Hence, our finding could just be explained by an increased risk of renal stones with young age in the general population. This eliminates most kinds of inclusion biases. It was not investigated whether these excluded patient groups differ from the final cohort, which makes this a possible source of error. Another group of patients were excluded because they were not found to fulfil the criteria of PHPT.
This should not have influenced the results of the study. This is a historic cohort study. However, bias may be reduced by the fact that all data were collected independently of the aim of this study. Furthermore, all medical and surgical records were retrieved and adjudicated by two researchers J Starup-Linde, E Waldhauer at the time of study. Potential disagreements were resolved by consensus. Surgery was performed at a single surgical department specialised in parathyroid surgery.
In all cases, the diagnosis of PHPT was confirmed by a histopathological examination of the removed tissue. Furthermore, the population in the region is primarily Caucasian, which makes the cohort homogeneous. Finally, the number included in our study is to our knowledge the largest in a study dealing with PHPT and renal calcification. We found a high prevalence of renal calcifications However, biochemical markers in general were poor predictors of the presence of renal calcifications, indicating that routine image diagnostics by CT scan may be needed for the identification of these in order to ensure proper treatment and to set the indication for surgery.
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Urolithiasis through the ages: data on more than , urinary stone analyses. Journal of Urology — Fraser WD. Lancet — Vestergaard P , Mosekilde L. Ugeskrift for Laeger 41 — Trends in urological stone disease.
BJU International — Prevalence of primary hyperparathyroidism and impact on bone mineral density in elderly men: MrOs Sweden. World Journal of Surgery 35 — Epidemiology of primary hyperparathyroidism in Tayside, Scotland, UK. Clinical Endocrinology 71 — Historical perspective of parathyroid disease.
Otolaryngologic Clinics of North America 37 — , vii. Andersen P , Mosekilde L. Tubular reabsorption of phosphate and calcium in primary hyperparathyroidism. Acta Medica Scandinavica — Khosla S. Endocrinology — Clinical and laboratory characteristics of calcium stone-formers with and without primary hyperparathyroidism. Mosekilde L.
Primary hyperparathyroidism and the skeleton. Clinical Endocrinology 69 1 — Parfitt AM. The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone diseases. PTH and bone cells: bone turnover and plasma calcium regulation. Metabolism: Clinical and Experimental 25 — Vitamin D metabolites and skeletal consequences in primary hyperparathyroidism. Clinical Endocrinology 68 — Minireview on regulation of intestinal calcium absorption.
Emphasis on molecular mechanisms of transcellular pathway. Digestion 77 22 — Vitamin D. American Journal of Physiology. Renal Physiology F8 — F Park S , Pearle MS. Pathophysiology and management of calcium stones. Urologic Clinics of North America 34 — Biochemical characterization of primary hyperparathyroidism with and without kidney stones. Urological Research 35 — Primary hyperparathyroidism: is there an increased prevalence of renal stone disease? American Journal of Roentgenology — The histology panel f shows a plug at the arrow and plaque at the arrowhead.
The tissue is partly scarred. 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.
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.
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.
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. 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 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. 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.
This must be measured in the same blood sample as calcium. Unlike hypercalcemia whose ascertainment may require many blood samples, just a few PTH values in the normal range or higher suffice. A few conditions raise serum calcium, and do not suppress PTH.
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. 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.
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.
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. 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. 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. Among 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. 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 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 vs.
Moreover, their blood pressures were higher vs. 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.
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. None had reduced serum 25 vitamin D nor reduced kidney function. Their upper limit for serum calcium of Although ours is very low because of atomic absorption as our technique, many commercial laboratories consider values over 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 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. 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. 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. 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.
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. 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. 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.
A large review of familial PHPT syndromes has been compiled for the European community and those interested might wish to read it. We have already discussed it in relation to its cause in defects of the CaSR and I will not repeat the matter here.
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. 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. It does not therefore much concern us here. 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. 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. This consists in what the name says — families afflicted with PHPT that do not harbor any of the other gene abnormalities in obvious forms. The latter have especially correlated with parathyroid cancer or cystic parathyroid tumors. 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. 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. 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 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. 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.
See your doctor if you have any signs or symptoms of hyperparathyroidism. These symptoms could be caused by any number of disorders, including some with serious complications. It's important to get a prompt, accurate diagnosis and appropriate treatment. The parathyroid glands maintain proper levels of both calcium and phosphorus in your body by turning the secretion of parathyroid hormone PTH off or on, much like a thermostat controls a heating system to maintain a constant air temperature.
Vitamin D also is involved in regulating the amount of calcium in your blood. Normally, this balancing act works well. When calcium levels in your blood fall too low, your parathyroid glands secrete enough PTH to restore the balance. PTH raises calcium levels by releasing calcium from your bones and increasing the amount of calcium absorbed from your small intestine.
When blood-calcium levels are too high, the parathyroid glands produce less PTH. But sometimes one or more of these glands produce too much hormone.
This leads to abnormally high calcium levels and low phosphorus levels in your blood. Calcium is best known for its role in keeping your teeth and bones healthy. But calcium also aids in the transmission of signals in nerve cells, and it's involved in muscle contraction. Phosphorus, another mineral, works along with calcium in these areas.
Hyperparathyroidism may occur because of a problem with the parathyroid glands primary hyperparathyroidism or because of another disease that affects the glands' function secondary hyperparathyroidism.
Primary hyperparathyroidism occurs because of some problem with one or more of the four parathyroid glands:. Primary hyperparathyroidism usually occurs randomly, but some people inherit a gene that causes the disorder. Secondary hyperparathyroidism is the result of another condition that lowers calcium levels.
This causes your parathyroid glands to overwork to compensate for the calcium loss. Factors that may contribute to secondary hyperparathyroidism include:. However, the black line shows that The important thing for you to see and teach your doctor , is that the incidence of stones does not go up as the blood calcium goes higher.
That is, a calcium of This next graph shows the same patients but this time we graphed them according to how long their calcium was above So this time the bottom X axis is the number of years their calcium has been above You can see that the longer a person has high calcium the higher the chance of getting kidney stones.
Even very mild elevations of calcium for a few years dramatically increases the incidence of kidney stones. One thing that we are not showing on these graphs is that the function of the kidney how good it works to filter and clean the blood decreases over time also. Not only do patients get kidney stones when they have high calcium for a few years, they also begin to develop kidney failure.
About half of all patients who have blood calcium levels even a little bit high for 10 years will begin to get a decrease in GFR, the number we use to determine the health of the kidney.
We have a blog discussing kidney failure and stones which includes x-rays and pictures. Men get kidney stones twice as often as women. This is true of all kidney stones, whether they are caused by a parathyroid tumor or not. The incidence of stones increases with age, with the peak being around 60 years of age.
Wow, guess what, the incidence of hyperparathyroidism increases with age, with the peak incidence being at age There is a test to measure the amount of calcium in your urine. This is almost always done by having you collect your pee in a jug for 24 hours and keeping that jug in your refrigerator the entire time disgusting!
This test is supposed to tell your doctors if you have too much calcium in your urine, and from this they are supposed to tell you if you are at risk for more stones. The concept being that people with higher calcium in their kidneys are more likely to get kidney stones.
Unfortunately, it isn't that simple and this test is pretty worthless. Let's take a look at the Hour-Urine results for 10, of our patients who had hyperparathyroidism. The normal range is less than , but you can see that most patients with hyperparathyroidism have urine calcium that is in the normal range.
We then made every patient with kidney stones have a red dot, and those that never had a kidney stone have a blue dot. And guess what, they are exactly the same. The amount of calcium in the urine is the same for those with kidney stones and those without kidney stones. If the amount of calcium in the urine had an influence on the formation of kidney stones in people with a parathyroid tumor, then all the blue dots no stones would be on the left side of the graph low urine calcium levels and all the red dots do have stones would be on the right side of the graph high urine calcium.
But this is not the case. The red and the blue dots are distributed equally along the x-axis. Thus, a 24 hour urine test cannot be used to determine which patient with high blood calcium or hyperparathyroidism is at risk of getting a kidney stone. So if your doctor wants to do this test for you and tells you to keep your pee in the refrigerator for a few days--UGH , you may want to take this page to them and show them that we can't tell who will and will not get stones by how much calcium is in the urine.
As a review from above, even mildly elevated calcium in the BLOOD will dramatically increase your risk of kidney stones and many other problems , with the risk being related to the duration of high calcium how many years above We've seen thousands upon thousands of people with kidney stones due to hyperparathyroidism.
We have found a couple of things that are important for you and your doctor to know. The typical patient with stones due to hyperparathyroidism has had one or two stones. Often it is one or two attacks, but the urologist says there are more inside.
Usually these people have never had a kidney stone before. The kidney stone problem is new. This is in distinct contrast to people who say "I've had 35 kidney stones over the past 20 years", because that is usually a kidney problem, not a parathyroid problem. Sure it is possible that you had kidney stones when you were 25 that weren't due to a parathyroid problem We see this frequently and this is classic for a parathyroid tumor--the first stone was not related to parathyroid problems, and the second one many years later was.
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