Hello, this is Dr. Bart Clark from Mayo Clinic in Rochester, Minnesota, coming to you with a presentation on hypoparathyroidism in adults and children. And these slides will give you an overview of the topic area with all the recent advances and knowledge in this area, which has expanded greatly, I would say, over the last 10 years. So this is an approach to the life cycle as patients, both younger adults, children, and older adults have this condition, and we need to treat them appropriately at the right time. And so these slides will talk about the hypoparathyroidism as it presents in adults. So you can see my financial relationships at the bottom. These will not affect the discussion in this, and we certainly will not discuss off-label usage of various products. So hypoparathyroidism in adults has a certain differential that is many times suspected because serum calcium is lower than expected initially, and then various other laboratory studies are checked to find out why parathyroid hormone deficiency usually is found, and levels can be variably low, moderately low, inappropriately low for the level of serum calcium. But the basic issue is PTH deficiency, and that's what defines hypoparathyroidism. PTH resistance, on the other hand, is also not uncommon, and as you know, pseudo-hypoparathyroidism can be diagnosed in adults, children, or young adults, and this varies over time. We expect that our pediatric colleagues will usually pick this up in childhood, but sometimes not. Sometimes the adult people or other primary care providers providing for them don't look into this very far. As adults, though, the other issue that we need to make sure is that the patients don't have hypomagnesemia. Hypomagnesemia can cause what appears to be hypoparathyroidism with low serum calcium, low serum PTH, and so every patient who is suspected of having hypoparathyroidism should have serum magnesium checked at least once to make sure it's normal. If it's low, then there's a differential that needs to be evaluated for that issue. The most common reasons that patients in adulthood will have hypoparathyroidism diagnosed is after surgery, usually after anterior neck surgery for various reasons, including hyperparathyroidism and more commonly, perhaps, thyroid surgery for thyroid nodular disease or thyroid cancer or goiter or other issues that lead to anterior neck surgery. But autoimmune hypoparathyroidism is fairly common. This presents without an anterior neck scar and would be the top of the list for possible differential diagnosis when a patient presents this way. Other patients, though, have iron overload, either due to thalassemia or hemochromatosis. Some have copper overload, rarely due to Wilson's disease. Metastatic disease to the parathyroid glands can knock off the parathyroid glands. If 90% of the parathyroid tissue is destroyed in the process of metastasis, clearly this is less common. Radioactive iodine therapy in very large doses, especially after treatment for metastatic thyroid cancer, can cause this. And then finally, magnesium deficiency or excess is always in there to prevent overlooking that. Now, genetic causes do show up in adults, too, and there's a variety of genetic causes. The purpose of this presentation will not be to go into great detail of that because there is current various review articles written on this by excellent groups that have done this recently. The mechanism of action of this condition is hypocalcemia that develops because of normal parathyroid glands either being removed at surgery or deficient for other causes. You can see the split here. Surgery is the lion's share of most of this, but the other causes do explain about 25%. The net effect of these events is that parathyroid function decreases, parathyroid hormone drops. Because of that, the effect on the skeleton diminishes. There is less release of calcium into the blood from parathyroid hormone stimulation of the skeleton. This also leads to decreased synthesis of 125-dihydroxyvitamin D by parathyroid hormone stimulating the renal 1-alpha-hydroxylase. The decrease in the 125-dihydroxyvitamin D leads to decreased intestinal absorption. And as a result of less stimulatory effect on the kidney, there's less calcium loss in the urine. So with these all changes leading to a decrease in extracellular fluid calcium, the feedback that normally would stimulate parathyroid glands to oversecrete or secrete more is not there. And so the loop essentially doesn't function, and this leads to reinforcement of hypoparathyroidism. Now biochemically, we expect certain findings. You can see the main ones here outlined in yellow. These patients always have decreased serum calcium or low normal serum calcium, high normal or increased serum phosphate, and inappropriately low normal or decreased intact parathyroid hormone. There's a spectrum in there, and if patients have lower parathyroid hormone than expected for their serum calcium level, it's also low at the same time, or the serum phosphorus is high at the same time, this should stimulate thought about possible hypoparathyroidism. The other changes that are occurring shown here on the list are also true, but usually not the reason that these patients are diagnosed. They may be, if they're tested, they may be recognized, or there may be a clue that the condition is present, but decreased markers of bone turnover, bone-specific alkaline phosphatase beta CTX telopeptides are usually low in this case. Total alkaline phosphatase is also decreased as a result. Urinary calcium is usually low normal to decreased before supplementation has started, and the calcium to creatinine clearance ratio is also diminished, just the opposite of what we expect in primary hyperparathyroidism. Finally, the serum 125 dihydroxy vitamin D levels are either decreased or low normal, and serum chloride and bicarbonate levels are also affected, not usually identified in this setting because we don't measure these very often, but if they are measured, they would show changes as expected. And then finally, by definition, the normal serum magnesium must be present because if it's low, that's a separate issue and may be causing the biochemical appearance of this condition when it's not really due to this. Now what about anterior neck surgery? This is the most common acquired cause of acute or chronic hyperparathyroidism. We know that post-surgical hyperparathyroidism is usually due to the inadvertent removal of or damage to the parathyroid glands or their blood supply. Some patients develop this after anterior neck surgery, even though parathyroid tissue was left intact with a good blood supply, and it develops later. So this comes up periodically. Patients who have surgery on thyroid or parathyroid glands or during neck dissection surgery for head and neck cancers may develop this. And of course, permanent hyperparathyroidism pretty much by definition has to be present for longer than six months after surgery. Estimates of how frequent this is are shown here. Post-thyroid surgical investigations show that permanent post-operative hyperparathyroidism ranges between about 0.5 to 6.6 percent. Not very common, but still maybe more common than we'd expect. And of course, centers that do more endocrine surgery have a less frequent event rate than what other centers do. But you realize that most anterior neck surgery these days, especially thyroid surgery, are done in centers that do not have a great deal of expertise in this. The estimates of post-thyroid surgical transient hyperparathyroidism, on the other hand, ranges as high as almost 50 percent. And the reason is that this is a transient event with recovery usually within 24 hours. But it can be very high if it's looked for within a short time after the anterior neck surgery. Higher risk of hyperparathyroidism has been reported in patients undergoing reoperation, more extensive thyroid resection, substernal goiter surgery, surgery for heteronectal cancer, or Graves' disease surgery. Acquired disorders that may cause hyperparathyroidism also must be considered, especially if the patient does not have an anterior neck scar. And this includes, then, the autoimmune condition, where it's either part of the autoimmune polyglandular syndrome type 1, especially in children, or it can develop as an isolated hyperparathyroidism due to autoimmune dysfunction in adults. It can occur in children, too. The accumulation of iron from treatment, usually for thalassemia or hemochromatosis, has been reported. It's a relatively uncommon event in these conditions, but it does show up. And in other countries, of course, it's more common. The accumulation of copper in the parathyroid glands leading to Wilson's disease is present, but a very low event rate, as you can see here, as low as 1 in 50,000 to 1 in 100,000 patients. It's very rarely occurring after iodine-131 therapy for thyroid disease, especially thyroid cancer, especially in the setting of metastatic disease or remaining burden of disease in the neck. This rarely occurs with metastatic infiltration of the glands. Like I said, it takes 90% destruction of those glands to cause this. And then finally, magnesium deficiency, either because of proton pump inhibitor therapy or excess, either usually from tocolytic therapy during labor and delivery, during pregnancy, this may occur and mimic the occurrence of hyperparathyroidism. Now, there's a large spectrum of symptoms. This can go from virtually nothing at all or very mild, which is fairly common, to a debilitating situation where patients are nonfunctional. And you can see the range of kinds of symptoms that patients expect or report. Most of the symptoms we attribute to the hypocalcemia, not due specifically to the hyperparathyroidism, but it's hypocalcemia causing the symptoms. There's a large inter-individual variation in the difference of these symptoms and the sensitivity of the patient to these kind of symptoms. So you can hear patients say, I have virtually nothing at all, or I have mild symptoms or occasional symptoms compared to those whose life has been destroyed by this and they're nonfunctional and really can't attend school or go to work. They're highly variable in their description. It varies over time. This is expected. The neuromuscular irritability, which is the source of the large, most commonly recognized symptoms, tingling, paresthesias, especially around the fingertips and toe tips, sometimes around the nose or the lips or the tongue tip can also happen. But muscle cramps, not just tetany, but muscle cramps and other muscles at the nighttime during the daytime after exercise are fairly common. Laryngospasm, on the other hand, or bronchospasm are very uncommon, but they do occur and they can mimic other symptoms. And then finally, of course, seizures may occur, especially in children that can be serious or life-threatening. So this is the range of the exposures. In the neurocognitive or neuropsychiatric area, brain fog is a very common description, similar to other patients who have type 1 diabetes and other conditions that also describe brain fog. So this is not unique to hypoparathyroidism, but it's basically a sense that they're mentally lethargic. They don't have the ability to concentrate or to focus on various topics, and it's hard for them to express themselves sometimes. This obviously, these symptoms may lead to increased anxiety and even sometimes depression. Now other symptoms and signs that we expect in this condition, this shows a patient who had low serum calcium, 7.3 milligram per deciliter, with a prolongation of the QT interval. You can see the intervals in the top panel. Lead 6 was looked at, and of course, the interval, QT corrected interval was 543 milliseconds. Several hours later, with correction of serum calcium back up to 9.2 milligram per deciliter, QT, sorry, shortening was actually found. The QT corrected decreased to 457 milliseconds. So this is the shortening of that interval as you'd expect, and the T wave looks closer to the QRS complex as it should. Now other significant changes that may affect even young adults or children and certainly adults is the effect on the skeleton. You see here, the control patient is the one who doesn't have osteoporosis. This is the normal healthy subject, whereas the slide panel on the left shows a patient with hypoparathyroidism showing increased density of the skeleton, more plate-like than rod-like structure in the trabecular elements, and this would be a tip-off that that patient has low PTH causing low bone turnover, low bone turnover markers, and acquisition of skeletal bone density. Now the last slide in this presentation talks about treatment of acute symptomatic hypocalcemia, which is what adults and physicians who take care of adults and children both are expecting. This is a standard protocol. It's not the only protocol out there, but it's a common one, and so I put it in here just for reference so that we don't forget. Patients who have acute symptomatic hypocalcemia need to be given intravenous calcium followed by oral calcium and other supplements as needed. A common way this is prepared is to use a 10% calcium gluconate solution diluted in 10 mLs of that up to 100 mLs, D5W, and this will be infused over 5 to 10 minutes to give about 90 milligrams of elemental calcium in a few minutes. This is important for rapid restoration of serum calcium, especially after seizures, other significant dysfunction that occurs. The longer infusion, slower infusion of 10 ampoules of calcium gluconate giving 900 milligrams total diluted in a liter of D5W at 50 mLs per hour will give about 15 milligrams of elemental calcium per kilogram over that several next hours, and this will more slowly restore serum calcium to baseline. The infusion is expected to raise serum calcium by about 2 milligram per deciliter over 8 hours. That's felt to be adequate for most patients. Many calcium chloride these days is avoided due to venous irritation that can lead to necrosis and sloughing of tissue, so this is avoided. Magnesium supplementation would be recommended if the patient were found to be magnesium deficient at the same time, and then as soon as patients are able to take oral preparations, they should begin oral calcium and vitamin D supplementation as felt to be appropriate for the setting. Most hospitals or inpatient facilities will not allow this calcium infusion to be given without cardiac monitoring, and so many of the times patients are put in a cardiac monitored bed exactly for this reason, so that if cardiac rhythm disturbance gets worse or develops, it's recognized and appropriately treated. I'll stop here for the adult presentation, and we'll come back to the pediatric presentation next. Thank you.

hypoparathyroidism

treatment strategies

calcium levels

magnesium deficiency

neuromuscular irritability