Primary hyperparathyroidism (PHPT) is a systemic disease caused by an excess of parathyroid hormone secretion. It causes calcium kidney stones but also multiple other abnormalities, especially of bone. Here, I am concerned with that subset of PHPT patients with kidney stones.
A Curable Cause of Kidney Stones
Unlike most stone formers those with PHPT have a good chance at permanent cure. This makes detection of PHPT a paramount aim for patients and their physicians. As I shall tell you, PHPT raises serum calcium above normal and is detected from blood test results. The elevation of serum calcium can be slight and variable so patience and persistence matter a lot. Once diagnosed, PHPT can be cured by a surgery that modern instruments and techniques have made very safe and highly successful in the hands of expert parathyroid surgeons. That is my story.
A Remarkable Experiment of Nature
As I shall attempt to tell you, the strict, fierce regulation of the parathyroid, bone, kidney, intestinal mineral axis normally admits of little variation of the serum calcium level despite rather large traffics of calcium and phosphate in and out of the body, and in and out of bone every day. Dozens of well known and lesser known hormones and signalling pathways, castellated in almost innumerable looping feedback relationships, maintain in serum an amazing calmness and steadiness.
But imagine if one, just one of the hormones involved, and not any one but one among the prime hormones, the kingly olympion hormone goes awry. Resets itself as indeed a royal monarch, a pharaoh might suddenly choose to change the direction of power. No scientist could contrive such an experiment in humans except perhaps for a few hours or days. But nature can do this, does do this, and allows us to observe what happens everywhere in the immense net of controllers when one, of its own, chooses to set the requirements of the body aside and pursue its own treasonous direction.
You might wonder at the picture: The Pharaoh’s Hosts Engulfed in the Red Sea, Lucas Cranach the Elder,1530. To Pharaoh the Hebrews’ desertion seemed treason, to Moses the behavior of Pharaoh a violation of an ancient pact. The very sea itself seemed an outrage of nature, to the Hebrews, their salvation an uncanny thing. To me, Chanach seems an invariable treat to look upon, a miracle painter. Most of all, the sheer mass of it, the vastness of details – is this not what I shall be writing about?
What I Can and Cannot Offer
I will not write downward, simplify until all meaning vanishes, leaving nothing but airy generalizations and a few pictures. But this field is vast, this disease beneficiary of thousands of primary scientific papers. So my best choice is a review of reviews. Accordingly, the linked references are to what seem to me reasonable reviews from recent time. We have contributed two clinical papers I think better than or as good as their like elsewhere, so I have used them for detailed illustration.
Because my goal is kidney stone prevention, always, I write that physicians may diagnose and cure this disease with a greater passion and facility. And if patients who know this curable disease lurks within their ranks seek with greater persistence a proper evaluation for it, that too furthers my desires. Likewise I believe prevention benefits when people understand things. So albeit in a summary fashion I have put in a lot of details.
Outline of Calcium PTH Axis
I drew the sketch pictured below to reveal the mere posts and beams of an elegant mansion.
Serum calcium (SCA) and phosphate (SP) reside in a suitably named rectangle. The red arrows – eg. from calcium to parathyroid hormone (PTH) – connotes down regulation. Blue arrows mean the opposite. For clarity I left out receptors.
For orientation, parathyroid glands number four on average and reside at the four corners of the thyroid gland in the neck. PTH signals kidneys, bone and the gut so as to maintain great stability of blood calcium and a less rigorous stability of blood phosphate concentration.
Low Serum Calcium Increases PTH Secretion
As if to run the system through an accustomed pathway, consider a healthy person who chooses to eat a diet low in calcium.
The GI tract (GUT) has little calcium to absorb, but kidneys lose some calcium in the urine every day. If nothing happened beside low calcium diet, serum calcium would fall. But the parathyroid glands possess a calcium receptor (CaSR) on their cell surfaces – a protein ensemble capable of responding to serum calcium. Even a slight fall of serum calcium signals release of preformed PTH in the glands and gradual increase of new PTH production. Here is a fine review of the process.
Protracted CaSR activation signals parathyroid cell proliferation. With time low calcium diet – as an example – can cause the four parathyroid to enlarge – a form of secondary hyperparathyroidism.
PTH Increases Kidney Calcitriol Production
PTH signals kidneys through PTH receptors to increase production of activated vitamin D, 1,25 dihydroxyvitamin D, or calcitriol. Calcitriol increases the fractions of calcium and phosphate absorbed by the gut (rCa and rP of gut) so more food calcium and phosphate enter the blood. Because of increased PTH signalling I just described, kidneys lose the extra phosphate in urine but retain much of the calcium.
In concert with PTH, calcitriol acts on bone cells to increase mineral losses. This increases bone mineral delivery into blood.
The net effects of PTH on bone and kidney maintain serum calcium normal without an increase of serum phosphate and with minimum increase of serum PTH itself. But bone mineral can be lost.
Calcitriol Down Regulates PTH Secretion
Like other steroid hormones, calcitriol acts via its receptor, the vitamin D receptor (VDR), to alter gene expression. Specifically, calcitriol downregulates the genes for the PTH precursor molecule, and also upregulates genes for the CaSR thereby increasing the amount of the CaSR on the cell surface so the serum calcium signal increases. Consequently, as increased PTH stimulates calcitriol production, calcitriol suppresses PTH forming a negative feedback control loop.
Serum Calcium and Phosphate Down Regulate Calcitriol Production
Just as calcitriol increases them, serum calcium and serum phosphate, independently, both down regulate calcitriol production – another feedback loop. Calcium acts via the CaSR in kidney proximal tubules. Phosphate presumably acts through another hormone, FGF23 (see directly below). Note that on the figure serum phosphate has a downward red arrow that might confuse things by suggesting that a fall in serum phosphate suppresses calcitriol. It is simply that I cannot draw everything in on one figure. PTH reduces phosphate retention by kidneys and lowers serum phosphate. Serum phosphate downregulates calcitriol. The fall in serum phosphate from PTH will reduce that inhibition so calcitriol increases – double negative.
By modulating calcitriol increase from PTH, serum calcium and phosphate stabilize their own blood concentrations.
Calcitriol Down Regulates Itself and Upregulates Kidney Calcium Retention
Calcitriol acts through the VDR in kidney cells that produce it – proximal tubule cells – to reduce its own production. Calcitriol increases production by bone cells of FGF23 – discussed below – that in turn suppresses calcitriol production through its own receptor complex. These feedback loops enables calcitriol to stabilize its blood concentration.
PTH and Calcitriol Increase Kidney Ca and Reduce Kidney P Retention
PTH and calcitriol signal kidney to increase the fraction of filtered calcium reabsorbed back into the blood (rCa in the kidney box). At the same time, PTH reduces that fraction for phosphate (rP, kidney). As a result, the kidneys retain the calcium that came into blood from food and from bone but discard the phosphate. This maintains the normal ratio of serum calcium to phosphate.
PTH and calcitriol increase kidney calcium reabsorption mainly at the distal convoluted tubule. PTH down regulates the sodium chloride cotransporter. This reduces NaCl entry into the cells and thereby facilitates calcium uptake. PTH and calcitriol increase the abundance of TRPv5 that permits cell calcium entry. Klotho, a protein made in the distal convoluted tubule removes carbohydrate from TRPv5 delaying removal from the cell membranes.
These hormones increase the abundance of calbindin, a protein in the cell that binds calcium and ferries it to the blood side membrane.
Through its receptor PTH down regulates phosphate reabsorption by signalling removal of Npt2A and Npt2C from the apical – tubule fluid side – membranes of proximal tubule cells. These two transport protein assemblages account for most of the reabsorption of filtered phosphate. So their removal from the cell membranes permits an abnormal fraction of filtered phosphate to leave the body. The elaborate signalling pathways are detailed in this excellent review. The PTH receptors – proteins PTH attaches to in order to signal cells – are on both the basolateral – blood site – and apical membranes of the cells so the hormone can act from both the blood and tubule fluid.
This hormone produced mainly by osteocytes (see below), also reduces kidney phosphate reabsorption but through a different receptor and signalling pathway. It acts like PTH in removing Npt2a and Npt2c from the apical membranes. So both facilitate kidney removal of phosphate liberated from bone or entering from food when PTH increases. Calcitriol and PTH upregulate FGF23 that in turn downregulates calcitriol and PTH production.
If dizzy from all this, think about it as if there were a reason. Higher PTH from, say, low calcium diet will raise calcitriol – more calcium and phosphate absorbed from food and removed from bone. PTH raises FGF23. The two act in concert to lower kidney phosphate retention while FGF23 suppresses calcitriol production – a sort of feedback regulation and both FGF23 and calcitriol downregulate PTH.
The Cell Surface Calcium Receptor (CaSR) Down Regulates Kidney Calcium Retention
I think of kidney CaSR as a parallel regulator of calcium reabsorption acting along with the PTH and calcitriol receptors. PTH and calcitriol act mainly in the distal parts of the nephron. CaSR acts mainly in the thick ascending limb of Henle’s loop, a region that reabsorbs far more calcium.
In humans kidneys cells of the thick ascending limb and distal convoluted tubule express CaSR on their basolateral (blood side) membranes. Activation of thick ascending limb CaSR reduces calcium reabsorption. Distal convoluted tubule CaSR signalling reduced TRPv5 membrane abundance in one study but its overall importance is as yet a matter of debate. Rising serum calcium will through the CaSR reduce kidney calcium retention, in opposition to effects of PTH. As if Nature could not resist yet another layer of control, calcitriol upregulates CaSR in renal tubules as it does in parathyroid cells, further countering the rise in serum calcium produced by PTH.
CaSR in the proximal tubule, on the apical surface (facing tubule fluid) may offset the effects of PTH to reduce phosphate losses. I omitted some of these regulations from my figure drawing to avoid clutter.
PTH Calcitriol and FGF23 Signal Bone Mineral Release
In concert with calcitriol, PTH signals bone to release mineral, hydroxyapatite. This is the same crystal that makes up calcium phosphate kidney stones and plugs kidney tubules. The extra calcium from bone enters the blood so serum calcium rises back toward normal.
Calcitriol and PTH
Like PTH, calcitriol acts on bone to cause release of calcium and phosphate from bone mineral. The effects of PTH are more rapid, those of calcitriol require hours to days. The two hormones, PTH and calcitriol, each signal production by osteoblasts – bone producing cells – of RANKL which binds to its receptor (RANK) on osteoclasts (bone mineral liberating cells) and osteoclast precursor cells. RANKL recruits more osteoclasts. Osteoblasts also produce a ‘decoy’ protein, osteoprotegerin, that binds RANKL and prevents its action – a kind of internal negative feedback regulation. The net effect is that low calcium diet via increased PTH and calcitriol leads to bone mineral loss via increased RANKL.
But bone mineral loss triggers increased bone mineral formation, so the process mainly acts to speed up bone mineral turnover. However when PTH is high for extended periods of time the net effects are for gradual loss of mineral as the increase of new bone mineral formation lags behind that of bone mineral dissolution.
Relation to PTH and Calcitriol
Osteocytes (former osteoblasts caught in the bone mineral they made) and osteoblasts themselves produce this hormone that reduces kidney phosphate retention like PTH does but by a different pathway. Calcitriol upregulates it and, as I already mentioned, it down regulates calcitriol production. PTH also upregulates FGF23 which in turn downregulates PTH secretion.
Regulation By Phosphate
High serum phosphate increases FGF23 production suggesting a phosphate based regulation system not wholly dependent on calcitriol and PTH. This mechanism is clearly evident in people with kidney disease. By contrast patients with PHPT have low serum phosphate.
Regulation of Bone Mineralization
What follows appears to be the contemporary beliefs about specific bone regulatory factors that might be important in PHPT bone disease. I have left out a number of pathways, and warn that much of what I can say comes from animal and cell work and may be untrue in intact human bone in vivo.
FGF23 is centered in an osteocyte network within bone that controls bone formation. Sclerostin, which PTH down regulates, itself down regulates production of the matrix in which bone mineral forms. It also upregulates FGF23 that promotes production of inorganic pyrophosphate a potent inhibitor of bone mineral – hydroxyapatite crystals. The result is low bone mineralization. When sclerostin is low, matrix production rises, FGF23 falls, and therefore inorganic pyrophosphate production falls and bone mineralization increases. Here is an excellent review with pictures. Inorganic pyrophosphate inhibits mineral formation both directly and by stimulating production of osteopontin, another crystal inhibitor, and non specific alkaline phosphatase. The latter normally inhibits inorganic pyrophosphate production – another of the dizzying feedback loops in the mineral system.
Sclerostin, incidentally, may possibly through upregulation of FGF23, reduce calcitriol and thereby urine calcium excretion
A Picture of this Elaborate Web
I cannot leave this mass of hormones and their mutual regulations without some try at synthesis. So many names, so many loops. Here, I placed the main names but left our RANKL RANK osteoprotegerin, and osteopontin – no more room. As I have already referenced each regulation step I omit them here. Blue lines show upregulation, red the opposite. Most receptors are left out to avoid clutter – FGFR and VDR are included.
PTH Calcitriol CaSR, VDR
Along the middle is the easy part. Serum calcium down regulates PTH via the parathyroid gland CaSR and calcitriol via the kidney CaSR (kidney CaSR not drawn in along these two lines). Down regulation of calcitriol by calcium is the red curve second from the right. Because I needed the VDR and want to avoid lines crossing , it points to the VDR – incorrect but visually workable.
PTH upregulates calcitriol that through the vitamin D receptor in parathyroid glands up regulates the CaSR that down regulates PTH secretion and down regulates the PTH gene expression – curves from VDR to PTH and FGF23.
Through upregulating kidney CaSR (CaSR is written once, but used for PTH and TAHL) calcitriol downregulates its own production. Through the intestinal VDR calcitriol increases calcium and phosphate uptake from food – long blue curves from VDR back to serum calcium and phosphate. PTH by reducing kidney Npt2A and Npt2C lowers serum phosphate. Through upregulation of the CaSR, calcitriol and serum calcium down regulate calcium reabsorption in the thick ascending limb which reduces calcium retention.
A key entry point for calcium entry into distal convoluted tubule cells, this transporter is upregulated by PTH and calcitriol. That promotes calcium retention.
FGF23, FGFR, Klotho Sclerostin
PTH and calcitriol upregulate FGF23 production which in turn through the FGF receptor (FGFR) down regulates calcitriol and PTH. Klotho, produced in kidney distal convoluted tubule cells is needed for FGF23 to bind to its receptor. Like PTH, FGF23 downregulates phosphate retention by reducing membrane Npt2A and 2C. Because PTH normally downregulates sclerostin which stimulates its production, FGF23 should be low in PHPT.
A Fearsome Corner of Biology
You might have guessed from my drawing and all of the other details I could not draw in that evolution has provided a powerful regulation system for serum calcium so it cannot vary except within a narrow range. That guess seems true. Imagine, then, the havoc and chaos when a key element of the system goes awry. Bone cells, intestinal cells, kidney cells, but most importantly the key signalers PTH, calcitriol, the calcium, receptor. When they become, so to speak, autonomous and regulate exterior to the needs of the entire system, disease results in many parts of the body. In writing this section I came upon this excellent review with clear pictures. Those hungry for a readable scientific paper might like it.
Effects of Low Calcium Diet
Could all this be a dream, some phantasm of troubled minds?
I found this isolated and probably little noticed set of observations and brought them here to illustrate that PTH and calcitriol indeed adapt to low calcium intake and that the remarkable complexity of regulation permits considerable dissociation between the magnitude of their relative change.
Among calcium stone formers without PHPT or any other systemic disease serum PTH and Calcitriol were measured under proper conditions while on a free choice and after 7 days of a low calcium diet. Figure 3 from the paper shows that among those with well preserved bone mineral density (group 3) PTH rose, as expected and so did calcitriol. Among those with slight or marked reduction of lumbar spine bone mineral density (groups 2 and 1, respectively) the rise of calcitriol was more marked and that of PTH much less so. Serum calcium fell slightly with the diet.
That bone mineral stores somehow condition the calcitriol PTH relationship could seem odd except we have inspected so many links between them and bone. What I have written down does not explain this graph, but the graph is an image, an imago dei. Something found in the real world to symbolize the shocking elaborations of the bone and mineral system.
Clinical Primary Hyperparathyroidism
The modulated and subtle increases of PTH with low calcium diet we call secondary hyperparathyroidism – a response that brings the system back into some semblance of normalcy. Other common reasons for such secondary hyperparathyroidism include insufficient vitamin D and even slight reductions of kidney function.
But what if parathyroid cells choose to grow and proliferate – commit high treason. And, as a result, raise the level of PTH as a primary event? What then?
It is, as I said at the beginning, a remarkable experiment of nature. As if to instruct us nature contrived this singular hormonal disorder so we can see how the system runs. But not for us did nature do this, being indifferent to us as to all that live on Earth. It just happens sometimes. Parathyroid glands lose their normal growth regulation and begin to over produce PTH and grow.
Kidney stone clinicians need special wariness because perhaps five percent of stone patients have PHPT. And, unlike most stone diseases, this one is usually cured by a surgery that modern technology has made surprisingly safe and easy for patients.
Serum Calcium Rises, Phosphate Falls
All factors raise serum calcium. Bone loses calcium and phosphate into the blood. Calcitriol increases because of high PTH. The higher serum calcium suppresses calcitriol, but lowered phosphate does the opposite. So high serum calcium opposes high serum PTH and low serum phosphate. The two outweigh the one. Calcitriol exceeds normal, and increases GI calcium and phosphate absorption into the blood. Kidneys release the phosphate but retain the calcium. Calcitriol would suppress PTH secretion but the glands no longer listen as attentively.
Serum PTH Is Not Suppressed
Although treasonous, the parathyroid glands may long remain not unreasonable. The powerful suppressive effects of increased serum calcium and calcitriol have sway in many people for many years. So serum PTH may stay in the normal range but does so despite elevated serum calcium that would – in a normal person – have driven PTH secretion to its minimum and serum PTH to below the lower limits of normal. For example, a primary increase of calcitriol that raised serum calcium would suppress serum PTH completely. Ultimately, as the gland or glands enlarge more and more, serum PTH rises above normal.
How, you might ask, can the abnormalities of PHPT remain if the very hormone remains normal? Easy. It is normal because of the abnormal serum calcium and calcitriol levels. If they – serum calcium and calcitriol – were normal, PTH would be high.
Urine Calcium Is High
PTH Increases and CaSR Reduces Calcium Reabsorption
I said PTH and calcitriol stimulate kidney cells to reclaim filtered calcium back into the blood, and that is what I meant to say. It does. But that effect is muted.
PTH stimulates calcium reabsorption late in the nephron, at the distal convoluted tubule. But the high calcitriol increases CaSR abundance not only in parathyroid glands but in the kidney and most specifically in the thick ascending limb – a region of major calcium reabsorption. The combination of increased CaSR and high serum calcium reduce calcium reabsorption in the thick ascending limb.
Once again, things balance each other, though not quite. PTH and calcitriol strongly increase calcium reabsorption in the distal convoluted tubule whereas the CaSR reduces it in the thick ascending limb. Overall, if one measures carefully, these opposing factors reduce the fraction of filtered calcium reabsorbed. That alone could increase urine calcium excretion. But another factor adds mightily, and to great effect – increased calcium filtered load from high serum calcium.
Hypercalcemia Increases Filtered Load of Calcium
Kidneys resemble a funnel. At their tops – filtration by glomerulae – they filter about 120 – 140 liters/day of water and salts from blood. Calcium not bound to protein and therefore free to filter measures about 45 mg/liter. So kidneys filter perhaps 5,400 to 6,300 mg of calcium daily. Even with hypercalciuria, urine calcium losses never reach much above 700 mg/day and in stone formers usually average 400 mg/day or less. So marked hypercalciuria reflects perhaps 7 – 9% of filtered load in the urine, normal urine calcium of 100 – 200 mg/day around 1 – 3 percent of filtered load.
Because serum calcium has increased from – let us say – 45 to 50 mg/liter, filtered load increases to 6,000 to 7,000 mg/d. Urine calcium levels run high, perhaps about 350 to 450 mg/day. This gives a range from 5.8 to 7.5% of filtered load in the urine. So the push pull of increased distal convoluted tubule and decreased thick ascending limb calcium reabsorption along with increases filtered load increases urine calcium.
Calcitriol Increases and More Calcium and Phosphate are Absorbed
Bone can lose calcium and phosphate and by doing that support long term increase of urine excretions for both. But in PHPT calcitriol increase from high PTH and perhaps low serum phosphate activates intestinal calcium and phosphate absorption.
Actual Results in Patients
I modestly propose that my own paper with Joan Parks and Elaine Worcester has the prettiest published graphs of data from patients with PHPT. We combined data from 105 patients who had PHPT proven by surgical cure with data from 260 normal people and 2416 calcium stone formers.
Serum Calcium and Phosphate
How The Figure Works
Let me explain this figure to you before you give up and leave the page.
The horizontal axes of all four plots show serum calcium, before (left) and after (right) surgical cure of PHPT. The vertical axes of the top panels show serum phosphate, the bottom panels urine calcium.
Dashed horizontal lines center on the mean normal values for serum phosphate or urine calcium. The dashed vertical lines show the normal mean and upper limit of normal for serum calcium.
Our normals show as mid size dots, common stone formers as a cloud of microdots, and PHPT stone forming patients as large dots.
Because we use atomic absorption measurements not available commercially, our serum calcium values almost never lie above 10.1 mg/dl – the rightmost vertical line.
Here I focus on the two upper panels.
Serum phosphate falls in concert with rising serum calcium among PHPT patients – upper left panel. Because PTH raises serum calcium and lowers serum phosphate – by reducing kidney phosphate conservation, we expect this pattern. What a treat to observe in real people what theory predicts!
The outer borders support density curves for normals, common stone formers, and PHPT as solid, fine dashed, and coarse dashed lines, respectively. These give a visual impression of how the points distribute. Indeed, common stone formers have lower serum phosphate values than normals, though PHPT far surpasses them. Of course the serum calcium for PHPT is far to the right – higher – compared to the normals and common stone formers.
Only two scattered blood calcium values from PHPT patients lie above 10.1, the upper limit for our laboratory. The PHPT data now overlay data from normals and common stone formers.
Urine and Serum Calcium
Now, take a look at the two lower panels.
The large dots in the lower left panel show the vigorous hypercalciuria of PHPT and how urine calcium rises with serum calcium. Rising serum calcium means rising filtered load of calcium and rising signal to the thick ascending limb CaSR so theory predicts urine calcium should rise with serum calcium. How nice to observe what theory predicts. No wonder stones occur given how high PHPT raises urine calcium!
After surgical cure, most things subside. But urine calcium remains as high in some cured PHPT patients as in common calcium stone formers. If 200 mg/d is the threshold for kidney stone risk, then about half remain at some risk. This means that cure of PHPT does not complete stone prevention. That residual hypercalciuria needs treatment as if it were idiopathic hypercalciuria. You might say, the border density plots for urine calcium all overlap – normals, PHPT, and common stone formers alike. The three kinds of dots overlap, too. Yes, I would say, but idiopathic hypercalciuria occurs among normal people, and commonly among stone formers. Among stone formers we treat it, among normals we do not. PHPT patients, here, all have been stone formers.
Because our work spanned 3 decades we worked through the development of PTH assays all with different units and sensitivities. To accumulate what we have measured, we scaled each assay to its upper limit and plotted the values we had against serum calcium from the same blood samples.
All blood calcium values matched or exceeded 10 – our upper limit in females, but PTH values commonly lay below the upper limit for the assay, shown here as the dashed horizontal line at 100%. These data, that many others have collected in greater abundance and higher assay quality, substantiate the theoretical point that one need not find high PTH values to diagnose and surgically cure PHPT. What counts is higher than normal serum calcium with PTH levels not suppressed.
Supersaturations and Stones
With such high urine calcium excretions how could be expect anything but high urine supersaturations? And we found them.
If anyone has not as yet encountered supersaturation as the main determinant of crystal formation in stone formers – despite our emphasis on it on this site, here is a good review.
Before surgery, both CaOx and CaP supersaturations (upper and lower left panels) rose with urine calcium excretion. For visual clarity we omitted the cloud of tiny points for common stone formers and show only their confidence ellipse in fine dashed lines. PHPT raises both CaOx and CaP SS above the other two groups.The mean values for both exceed normal and common stone formers – you will find the means and statistics in Table 1 of the article.
But on close look that for CaP creeps up higher along the right sided border plot; see where the coarse dashed line bulges in the upper portions.
From this one might expect both CaOx and CaP stone, and we found them. If we call CaP stones those that contain above 50% apatite, 11% of common stone formers produced them vs. 22% of PHPT patients – a significant difference. But this difference concerned only men; women PHPT and common stone former alike produced about 20% phosphate stones.
The message: CaOx stones or CaP stones make no difference – both kinds of stone former can have PHPT as a cause.
Surgical cure abolishes the fascinating mineral abnormalities of PHPT but do stones stop?
We adjusted for the interval between the first stone and surgery and thereafter for the interval from surgery to our last contact with patients, as well as for the number of pretreatment stones. This gave us stones essentially per year of observation. Among PHPT values were 8 before vs. 0.8 after surgery. No one doubts surgical cure reduces stones in PHPT, so our data are just another drop in the ocean.
How Stones Form
Thus far only our research group has presented data about how stones form in people with PHPT. Because each patient study demands great effort and expense, and grant support imposes considerable limits, we could study only five patients. But from them we harvested huge amounts of information. We hope others will do more cases and confirm and extend our work.
So far as we presently know, stones can form over interstitial plaque or over tubule plugs. We found evidence for both.
The upper left panel of this picture shows one papillum from a PHPT patient during stone removal surgery. The white box outlines a small stone on plaque. In the blowup inset to the right, a black line outlines the stone. The single arrow points to the plaque border. A single arrowhead points to more white plaque just below the box. The double arrowheads point to crystal plugs in tubules whose ends protrude into the urinary space. The single arrow at about 6 o’clock points to another protruding plug end.
Panel b shows another papillum from this same patient with a large area of plaque highlighted by the single arrowhead. Yet another papillum (panel c) shows a small attached stone at the asterix just above a large area of plaque. Finally, a fourth papillum (panel d) shows a large plug whose end protrudes quite a way out into the urinary space.
All five patients showed evidence for some plaque and some tubule plugging, but plaque and plug abundances varied widely between patients and even between papillae of a single patient. Accordingly, some papillae seemed almost normal, others very damaged and deformed.
For 15 years we have obtained tiny biopsies during surgery from those who gave us consent. Often, as here, we studied the tissues by microscopy and also by micro – CT analysis. For this latter, special equipment makes very high resolution CT images of tissue samples – these are very tiny! – that show tubule plugging and plaque.
The left panels below show such a CT image of three plugs within one papillary biopsy sample. A microscopic image (panel b) of the large deposit at the arrow in panel a shows the hugely dilated inner medullary collecting duct that contained the deposit. No cells line the duct; they are all dead. Presumably plugging killed them.
Panel c shows both multiple smaller plugs by CT that arrows point to and some plaque at the single arrowhead. In the histology section – panel d – the arrows point to plugs. Similarly, but with more abnormalities, panel e shows many deposits (arrows) and regions of plaque (arrowheads). The histology (panel f) shows a plug at the arrow and plaque at the arrowhead. The tissue is partly scarred.
In all cases, hydroxyapatite crystals comprise both the plaque and plugs.
Damage Can Be Extensive
I should not burden this article with yet more pictures but simply say that compared to the idiopathic calcium stone formers patients with PHPT most resemble those with calcium phosphate stone. They, too, have many plugs, loss of lining cells, and papillary deformities.
But PHPT goes further and damages more. Deposits reach up from the medulla all the way into the cortical collecting ducts. The cortex of kidneys contains the crucial glomerulae and complex proximal and distal convoluted tubules. Damage in that region tends to cause a loss of kidney function.
PHPT Can Reduce Kidney Function
In principle, any stone disease can damage kidneys by obstruction or requiring surgical procedures. In fact, large population surveys show reductions of kidney function as a general trait of stone formers in general. But PHPT reduces kidney function more, and with greater regularity than we find in the common idiopathic calcium stone patients.
PHPT also associates with vascular disease and reduced longevity. This is no place to detail such broad issues that many reviews cover very well indeed.
PHPT Exposes Kidney Cortex to High Calcium levels
Keep in mind that PHPT imposes on kidneys both high blood and high urine calcium. The latter occurs in routine stone formers, the former does not. The medullary collecting ducts have a sturdy character. Because of water conservation, tubule calcium concentrations can be very high in even normal people. But glomerulae, proximal tubules, and even the distal convoluted tubules do not normally encounter high calcium levels. They have a delicacy about them. Injury to these cortical structures can bring on kidney disease and even kidney failure.
Diagnosis Of PHPT in Stone Formers
Whereas borderline or frankly elevated serum calcium levels pose diagnostic problems in general, among calcium stone formers the range of causes for such levels narrows. In my fifty years of kidney stone prevention work diagnosis of PHPT and separation from look alike diseases has cost me little trouble.
The cornerstone of diagnosis deserves meticulous attention to all details.
We draw all our bloods fasting, in the morning. In our CRC studies we documented modest changes in serum calcium with food that could complicate diagnosis.
PTH levels in plasma remain stable whereas those in serum do not. Therefore we prefer plasma samples for PTH assays. We often say ‘serum PTH’ but I usually obtain plasma PTH levels.
We are among the few who use atomic absorption calcium measurements standardized using aqueous standards. The method narrows the variability of the assay and permits diagnosis in patients with very modest hypercalcemia. But modern high throughput instruments can suffice if laboratories take care to standardize carefully and establish a normal range.
Having this technique has spoiled us. We shun common aids to diagnosis such as ionized calcium and albumin corrected serum calcium. They may help others.
Evaluation of Results
In a calcium stone former, even one serum calcium above the normal range for the laboratory in use prompts me to order more. The cost in time and test charges dwindles to nothing at all compared to a missed diagnosis and opportunity for surgical cure. Put against the tens of thousand of dollars paid for even a single kidney stone surgery, or the many thousands of dollars for a mere ER visit, how can one stint on blood measurements that in total could consume perhaps a thousand to two thousand dollars at the most?
With multiple samples, in most patients, one finds stable average calcium values above normal or not. I am personally unrelenting and pursue serum calcium evaluation as long as I need to until I am satisfied.
I do this because serum calcium varies from day to day in patients with PHPT and one may need 10 or even 15 measurements or more in some cases to be sure.
Very many drugs can alter serum calcium. Famous ones include thiazide diuretics, lithium, and vitamin D excess that raise it, and loop diuretics like furosemide that lower it. Textbook chapters and reviews list all possible candidates and physicians refer to them. The crucial idea for a broad audience is this: Suspect any drug. If possible evaluate for PHPT in the absence of drugs. Never eat before blood sampling; that includes coffee and especially coffee creamers. Stop any calcium supplements, herbs, and vitamins at least a week before evaluation.
PTH Not Suppressed
Normal or High Values in PHPT
This must be measured in the same blood sample as calcium. In PHPT patients PTH levels can be normal or high. Unlike hypercalcemia whose ascertainment may require many blood samples, just a few PTH values in the normal range or higher suffice.
Normal or High Values in Other Conditions
A few conditions raise serum calcium, and do not suppress PTH. Familial hypocalciuric hypercalcemia (FHH), a genetic disorder of CaSR functioning, does this and separates from PHPT in having a low urine calcium excretion. Lithium treatment and hyperthyroidism can mimic PHPT.
FHH offers an insight into the importance or lack thereof of the CaSR apart from kidney and parathyroid gland. Heterozygotic patients with inactivating gene mutations have hypercalcemia, normal or high PTH and low urine calcium excretion, as I described, and yet display no other significant abnormalities of muscle, balance, or quality of life. Perhaps one good gene copy suffices in other tissues – such as intestine. Certainly, knockout of both alleles in mice causes a severe disorder much like PHPT. Correspondingly, in humans homozygous inactivating mutations of the CaSR cause neonatal severe PHPT.
Association and clinical trial data do not support an important role of CaSR abnormalities in vascular disease. Proposed roles for CaSR genetic variants as causes of kidney stones have not been convincing.
If suppressed, something other than PHPT has caused the problem. Malignancy, granulomatous diseases, excessive vitamin D ingestion, and CYP24A1 deficiency come to mind.
Urine Calcium Not Low
One expects elevated urine calcium excretion as a common trait given stones and PHPT although in fact patients with just bone disease and no stones had urine calcium levels no different from those with stones. Our own data show very few patients with normal urine calcium levels, and these were older women with modest renal function impairment. Measurement of urine calcium will disclose the uncommon FHH patient as FE calcium will be very low – usually below 1%.
In our own report we present patients for whom we could neither recommend surgery nor completely rid ourselves of suspicion that PHPT lurked just beyond our reach. Many went on with little difficulty for years, treated like common stone formers. Only a certain wariness separated them, in my mind, from all the rest.
Normocalcemic Primary Hyperparathyroidism
I know many papers describe normal serum calcium with high PTH as a form of PHPT but personally doubt the usefulness of such a diagnosis in calcium stone formers. Unlike the numerous asymptomatic PHPT patients one encounters in general practice, our patients form calcium stones. Unwilling to operate without hypercalcemia, I treat their stones as I would any idiopathic calcium stone former. In all my years of work almost none went on to frank hypercalcemia. But a few did. So I believe that among the many people who present this way hide a few in whom PHPT smolders.
As a corollary, some patients with PHPT can easily pose as idiopathic calcium stone formers. Even marked hypercalciuria can be idiopathic in such people. Therefore, we need to measure fasting serum calcium in stone formers more or less yearly. Whenever serum calcium seems to rise, that can be a clue that underlying PHPT has become manifest and deserves serious attention. Cure far surpasses even the best management.
Low Calcium Diet
Among 118 people who in a Norwegian population survey had a PTH level above normal. Of these, 82 remained as candidate for additional studies 3 years later. Of those with persistent high PTH, one man and 7 women had developed hypercalcemic and diagnosed with PHPT. In 56 others PTH had remained high, and in 26 it had fallen to normal. Both groups – stayed high, fell to normal – were compared to 131 well matched people from the original cohort whose PTH levels were normal.
Compared to the normals, the people with persistently high PTH had slightly lower serum calcium levels, and by food table analysis lower calcium intakes (400 vs. 592 mg/day). Moreover, their blood pressures were higher (154 vs. 143 mmHg systolic). Only the women, not the men, displayed the higher blood pressure. Although bone mineral densities did not differ in general, among those with persistent high PTH spine bone mineral density was lower when adjusted for quartiles of BMI.
A Coherent Clinical Entity
Reputable mineral research groups have reported cases, mainly older people with bone mineral reduction, whose PTH levels are high and whose serum calcium levels are always normal. In this review of the Columbia University experience of 37 patients who met these criteria, 95% were women, 84% of the women were menopausal, and 73% had low bone mass. None had reduced serum 25 vitamin D nor reduced kidney function.
Over 4 years 22% developed frank PHPT. Their upper limit for serum calcium of 10.4 mg/dl, however, seems high. Although ours is very low because of atomic absorption as our technique, many commercial laboratories consider values over 10.2 mg/dl as an upper limit. Of interest in this point, those who developed PHPT tended to have the highest serum calcium levels.
A review of this subject, that includes references to the 2014 International Workshop on asymptomatic PHPT dutifully reviews the many exclusions needed to fully define high PTH and normal serum calcium as a reliable clinical entity: low vitamin D, any intestinal cause of calcium malabsorption, reduced kidney function, absence of idiopathic hypercalciuria, and exclusion of drugs at the times of measurements. Neither review mentions the obvious – low diet calcium intake that can produce exactly the picture described in these patients. Kidney stones are frequently present and bone mineral loss and fractures. Some patients have come to parathyroid surgery.
My View in Stone Disease
To me, the entity could arise from low diet calcium. I would not at this time recommend surgery but rather high diet calcium, with suitable low sodium intake or even thiazide to moderate urine calcium losses. The patients are mostly older women and some appear to have PHPT with borderline serum calcium levels. Given the generous upper limits mentioned above, I am not surprised that some – those with the higher values – simply had PHPT. I treat and wait; if serum calcium rises, I recommend PT surgery.
Bones Lose Mineral
Serial measurements can show a gradual fall in bone mineral density of the spine and forearm over time. Of these the distal radius is most affected, spine the least so. The loss of bone is more proportional to serum calcium than to level of PTH. After surgical cure patients restore their bone mineral. Although not essential in stone formers, I and most others evaluate bone mineral in PHPT patients.
What goes wrong with bone – beside the obvious loss of bone mineral occupies considerable modern research talent. One abnormality concerns sclerostin, a hormone I have mentioned in regard to the multi-hormone loops of mineral metabolism. Osteocytes – bone cells – make sclerostin that inhibits bone formation by osteoblasts – the bone cells that produce bone. PTH is thought to inhibit expression of the Sclerostin gene. Not surprisingly serum sclerostin levels in PHPT lie below those of normal people. This alone would lead to increased bone formation, not loss of bone mineral, so more must be disordered in PHPT.
As noted above in earlier sections this hormone is increased by both PTH and calcitriol and increases local inorganic pyrophosphate synthesis. Pyrophosphate inhibits crystallization and new bone formation.
Effects of CaSR
The dynamics of bone mineral regulation gleaned mainly from animals posit a role for the CaSR. Mature osteoblasts produce bone matrix that mineralizes much like kidney stone do but in a productive and controlled manner. When prompted to produce bone these cells produce RANKL (R) so that the ratio of R to its ‘decoy’ ligand (that captures R and prevents its biological actions) osteoprotegerin (O) rises. Free R stimulates formation of osteoclasts that break bone mineral down. CaSR stimulation in osteoblasts can reduce or increase the R:O ratio diminishing osteoclasts and fostering bone formation, or, in older animals raise that ratio so that bone mineral loss rises with formation – coupling. In trabecular bone – like vertebral bodies – mineral can increase while in cortical bone – wrists, for example, it can fall.
Common symptoms include constipation, and various mental and emotional changes that can resemble depression. Surgical cure may reduce the neuropsychiatric manifestations of PHPT.
When serum calcium is very high, one encounters loss of appetite, even nausea and vomiting, polyuria, dehydration and a vicious cycle leading to increasing serum calcium and kidney failure. But this course of events is very rare in routine PHPT. I have never encountered it in my stone practice.
Reduced kidney function has been repeatedly documented in PHPT. In asymptomatic PHPT falling function has been considered a reason for surgery. Among stone formers with PHPT surgical cure is a primary aim.
What Causes PHPT
Essentially enlarged glands in all forms of PHPT reflect neoplasia – cell proliferation that creates tumors that are for the most part benign but can occasionally possess the traits of malignancy.
As glands enlarge they exhibit reduced sensitivity of to serum calcium due, probably, to a reduction in the abundance of the CaSR. This leads to increased PTH secretion. Because basal PTH secretion by parathyroid cells remains above zero whatever the level of serum calcium, simple increase of cell number can progressively raise PTH secretion and serum PTH levels.
In 85% of PHPT cases parathyroid glands form a single adenoma – benign enlargement. In 15% of cases multiple glands enlarge – so called hyperplasia. Carcinoma is rare, at less than 1% of cases.
A large review of familial PHPT syndromes has been compiled for the European community and those interested might wish to read it.
Reviews quote about a 10% figure for PHPT cases that have a familial – genetic basis. A recent review lists FHH, under the more exact name FBHH, as a form of this disease as it is familial and consists of increased serum calcium with normal or increased PTH. We have already discussed it in relation to its cause in defects of the CaSR and I will not repeat the matter here.
Multiple Endocrine Neoplasia Type 1 (MEN 1).
This well known genetic disease accounts for about 20% of familial PHPT. The affected people inherit one defective gene copy but if the parathyroid cells lose the other as a somatic mutation they develop parathyroid tumors that overproduce PTH. Carriers with one normal copy seem normal. The MEN1 gene codes for menin, a nuclear protein that suppresses cell proliferation. MEN 1 gene deletions cause not only four gland enlargement PHPT but also a mixture of islet cell and pituitary endocrine tumors and endocrine tumors of the duodenum that produce the hormone gastrin that stimulates gastric acid production and fosters peptic ulcer. Other tumors include adrenal glands, thyroid glands and benign lipomas – fatty deposits beneath the skin. PHPT is usually the first manifestation of MEN 1 gene abnormalities.
Multiple Endocrine Neoplasia Type 2A (MEN 2A).
This complex disease arises from mutations in the RET proto-oncogene. Patients have mixtures of thyroid cancer, catecholamine producing tumors of the adrenal glands – pheochromocytoma, and PHPT. But PHPT is present in only about 35% of cases and the diagnosis is made because of the other two tumors. It does not therefore much concern us here.
Multiple Endocrine Neoplasia Type 4 (MEN 4).
This consists in parathyroid adenomas or four gland hyperplasia associated with pituitary, thymus, and adrenal tumors, and tumors involving the stomach and endocrine pancreas. It resembles MEN 2A. It arises from defects in the CDKN1B gene.
This autosomal dominant condition includes parathyroid adenomas – single or multiple enlarged glands but not all four glands – and parathyroid cancers, along with fibrosis tumors of the jaws, kidney tumors and cysts, and uterine tumors. It arises from mutations in the HRPT2 gene that produces a protein called parafibromin that inhibits cell proliferation. Like MEN 2A this disease is so colorful one diagnoses it readily and cannot confuse it with commonplace PHPT of kidney stone formers.
Familial Isolated PHPT (FIHP)
This consists in what the name says – families afflicted with PHPT that do not harbor any of the other gene abnormalities in obvious forms. It accounts for about 1% of PHPT cases and appears at an earlier age than most PHPT. Diagnosis depends on exclusion of gene abnormalities and clinical findings of MEN 1 and HPT – JT. Among cases in series, some patients have had abnormalities of MEN 1, CaSR and HRPT2 genes. The latter have especially correlated with parathyroid cancer or cystic parathyroid tumors.
Non familial PHPT arises from isolated single adenomas in 85% of patients and multiple gland enlargement in the rest. They are benign neoplasms that can grow progressively larger but almost invariably remain benign in lacking a potential for spread beyond the gland capsule.
Unlike the familial diseases gene abnormalities are not inherited but arise as somatic mutations. They mainly affect CaSR functioning, but also genes associated with familial syndromes such as MEN 1 and CCND1. Although adenomas may exhibit reduced CaSR abundance and therefore signalling sensitivity, no gene abnormalities of the CaSR or its signalling pathways have been found.
An alternative pathway to adenoma may be epigenetic abnormalities involving aberrant hypermethylation of tumor suppressor genes. Some recent studies have disclosed microRNAs. This excellent review provides references for all of what I say here.
This term has a blurred usage in practice. Few criteria reliably distinguish between adenoma and hyperplasia in a single gland. So the term hyperplasia usually stands for multiple enlarged glands. When multiple, adenomas may have a greater propensity to recur – normal glands enlarge later on and require another surgery. Often, if careful, familial PHPT will become apparent from family history. But at least half of multigland enlargement is non familial.
I omit here any review of preoperative imaging or of surgical approaches or surgical pathology as too far outside the goals of this site. Suffice that skilled endocrine surgeons are best for this kind of work as opposed to more general surgeons. My own career experience has been with endocrine surgeons specially skilled in parathyroidectomy. Given that the surgery has considerable complexity and cure is a common expectation, and also given that parathyroid surgery for PHPT is not a particularly common clinical activity I strongly support the idea of using surgeons whose career has centered on such work.
This recent review discusses imaging and surgery. It summarizes the Fourth International Workshop on PHPT that focused on guidelines for asymptomatic PHPT but includes comments about surgery and imaging as a guide to surgery.
I mentioned our own published data in an earlier section. A review of surgical outcomes of PHPT stone formers reports only one patient with a new stone over 100 months of followup. Another reports virtually no real new stones but only passage of prior stones from kidneys. A very recent review of PHPT summarized multiple observational studies all much the same. Although we have no prospective trials of surgery vs. medical management of stones in PHPT the observational data and the routine nature of curative surgery makes such a trial unlikely and perhaps no longer doable. The prime meaning is that surgical cure is ideal for patients who form calcium renal stones.
On the other hand, another, meta analysis, review found that recurrence rates of new stones after cure remained elevated compared to background rates of new stones in normal control populations. Even so the authors agree that surgical cure benefits stone disease but that postoperative management against new stones should continue. We have found much the same, in that residual hypercalciuria needs management. I illustrated this residual problem earlier.
What Does It All Come Down To?
Here you are, at my final say on PHPT.
Look for it in every calcium stone former, and look with diligence and a suspicious eye. For PHPT is a systemic disease with real potential to harm people that can be cured in most by modern and highly effective and safe surgery. Whereas many older women who have PHPT without any apparent consequence may never need a surgery and do well, no one recommends against surgical cure for stone formers.
Even if normocalcemic, as most are, calcium stone formers may harbor among their ranks a few smoldering normocalcemic PHPT patients who will manifests their disease only over time. This means I favor yearly fasting blood tests that no one thus transformed misses their chance for a cure.
Exclusion of all systemic diseases begins all stone prevention efforts. Frankly it is a fool’s errand to treat any calcium stone former without first excluding systemic disease as the cause. This requires serum and 24 hour urine testing and significant clinical ability. True, a majority will have nothing but idiopathic calcium stones, and whatever money and time used was used to no direct gain. But even one PHPT patient left untreated, even one, could in a year or two of unbridled stones mount up surgical costs in the tens of thousands of dollars. And miseries and dangers too. Even more, that patient’s disease can probably be cured.
Worse happens if one through lack of proper testing misses even more damaging diseases like severe hyperoxaluria. Acute kidney injury and even irreversible kidney failure wait on such patients from even incidental dehydration.
For these and other reasons I am opposed utterly to those clinically naive statisticians who advise all calcium stone formers be treated without blood and 24 hour urine testing. No idea is more likely to cause some patients real harm and, although I hesitate to mention the vulgar, some unlucky physicians their unwelcome day in court.