia (Hypercalcaemia of malignancy)?
Squamous cell carcinoma (lung, head/neck, Oesophageal, cervical) Breast Renal Ovaries Pancreas Prostate T-cell lymphoma
Hereditary Vitamin D resistance syndromes.
What is the difference between VDDR type 1 and 2?
(PEP lecture)
Features of VDDR type 1: (Due to defect/lack of 1-Alpha Hydroxylase enzyme in the kidney --> unable to convert 25-OH Vit D to 1-25-OH Vit D) No alopecia Osteomalacia Hypocalcaemia Secondary hyperparathyroidism LOW 1-25-OH vitamin D
Features of VDDR type 2: (Due to a defect in the Vit D receptor in nucleus, which is unable to bind 1-25-OH Vit D) Osteomalacia Alopecia Hypocalcaemia Secondary hyperparathyroidism Normal 25-Vit D HIGH 1-25-OH Vit D
Describe the conversion of 25-OH Vit D to 1,25-OH Vit D in the renal tubules.
Contrast what stimulates and inhibits this reaction.
1-ALPHA HYDROXYLASE is the enzyme in the renal tubule that converts 25-OH Vit D to 1,25-OH Vit D.
1-alpha Hydroxylase is STIMULATED by:
- PTH
- Low Ca
- Low PO4
- Low FGF23
1-alpha Hydroxylase is INHIBITED by:
- 1,25-OH Vit D (negative feedback on itself)
- High Ca
- High PO4
- High FGF23
What are the extra-renal cells with 1alpha Hydroxylase activity?
How is this enzyme regulated?
1-alpha Hydroxylase enzyme converting 25-OH Vit D to 1,25-OH Vit D is present in:
- macrophages
- keratinocytes
- hair follicles
- cardiac myocytes
But the regulation of 1-alpha hydroxylase in non-renal tissue is
- NOT stimulated by PTH (as no PTH receptors)
- NOT inhibited by FGF23
- inhibited by corticosteroids (hence can use steroids in sarcoidosis)
- stimulated by gamma interferon, TNF alpha and IL2
What are the causes of Hypercalcaemia associated with elevated 1,25 OH Vit D?
SARCOIDOSIS most common
Other granulomatous disease : Wegeners, acute granulomatous pneumonia, talc or silicone granulomatosis
Cat scratch fever
Crohns
What are the target serum 25-OH Vit D levels for:
- End of winter
- Summer
- Falls prevention
- Fracture prevention
- End of winter >50 mmol/L
- Summer >60
- Falls prevention > 60
- Fracture prevention > 75
Describe the regulation of PO4 in the renal tubules
PO4 is reabsorbed against the electrochemical gradient in Prox tubules via the Na-phosphate transporter NPT2a.
Regulation of NPT2a:
Low PO4 –> causes insertion of NPT2a into plasma membrane of Prox tubular cells –> increases Po4 reabsorption
High PO4 –> INCREASES SERUM FGF23 –> rapid internalisation and lysosomal destruction of NPT2a –> reduces PO4 reabsorption
What is FGF23?
HIGH SERUM PO4 INCREASES FGF23!!!
–> FGF23 acts to lower PO4.
(“PHOtos increase my FIGure!…Please stop, I’m NOT PHOTOGENIC TODAY (NPT)” = PHOSPHATE increases FGF23 which reduces NPT2a)
FIbroblast growth factor 23 REGULATES PHOSPHATE HOMEOSTASIS.
- Rises in response to HIGH serum phosphate
- Decreases NPT2a expression
- Decreases 1,25 OH Vit D
- Acts independently of PTH
- Is inactivated by PHEX endopeptidase
FGF23 has 2 mechanisms to lower PO4:
- -> FGF23 DECREASES NPT2a (sodium-phosphate transporter) EXPRESSION in the proximal tubule.
- -> DECREASED PO4 reabsorption
- -> LOWERS SERUM PO4
AND…
- -> FGF23 DECREASES 1,25OH Vit D
- -> DECREASED PO4 absorption
- -> LOWERS SERUM PO4
ALSO simultaneously, as a physiological response to a high serum PO4 (independent of FGF23)
PTH IS INCREASED.
( due to
- direct stimulation of PTH secretion, and
- indirectly, as a result of reduced serum Calcium
- ** Osteocytes secrete FGF23 (ie a bone derived hormone!)
- inhibition of 1-alpha Hydroxylase enzyme activity)
What is the body’s physiological response to a LOW serum phosphate?
Decreases FGF23 –> enhances expression of NPT2a –> increased PO4 reabsorption at the renal tubule
Increases 1,25 OH Vit D synthesis
- -> increased intestinal absorption of Ca and PO4
- -> increased release of Ca and PO4 from bones
- -> increased renal reabsorption of Ca and PO4
What are the conditions associated with increased FGF
23?
(PEP lecture)
3 conditions: all are Hypophosphataemic rickets disease
- AUTO DOMINANT HYPOPHOSPHATAEMIC RICKETS
Mutation that results in decreased cleavage/degradation of FGF23 - X-LINKED HYPOPHOSPHATAEMIC RICKETS
Loss of function mutation in PHEX gene –> decreased cleavage/degradation of FGF23 –> renal PO4 wasting –> rickets in age 2-3 - ONCOGENIC OSTEOMALACIA
Increased Tumour production of FGF23.
Tumours are usually small benign MESENCHYMAL TUMOURS.
Oat cell carcinoma, Sclerosing haemangioma, Fibromas.
Localisation: Whole body MRI, Octreotide scan, PET, or (***most useful) Gallium-Octreotide scan
What is the association with Ca supplements and risk of Cardiovascular events?
There is NO increased risk of cardiovascular events in patients on Ca and Vit D.
Ca supplements should only be used when dietary Ca intake can not be achieved. Food remains the best source of calcium.
Elderly people and patients with renal impairment who take Ca supplements “may” be at higher risk of CVD but there is no need to discontinue their use- just limit to low dose 500-600mg Ca a day
