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Familial Hypocalciuric Hypercalcemia + other calcium sensing disorders – pathophysiology, treatment

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“Familial hypocalciuric hypercalcaemia as the name suggests is a cause of hypercalcaemia. It runs in the family and is characterized by autosomal dominant inheritance with high penetrance. Affected people typically present in childhood where they get hypocalciuria (peeing low amounts of calcium) despite having elevated calcium levels in the blood hypercalcaemia”

Hello in this video we’re going to talk about familial hypo calcium hypercalcemia and other calcium sensing disorders familial hypocalceuric hypercalcemia as the name suggests is a cause of hypercalcemia it runs in the family and is characterized by autosomal dominant inheritance with high penetrance affected people typically present in childhood where they

Get hypocalciuria peeing low amounts of calcium despite having elevated calcium levels in the blood hypercalcemia problems with the reason for these changes is due to problems with calcium sensing in the body familial hypocalceuric hypercalcemia is one type of calcium sensing disorder another type a complete opposite is autosomal dominant hypocalcemia which

We will touch on later on let’s talk about the normal physiology first so parathyroid gland contains parathyroid cells which are called chief cells the chief cells contain parathyroid hormones which are ready to be released these cells respond to calcium levels in the blood via calcium sensing receptors abbreviated casr this is a g-protein-coupled receptor

When casr notices that there are low levels of calcium the chief cells will begin releasing parathyroid hormone parathyroid hormone her main goal is to increase blood calcium levels and it does this by targeting three main organs in the bones parathyroid hormone promotes bone resorption through the action of osteoclasts osteoclasts are the bone eating cells

Which will release calcium and phosphate in the blood parathyroid hormone also targets the kidneys it increases calcium reabsorption but decreases phosphate reabsorption parathyroid hormone also targets an enzyme in the kidneys called one alpha hydroxylase this enzyme promotes the conversion of calcidil to calcitriol which is the active form of vitamin d active

Vitamin d is known as 125-dihydroxycholic calciferol abbreviated here and its role is that it targets the gut increasing calcium and phosphate absorption so in summary parathyroid hormone will increase serum calcium levels the rise in serum calcium levels will be detected by the calcium sensing receptor the casr and the casr will put a break on the parathyroid

Cells to stop releasing parathyroid hormone it’s a fine balance the chief cells uses the calcium sensing receptors to sense blood calcium levels and respond appropriately on a side note the production of active vitamin d has a negative feedback as well on the parathyroid gland telling it to ease up the production of parathyroid hormone because it’s no longer

Required familial hypocalciumic hypercalcemia is caused by inactivating mutation of the calcium sensing receptor and so basically in the presence of high calcium levels the calcium sensing receptors don’t detect this properly and will still release small aliquots of parathyroid hormone further increasing blood calcium levels people with familial hypocalciuric

Hypercalcemia typically only have mild hypercalcemia patients with familial hypocalceuric hypercalcemia still have a functional calcium sensing receptor it’s just the set point of which it responds to high calcium levels is now higher so as an example depicted by this graph you have on the x-axis serum calcium levels and on the y-axis the calcium sensing

Receptor regulation of parathyroid hormone release normal serum calcium levels is between 2.2 and 2.6 millimoles per liter and this is well maintained by the calcium sensing receptor regulating the parathyroid hormone release right well in familial hypo calcium hypercalcemia the graph shifts to the right meaning there is decreased sensitivity to serum calcium

Levels this means that calcium sensing receptors regulation of parathyroid hormone release will only respond to higher calcium levels and hence you typically only get a mild hypercalcemia because the calcium sensing receptor is still working it just requires a lot more prompting to work familial hypocalceric hypercalcemia also causes physiological changes in

The kidneys so as we’ve learned the kidneys respond to parathyroid hormone by absorbing calcium but also causes phosphate excretion it does so by targeting cells in the proximal convolated tubule inhibiting the sodium and phosphate symptoma causing phosphouria and therefore reduces blood phosphate levels throughout the nephron the kidneys also contain these

Calcium sensing receptors the most important effect of calcium sensing receptors here is probably found in the thick ascending limb of the loop of henle here in purple the calcium sensing receptors are found on the basal surface of the cells and so on the bottom close to the bloodstream we are now talking about normal physiology the thick ascending limb of the

Loop of henle contains a co-transporter on the apical surface basically where the lumen is where p is the co-transporter carries one sodium two chloride and one potassium this is the transporter which the class of diuretics called loop diuretics inhibit anyway although the process of transporting these electrolytes is electrically neutral most of the potassium

Reabsorbed by the co-transporter leaks back into the lumen to drive further inward sodium chloride transport this movement of cationic potassium into the lumen plus the reabsorbed chloride out of the basolateral surface of the cell will generate a net trans epithelial potential difference what does this mean well the interstitial fluid and capillaries will be

Negative in respect to the tubular lumen the resulting lumen electropositivity will drive the passive reabsorption of cations sodium but also the calcium and magnesium via paracellular pathways between the cells i hope that made sense on a side note you have these proteins called chlorines which help in paracellular transport of calcium and magnesium ions from

The lumen into the blood so as we have learned when someone has hypercalcemia normally this tells the parathyroid gland to stop producing parathyroid hormone right but also hypercalcemia is detected by the calcium sensing receptors in the kidneys which results in a number of things one it will inhibit sodium potassium atpase here it will inhibit the potassium

Efflux pump on the apical surface and it will inhibit clodins and so in summary in hypercalcemia calcium sensing receptors here will respond by reducing the reabsorption of calcium and magnesium and this will result in elevated calcium levels in urine hypercalceuria which will help the body transition back to normocalcemia normal levels of calcium in the blood

In familial hypocalceuric hypocalcemia there is inactivating mutation of the calcium sensing receptor the receptors don’t work and you end up reabsorbing the calcium and magnesium leading to hypocalciuria and mild hypercalcemia and hyper magnesemia it is an important concept to remember that familial hypocalciumic hypercalcemia as the name suggests causes hypo

Calcium investigations and other supportive investigations for diagnosis is a urinary calcium and creatine ratio less than 0.01 a reduced 24-hour urinary calcium and genetic testing especially if family history is difficult to obtain an important differential diagnosis is asymptomatic primary hyperparathyroidism which also causes you know hypercalcemia but

It’s important to know the difference because the cause and treatment of the two are different in primary hyperparathyroidism the the main cause is typically a benign adenoma it is a very common cause of hypercalcemia compared to familial hypo calcium hypercalcemia which is a rare cause of hypercalcemia a good differentiating factor is that familial hypocalcia

Hypercalcemia there is a family history and it typically only causes a mild hypercalcemia in primary hyperparathyroidism people can range from asymptomatic to full-blown symptomatic hypercalcemia which i will not discuss what these symptoms are the treatment of primary hyperparathyroidism is a parathyroidectomy whereas in familial hypocalcia hypocalcemia it

Is observation and possibly calcimitics finally in primary hyperparathyroidism the calcium sensing receptors still work they function normally and therefore in the presence of hypercalcemia the kidneys will inhibit the reabsorption of calcium and magnesium resulting in hyper calcium urea rather than hypo calciuria in familial hypocalceuric hypercalcemia going

Back to calcimimetics sorry the chaosmatics is a drug that mimics calcium the body perceives that they have much more calcium than they actually do which will essentially be detected by the calcium sensing receptors and and thus they will respond appropriately so that concludes the talk on familial hypocalcia hypercalcemia but another calcium sensing disorder i

Want to talk about is autosomal dominant hypocalcemia which is an activating gain of function mutation of the calcium sensing receptors essentially the calcium sensing receptors are active and tightly regulates parathyroid hormone release it essentially puts a break on the release of parathyroid hormone in the kidneys the same thing the calcium sensing receptor

Is activated and so you are inhibiting calcium and magnesium reabsorption and so as a result you get you know hypocalcemia now remember the serum calcium graft i spoke about earlier well now you require a much lower calcium level to cause parathyroid hormone release and the reabsorption of calcium and magnesium in the kidney patients with autosomal dominant

Hypocalcemia typically have mild hypocalcemia thank you for watching i hope you enjoyed this video

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Familial Hypocalciuric Hypercalcemia + other calcium sensing disorders – pathophysiology, treatment By Armando Hasudungan