In my very long and complicated article I detailed primary hyperparathyroidism (PHPT) like a good scientist should. With all my heart I tried to make it plain enough for people in general to get a sense of how things work, but looking back on it, I doubt many will. Anyway, this book structure makes a place for summary and synthesis.
Is this PHPT lite?
It is PHPT practical, devoid of all but assets material to evaluation and treatment. Even so, in those areas I go into perhaps greater depth than in the parent article. The two articles complement each other as best I can arrange.
Alabama Grist Mill Dam by Beverly Hammond catches the sense of how PTH works on serum and urine calcium and phosphate. Also, it is beautiful.
A Disease of Misrule
PHPT arises because the parathyroid glands produce their hormone – parathyroid hormone (PTH) in excess of need and out of harmony with the mineral system within which PTH is the central regulator.
One could say through the actions of PTH the parathyroid glands rule the calcium kingdom, so powerful are its effects. And like the ruler of a well structured nation they are, in turn, held in check as were the ruling kings and queen of England by their royal subjects and their parliament.
But like those rulers of an earlier time might take to rampage that imperils their very kingdom, against which no force prevails to bring them back into the proper order of their world, like that is this disease. And as what only revolution – even regicide – could cure, so comes the surgeon in this case, to do that very deed.
Now, let me tell about the agent of this ruler, the imperial hormone, PTH, principle among peers. I have drawn a simple picture of its rule. See where it stands – above the rest, prime, enacting the will of the crown royal.
Kidney and GUT
Look first at calcitriol, active vitamin D, at the bottom in the kidney rectangle. PTH orders kidney cells to increase calcitriol production – blue lines mean stimulation. Calcitriol in turn signals gut cells to absorb more calcium and phosphate from food. So through calcitriol, PTH raises the amount of both minerals entering the blood which would tend to raise their concentrations.
PTH does the same for bone. It causes bone cells to break down its calcium phosphate mineral phase so that extra calcium and phosphate enter the blood. The red line means bone mineral goes negative – is lost.
Opposing Actions on Ca and Phos
To raise serum calcium more, PTH signals kidneys cells to conserve calcium. Remember, calcium is filtered out of blood in large amounts, but only 1% to perhaps 7% of what is filtered escapes into the urine – the rest is reclaimed back into the blood.
But unlike for calcium, PTH signals kidney cells to lower the fraction of filtered phosphate reclaimed back into blood. So serum phosphate is under opposing influences: More comes in from food and bone, kidneys conserve less. Serum phosphate level falls.
Why should it fall when the flow of phosphate in from food and bone increases? Why don’t the two effects balance out the third?
It is like the milldam. Let the stream run as it will, yet the dam adjusts the height of the pool behind – upstream of it. Lower the dam, and as soon as the pool empties down to the new dam level the flow downstream – urine phosphate losses here – is what it was when the dam was higher. Even if the stream flow is increased – more phosphate in from food and bone, the height of the pool remains low because the dam is set low. No flow can keep the pool above the dam for very long.
A Disordered Kingdom
Think of it. The serum calcium, over favored, so to speak, too high. And serum phosphate, normally calcium’s equal, now too low. All out of balance. Both of them move in excess through the body. Into blood from bone and in from food. And both go out through the kidney narrows, those long thin nephron tubes that on their way through they put in jeopardy. Being both in excess, how can calcium and phosphate fail to crystallize from time to time and block the tubules or form the stones we write about?
I said through this hormone, like the monarch of well run kingdom, the parathyroid glands rule within the check and balances of watchful peers and parliaments. Call them feedback loops, if you like.
Of them I illustrate only three.
Serum Calcium on PTH
Foremost, serum calcium controls PTH secretion through the calcium sensing receptor on the surfaces of parathyroid cells. LIke – if I might once again harken back to an earlier time, king and archbishop, the serum calcium controls and is controlled by the parathyroid glands. Calcium acts directly on the gland whereas PTH acts to influence serum calcium indirectly through reordering the actions of kidney, gut, and bone as I showed in my drawing.
Serum PTH, Calcium, and Phosphate on Calcitriol
Serum calcium and serum phosphate both suppress kidney production of calcitriol – red lines from them to calcitriol. So as serum calcium rises it reduces calcitriol production. But fall of serum phosphate further stimulates calcitriol production by taking its foot off the brake. Since PTH and low serum phosphate stimulate calcitriol production and only higher serum calcium offsets them, it is two to one: the net effect is that it rises.
Calcitriol on PTH
In the full article, I point out that calcitriol itself suppresses PTH. Calcitriol increases expression of the calcium receptor gene so the abundance of the receptor increases; this makes any calcium signal stronger by virtue of there being more signallers. That effect lowers PTH secretion by the glands for any given serum calcium level. Calcitriol inhibits the expression of the genes for the precursor molecule of PTH – pre pro PTH. This acts in concert with the signaller effect.
Failure in PHPT
But in PHPT the parathyroid glands produce PTH outside of normal regulation. They make too much hormone whatever the serum calcium or calcitriol. What should be an elaborate conversation turns into a lecture: PTH production rises and drives the system out of the normal bounds causing disease.
What Makes the Glands Rampage
Just as learned historians peer into distant times seeking the inner causes of misrule so do scientists into the genes and interior behaviors of the glands. And there they find the many reasons that explain why the glands should throw off their obligations and pursue the expansion of their own powers to the general deterioration of their domain – bone disease, stone disease, damage from high calcium to vessels, to brain function, stomach acid production, pancreatic function.
Main Abnormalities Produced by PHPT
When we come upon it, PHPT has already progressed to that kind of deterioration. Serum and urine are abnormal. But taken one by one, almost all of the abnormalities could have other causes. It is the pattern of those abnormalities that allows us to diagnose PHPT as their cause. And because the cure is surgery, to recognize that pattern and shun false diagnoses is for all physicians an imperial responsibility.
PHPT raises urine calcium, a lot because extra calcium is absorbed from food and liberated from bone. That alone probably accounts for the kidney stones. But as a group, calcium stone formers also excrete more calcium in their urine than would a group of otherwise unselected men and women without stones, and that extra calcium arises from idiopathic hypercalciuria (IH).
So, just a high urine calcium need not mean PHPT – in fact in most cases it is due to IH.
Low Serum Phosphate
We just spoke about the low milldam and the stream. More phosphate flows through from food and bone into the urine but PTH has lowered the dam. So PHPT lowers serum phosphate.
But low serum phosphate occurs in many kidney stone formers. Some have IH and therefore high urine calcium and low serum phosphate.
Low serum phosphate, therefore, even with a high urine calcium need mean nothing more than IH and certainly does not diagnose PHPT.
High Serum (or plasma) PTH
Should one even measure PTH in a routine calcium kidney stone former? I do not.
But say you did, or your physician did, and the value exceeds normal. Low calcium diet can raise PTH, so can low vitamin D. Even the most modest reduction of kidney function, a level common among older people, raises PTH despite adequate calcium intake and vitamin D. Some say IH raises it, sometimes.
High serum PTH by itself, and even with high urine calcium and low serum phosphate do not diagnose PHPT.
Reduced Bone Mineral or Nephrocalcinosis
PHPT reduces bone mineral but so does low calcium diet, especially in IH. Even all of hypercalciuria, and low serum phosphate, and high PTH and low bone mineral density together, even this fourfold complex is not PHPT all by itself.
The same for nephrocalcinosis. An antique term of art suitable for an earlier period in medical history, multiple kidney calcifications in no way adds to the diagnosis of PHPT.
High Serum Calcium
Here – the talisman, the very make and mark of PHPT – this one finding sets PHPT apart from all the rest.
PHPT Raises Serum Calcium Three Ways
When the parathyroid glands themselves produce PTH in excess, not in response to something else but on their own accord, by themselves so to speak, the hormone directly or indirectly raises kidney calcium retention, bone mineral loss, and intestinal calcium absorption – all three together.
Serum calcium rises as the water pool behind a rising dam, and here the stream flows with more abundance – from bone and food. So the urine calcium is high even though calcium retention by the kidney is high: The dam wall is higher and the stream is flowing faster, too.
High Serum Calcium Cannot Force PTH Below Normal
The PTH level itself if in the normal range is too high. That normal range is for a normal serum calcium.
Remember, the primary controller of PTH is serum calcium. If low calcium diet or vitamin D deficiency lowers serum calcium even slightly, PTH will rise to correct it back. If serum calcium should rise from, as an example, very high vitamin D intake or very high calcium intake, serum PTH will fall to correct it. So the high serum calcium, were it primary – something on its own – would suppress PTH to its lowest level.
Therefore, a high serum calcium without suppressed PTH means it is the glands themselves that are raising PTH – that is PHPT.
The Diagnosis of PHPT
Thus it is, the diagnosis rests on an elevated serum calcium and a PTH level either in or above the normal range – not low.
The Urine Calcium Must Be Not Low.
There is a genetic defect of PTH regulation, not rare, in which serum calcium is high, PTH normal or even high, but urine calcium very low. That defect, familial hypocalciuric hypercalcemia, runs in families and one must pass it by for it needs no treatment. Stones, if present, have some other cause.
It may be that bone mineral is low, or kidneys have many stones or calcifications in them, or serum phosphate is low, or all or none, and still the prime combination of high serum calcium, and not suppressed PTH with adequate – not low – urine calcium is almost enough.
I say almost because there are four more steps.
No Drug or Disease Causes The Abnormalities
Because these drugs lower urine calcium and prevent calcium stones, many patients take them. They raise blood calcium levels perhaps because they enhance renal calcium conservation – raise the milldam. A patient with idiopathic hypercalciuria taking a thiazide diuretic and who still excretes even a normal amount of calcium will seem to have PHPT because serum PTH levels will be normal and urine calcium not abnormally low.
Every physician knows this, but every stone patient needs to know it, too. Physicians may not know what their patients took when blood was drawn. Although in almost every case they will discover the drug as culprit, time and money get wasted for no reason. As a safe interval, one should stop the drug a week before drawing blood for the initial evaluation of any patient.
But what about follow up evaluations? Stopping the drug a week before won’t work. We want to know how well treatment has controlled urine calcium. So 24 hour urine and blood testing must coincide with drug use.
PHPT may appear during treatment and manifest as a rising serum calcium level, but thiazide can make it seem as if that has happened. What can we do?
The secret: tolerate slight increase of serum calcium. If seemingly too high too often, or rising over time, then stop the drug for a week and re-measure.
This ion, used for bipolar disorders, reprises the physiology of PHPT: high serum calcium and not suppressed PTH. But urine calcium has generally been low – as in familial hypercalcemia. Case reports document PHPT in some patients long after the drug has been stopped. Though not a likely cause of stones, lithium can cause massive confusion during evaluation of stone formers.
Whether primary or from excessive thyroid hormone replacement, states of systemic hyperthyroidism can include high serum calcium. PTH levels tend toward the low or even suppressed side. Be sure about thyroid status when evaluating for PHPT.
Low PTH Conditions
High serum calcium with low PTH – suppressed below normal – do not concern us here. Some stone forming states like sarcoidosis, and CYP24 deficiency cause this, as do malignancies and other disorders.
Normocalcemic Primary Hyperparathyroidism
Does It Exist?
Given all I have said and the many factors that can raise PTH levels apart from PHPT, this diagnosis never fails to baffle and almost amuse me. Of course we can see normal serum calcium with increased PTH in low calcium diet or vitamin D intake, and any level of reduced kidney function. Just being older makes exclusion of mild kidney function loss difficult indeed.
Even so, some people do have high PTH for no apparent reason, and every one of us has a few cases that went on to raise their serum calcium levels. The big article links to long reviews of this topic by respected authorities who say more or less what I have just said, but say it better.
What Do We Do?
Who are these people and what do they look like?
They look like IH with elevated serum PTH levels.
I see no approach but to treat them like IH and wait. If they indeed have an early parathyroid disorder they will gradually raise their serum calcium levels and warrant surgery. Surgery in advance seems folly to me. What if the problem were indeed diet or slight kidney function reduction?
Everyone I write for here has calcium stones, so treatment must be done. That leaves surgery or medical treatment directed at IH. I cannot but favor the latter, and watch carefully along the way.
Treatment of PHPT
My job is to establish the diagnosis. After that, the surgeon does the rest.
That means I do not require the surgery to confirm my diagnosis. I need to know beforehand.
In case the surgery finds not abnormal glands, it means the surgery failed – the disease is present still. If abnormal glands are found and their removal cures the abnormalities, well and good, but the original diagnosis should not require such surgical confirmation.
I mean by this, that if you do as I have said, the diagnosis can be made with surety and surgeons sent on their difficult tasks with confidence. They will do scans, and if the scans find abnormal glands or not should make no difference if I have done my work properly. Likewise for their surgery.
The corollary: Much like carpentry – measure twice, cut once.
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