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CME / ABIM MOC

Disorders of Low Parathyroid Hormone: Do You Recall Where Autosomal Dominant Hypocalcemia Type 1 Fits? 

  • Authors: Bart L. Clarke, MD; Aliya Khan, MD, FRCPC, FAPC, FACE
  • CME / ABIM MOC Released: 4/21/2022
  • Valid for credit through: 4/21/2023
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  • Credits Available

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    ABIM Diplomates - maximum of 0.50 ABIM MOC points

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Target Audience and Goal Statement

This activity is intended for endocrinologists, primary care physicians, nephrologists, pediatricians, neurologists, emergency medicine, and other healthcare professionals in a position to screen for, diagnose and manage disorders of low calcium. 

The goal of this activity is that learners will be better able to screen, diagnose, and manage autosomal dominant hypocalcemia type 1 (ADH1), a rare form of hypoparathyroidism.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Prevalence/etiology of various forms of hypoparathyroidism
    • Screening, diagnosis, and management of ADH1
    • Patient education related to ADH1


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Faculty

  • Bart L. Clarke, MD

    Metabolic Bone Disease Core Group
    Division of Endocrinology, Diabetes, Metabolism, and Nutrition
    Professor of Medicine
    Mayo Clinic College of Medicine
    Rochester, Minnesota, United States

    Disclosures

    Disclosure: Bart L. Clarke, MD, has the following relevant financial relationships:
    Consultant or advisor for: Amolyt Pharma; Ascendis; Calcilytix; Shire; Takeda
    Research funding from: Ascendis; Shire; Takeda

  • Aliya Khan, MD, FRCPC, FAPC, FACE

    Professor of Clinical Medicine
    Director, Calcium Disorders Clinic
    McMaster University
    Hamilton, Ontario

    Disclosures

    Disclosure: Aliya Khan, MD, FRCPC, FAPC, FACE, has the following relevant financial relationships:
    Consultant or advisor for: Alexion; Amgen; Ascendis; Takeda
    Speaker or member of speakers bureau for: Amgen; Ultragenyx
    Research funding from: Amgen; Ascendis; Chugai; Radius; Takeda; Ultragenyx

Editors

  • Anne G. Le, PharmD

    Senior Medical Education Director, Medscape, LLC

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    Disclosure: Anne G. Le, PharmD, has no relevant financial relationships.

  • Frederick Stange, DO

    Scientific Content Manager, Medscape, LLC

    Disclosures

    Disclosure: Frederick Stange, DO, has no relevant financial relationships.

  • Renata Feldman, PharmD

    Scientific Content Manager, Medscape, LLC

    Disclosures

    Disclosure: Renata Feldman, PharmD, has no relevant financial relationships.

Compliance Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC

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    Disclosure: Amanda Jett, PharmD, BCACP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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CME / ABIM MOC

Disorders of Low Parathyroid Hormone: Do You Recall Where Autosomal Dominant Hypocalcemia Type 1 Fits? 

Authors: Bart L. Clarke, MD; Aliya Khan, MD, FRCPC, FAPC, FACEFaculty and Disclosures

CME / ABIM MOC Released: 4/21/2022

Valid for credit through: 4/21/2023

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Activity Transcript

Bart L. Clarke, MD: Hello. I'm Dr Bart Clarke, Professor of Medicine at Mayo Clinic College of Medicine in Rochester, Minnesota. We'd like to welcome you to this program titled “Disorders of Low Parathyroid Hormone: Do You Recall Where Autosomal Dominant Hypocalcemia Type 1 Fits?” Joining me today is Dr Aliya Khan, Professor of Clinical Medicine and Director of the Calcium Disorders Clinic at McMaster University in Hamilton, Ontario, Canada. Welcome to our discussion, Aliya.

Aliya Khan, MD, FRCPC, FAPC, FACE: Thank you so much, Bart.

Dr Clarke: Our objectives over the next 25 minutes or so will be to review the following. We want to talk about the epidemiology of this disorder, hypoparathyroidism due to autosomal dominant hypocalcemia type 1, ADH1, for short. We'll discuss the pathophysiology of the disorder and the role of the calcium-sensing receptor and calciotropic hormones in causing the disorder. We'll talk a bit about genetic testing for the condition and then summarize conventional therapy and the future of therapy for ADH1.

I'll start with a brief introduction to the topic. The mechanism of hypocalcemia in hypoparathyroidism is shown here briefly. Three quarters of our patients developed this condition because of postsurgical interventions. The other quarter of the patients have other causes behind them. And of course, it turns out that this condition, ADH1, is a genetically inherited condition. This would be expected in patients where there's a familial disorder or a new mutation causing the genetic disorder. In either case, the parathyroid hormone levels are low because parathyroid glands fail to secrete adequate amounts of parathyroid hormone. And as a result, the bones are less stimulated to give up calcium into the extracellular fluid; the kidneys are less stimulated to make 1,25-dihydroxyvitamin D from 1-α hydroxylase production; and the kidneys themselves will decrease the reabsorption of calcium into the blood, so there will be increased calcium that goes into the urine. The net effect of all this is that feedback on the parathyroid glands is less established than in the normal situation.

The pathophysiology of this disorder, known as OMIM 601198, that's the Online Mendelian Inheritance in Man 601198, is characterized by a number of changes. There is biochemical hypoparathyroidism due to the autosomal dominant germline heterozygous gain of function mutations that occurs in the calcium-sensing receptor. That's in type 1 ADH. In type 2 ADH, there is the guanine nucleotide-binding protein subunit alpha-11 that has the mutation in it causing the same biochemical phenotype. There are more than 70 ADH type 1 mutations that have been identified to date. 95% of these are missense mutations or substitutions, but 5% are in-frame or frameshift insertions or deletions. These mutations tend to cluster in the extracellular domain of the calcium-sensing receptor or in the intracellular or C-terminus. ADH1 causes about 70% of the total ADH cases. The other 30% are ADH2.

The calcium-sensing receptor is localized on chromosome 3q13.3-21.1. The protein that is produced from this gene is a 1,078 amino acid, 120-160 kDa class C G-protein-coupled receptor, most highly expressed in parathyroid glands and the kidneys. The extracellular internal domain binds calcium via cooperative binding in a very elegant mechanism and intracellular tail signaling to the cytoplasm via intracellular calcium and other secondary pathways. ADH1 typically causes low serum calcium and PTH levels in the blood with normal or increased 24-hour urine calcium with an increased risk of kidney complications. This shows a schematic of the calcium-sensing receptor showing the very large, at least 600 amino acid extracellular domain, at the top of the slide. The middle slide shows the 7 transmembrane domain, and then the bottom right of the slide shows the intracytoplasmic tail. Both the 7 transmembrane domain and the intracytoplasmic domain have about 200 amino acids each. And you can see that certain N-glycosylation sites are found extracellularly that help the extracellular domain function. Cystine residues are also found that are contributing to this. Internally, there's at least 5 phosphorylation sites that are phosphorylated by protein kinase C to downregulate function of the receptor. This shows in more detail the intracytoplasmic signal that we won't spend a lot of time on, but the extracellular domain is shown here binding calcium going through the transmembrane domain and binding mainly to Gq/11 but also to Gi/o, 2 different G-protein-coupled receptors, and then these mediate the transmembrane signaling through phospholipase C to the left that goes to inositol trisphosphate that regulates the release of calcium intracytoplasmicly from the cytoplasmic reticulum.

And then also through diacylglycerol protein kinase C and MAP kinase. This is another pathway that up regulates the production of proteins from the nucleus. The Gi/o portion of this usually activates adenylate cyclase, which leads to metabolism of cAMP, downregulation of protein kinase A, and this also stimulates MAP kinase pathways. It's a very complex intercellular signaling pathway.

The epidemiology of this is not well understood because it's a rare condition, but 2 different studies have shown prevalence rates between 3.9 and 5.8 per 100,000 using different cohorts. The DiscovEHR cohort analyzed 51,000 patients by whole exome sequencing and found 2 patients who have this condition. This was in a single large US healthcare system. 50% of these patients are known to have moderate asymptomatic hypocalcemia that's found incidentally. The other half have symptomatic hypocalcemia, sometimes in association with Bartter syndrome type 5, which causes hypokalemic alkalosis and hyperreninemic hyperaldosteronism, which alters potassium and other levels in the blood. 10% of these patients are known to have significant hypercalciuria that leads to nephrocalcinosis and nephrolithiasis. And about 35% of these patients are found to have ectopic or basal ganglia calcifications. There is a tendency for hypomagnesemia in this condition, as in other related disorders.

Now, Aliya, I'd like to turn to you to ask you to discuss what we know about the diagnosis and evaluation of ADH clinically.

Dr Khan: Sure. Thank you so much, Bart. That was a very comprehensive overview. As you know, we developed standards of care for hypoparathyroidism in adults, and this was a Canadian and International consensus, and it was led by both of us with our international colleagues around the world. We discussed how hypoparathyroidism should be evaluated today, and we discussed how we should be managing this condition. We know that the presentation of hypoparathyroidism really depends on the duration and the severity and the rate of onset of hypocalcemia. Patients may have symptoms of muscle cramping or twitching or circumoral numbness and paresthesia. They may actually ignore these symptoms and they may not even be recognized to be significant by their physician. Then the hypocalcemia will persist and progress if these symptoms are not identified, and it can actually result in depressed systolic function and congestive heart failure. We know that calcium is essential for QT, and prolonged QT interval is seen. This can result in bradyarrhythmias. Calcium is important for lung function, and in the presence of hypocalcemia, our patients can experience laryngospasm and bronchospasm, which can be really quite terrifying for patients, and it can have many neurologic presentations as well with seizures, confusion, and tetany. And we really want to emphasize today that it is important for us to identify hypocalcemia as early as possible so that we can fully evaluate these individuals and confirm their underlying diagnosis.

As you've mentioned, Bart, the diagnosis of hypoparathyroidism is confirmed if our patient has a low serum calcium. And calcium binds to albumin, so we always correct calcium for albumin. It must be a calcium adjusted for albumin or an ionized calcium. If we have a low calcium corrected for albumin or an ionized calcium in the presence of a low or inappropriately normal PTH verified on 2 occasions, at least 2 weeks apart, and in the presence of a high phosphate, we can confirm that they do have hypoparathyroidism. Now, a high phosphate is not required for the diagnosis but is often present. We have to remember that PTH will enhance calcium reabsorption in the kidney, but it also causes phosphate loss through the kidney. If we have inadequate levels of PTH, then there will be the loss of the renal calcium reabsorption and we will have high urine calcium loss, and this will result in low calcium. We will also have elevation in phosphate because phosphate is not being cleared through the kidney. We will have a high phosphate, a low serum calcium, because it is being lost through the kidney, and there will be hypercalciuria. This hypercalciuria contributes to the development of renal stones and nephrocalcinosis, which is calcification of the renal parenchyma. As you mentioned, Bart, PTH enhances the conversion of 25D to 1,25D. 1,25D allows us to optimize absorption of calcium and phosphate from the bowel, and also plays an important role in bone remodeling. Patients who have hypoparathyroidism have not only a deficiency of PTH, but they also have low levels of 1,25D. Both of these deficiencies result in the low serum calcium and they result in the hypercalciuria. The low levels of 1,25D will decrease calcium and phosphate absorption from the bowel. When we replace it, we have to remember that when we replace active vitamin D, this will increase phosphate absorption and may exacerbate the hyperphosphatemia. We know that 75% of patients approximately who have hypoparathyroidism have this because of prior surgery on the thyroid or the parathyroid glands (ie, prior neck surgery resulting in damage to the parathyroid glands or to the blood supply). 75% will have that. But the remaining 25% have a number of important causes. It's important for us to evaluate our patients because there are important causes for nonsurgical hypoparathyroidism.

The most common cause of nonsurgical hypoparathyroidism is autoimmune disease. This may be in isolation, or it may be part of the autoimmune polyendocrine syndrome 1, which is an association with mutation of the AIRE gene. When we have a patient who has clinical and biochemical features of hypoparathyroidism with low calcium or a low or inappropriately normal PTH, we need to find out why. Is it surgical or nonsurgical? And if it's nonsurgical, what is the underlying cause for the nonsurgical hypoparathyroidism and we go through the checklist. If we don't identify a cause, yes, we can give them the label that it is indeed idiopathic.

Let's talk about some of the genetic mutations which can affect the formation and the function of the parathyroid glands. If this is isolated hypoparathyroidism, this can be an association with mutations in the GCM2 gene. They may also be due to mutations in the calcium-sensing receptor gene, both type 1 and type 2 as you've described, Bart. They may also be mutations in the PTH gene. These are the genes that can result in isolated hypoparathyroidism.

It's also important to remember that calcium and magnesium hemostasis is linked. Patients who have ADH can also have significant problems with hypomagnesemia. This makes it more difficult to treat patients with hypoparathyroidism due to autosomal dominant hypocalcemia, because not only do they have hypocalcemia and hypercalciuria, but they also have magnesium loss in the kidney. The paracellular transport of magnesium is also affected. Magnesium deficiency when it is severe, will result in a paradoxical block of PTH secretion because intracellular magnesium is a co-factor for adenylate cyclase and results in a tissue resistance to PTH in the bone and the kidney. But it is important for us to correct magnesium in order to optimize homeostasis.

When we evaluate our patient with hypoparathyroidism, it's important to take a careful family history as well. Is there a family history of calcium abnormalities? Are the parents consanguineous? Are they related? Did they have head and neck surgery? Take a careful gonadal history. Is there a history of thyroid disease? Have they had urinary tract infections? Do they have other features of additional disease, other endocrinopathies or other conditions such as deafness, cognitive impairment? Do they have other neurologic features? Do they have a high-arched palate? Do have a cleft lip? Do they have features of DiGeorge syndrome or cardiac disease? It's very important to take a careful history and do a careful physical exam.

We can examine the patient also. Check for Chvostek’s sign. We would tap the cheek 2 cm interior to the ear lobe below the zygomatic process and see if the patient has twitching of the upper lip. We can also check the Trousseau’s sign and elevate the blood pressure cough over systolic for 3 minutes and check to see if there is carpal spasm. If we see when the blood pressure is elevated over the systolic pressure for more than 3 minutes and there evidence of carpal spasm, the patient has Trousseau sign, which is a clinical feature of hypocalcemia. But these signs may sometimes be present in people who have normal serum calcium as well. Ask about oral candidiasis. Do they have features of vitiligo, do they have adrenal insufficiency. Check adrenal function? Do they have features of APS-1? Do they have stigma of liver disease? Is there possibility of hemochromatosis? Look for congenital anomalies, hearing loss, retardation, genetic conditions which are associated with parathyroid disease.

In the lab profile, it's important for us always to check the calcium, corrected albumin or check the ionized calcium and adjust it for pH. Check phosphate, magnesium, renal function, parathyroid hormone. Check both of the vitamin D assays, and you can also evaluate intracellular magnesium. As we've mentioned, we need to ensure that vitamin D levels are normal, because vitamin D insufficiency will further impair calcium and phosphate absorption in the bowel. Over to you, Bart.

Dr Clarke: Aliya, thank you for this excellent overview. I'll talk a little bit about genetic testing and genetic counseling as well. Whole genome testing may not be necessary in this case if we suspect ADH1, but if the genetic causes are not yet known, further broader testing may be necessary. Usually in the same family, as long as the proband is diagnosed, of course, then the same mutation will be found in siblings, parents, other family members. It minimizes the cost and effort that's required to find activating mutations. In order to find the first activating mutation though, the whole calcium-sensing receptor gene usually must be sequenced, and this is expensive, time consuming, although there are multiple vendors available at this point to do sequencing either as an individual test or as part of a panel that sometimes might be necessary because of the possibility of other causes. It usually takes about 3 to 4 weeks to get the single calcium-sensing receptor gene test or results. Insurance, at least in the US, does not cover this. Patients have to pay out of pocket. Once the mutation is identified though, this reduces the cost for other family members who may have the condition so that they can be tested just for that single mutation. Now, when we test these patients, many times we're not sure if the patient has ADH1 or some other mutations. These can be done as part of a panel. Once the results are identified -- patients have to agree to do the testing, of course -- then the question is how to explain the mutation to the patients and their families. This oftentimes requires a genetic counselor able to do this.

This particular slide shows a sequence of ways to look at this in terms of genetic testing. You'll notice that patients who have hypothyroidism, it may be suspected as being syndromic or non-syndromic based on other features or known to be a familial disorder. Perhaps this is the first member of the family who might have the mutation. A number of features point in one direction or another. I won't take the time to read through this. You can look at this. Many of these have been covered by Dr Khan here in the last few minutes. If the patient is thought to have non-syndromic hypothyroidism, this is where ADH type 1 and type 2 fit. You can see in the far right corner of the slide that these patients usually do not have associated features and they're non-syndromic. Therefore, we're looking for these along with other mutations. You can see some of these other mutations listed here, but this should be the sequence of testing. If the patient has syndromic features, of course, then other gene tests shown on the left hand side of the slide should be checked for.

Now, let's talk about therapy for these patients. Aliya, back to you.

Dr Khan: Thank you so much, Bart. As we confirmed in our guidelines, Bart, we said that the goals of therapy are to correct and address the signs and symptoms of hypocalcemia. We want to maintain that serum calcium in the low-normal reference range or slightly below normal. We know that when we correct patients' calcium, they feel great. But we also want to ensure that not only are we making them feel great for today, but we're also minimizing their long-term complications. Excessive supplementation of calcium and active vitamin D may potentially be harmful, because if we give active vitamin D excessively, it will result in further elevations of phosphate. Our goal is to maintain the serum calcium in the low-normal reference range or slightly below the normal reference range. We want to maintain a calcium phosphate product which is normal. We want to avoid hypercalciuria. We definitely want to avoid hypercalcemia because this has been associated with declines in renal function. We want to avoid hyperphosphatemia. It's important for us to check phosphate levels and ensure that these are normal. Obviously, we want to avoid renal and extraskeletal calcification.

As we have mentioned, the treatment options for conventional therapy include calcium carbonate or calcium citrate. We want our patients to take the calcium with food. Whenever they eat, they should take a calcium supplement, because this will bind into the phosphate in the food and eliminate it. This will serve not only as a means of improving the serum calcium, but it will lower their phosphate when they take the calcium with food. Remember, if our patients are on a PPI, the PPI will decrease acid production. And calcium carbonate requires an acidic environment for optimal absorption. If our patient is on a PPI, I switch them to calcium citrate. We need to ensure that our patients have normal vitamin D levels. The 25-hydroxy vitamin D should be between 75 and 125 nmol/L. We can give this in the form of cholecalciferol. If the vitamin D levels are very low, like if they're below 25 nmol/L, then I use ergocalciferol (D2), 50,000 international units once a week. We will repeat the vitamin D assay 3 months later because it takes 3 months to reach steady state. We want to normalize the 25-hydroxy vitamin D assay. We've given calcium, we've normalized our vitamin D, now we can go ahead and give active vitamin D. We have 2 molecules available to us: calcitriol and alfacalcidol. Calcitriol is twice as potent as alfacalcidol. We can start calcitriol 0.25 mcg once a day or twice a day and gradually increase the dose. Now, remember the half-life of calcitriol is 5 to 8 hours, and steady state is reached in 5 to 6 half-lives. When we're titrating our patient and increasing the dose of the calcitriol, I like to check that serum calcium, corrected albumin or ionized calcium and phosphate, within 2 to 3 days after. Don't wait for a week or 2 weeks so the patient may not have enough active vitamin D on board and may end up having a further decline in this serum calcium, or they may overshoot. Close monitoring is critical, especially in an unstable patient. Remember half-life is only 5 to 8 hours. We will reach steady state in 5 to 6 half-lives. Hydrochlorothiazide can be very useful and we need to give fairly significant doses, 25 to 100 mg a day. I find that it's usually not that well tolerated in younger people because of hypotension. It's a big problem in patients who have autosomal dominant hypocalcemia. It would seem to be the drug of choice because of the fact that it can enhance renal calcium reabsorption, but because of the hypomagnesemia that it induces, this is a problem.

Then as you know, Bart, you and I were involved in developing the hypoparathyroidism guidelines that we have now submitted to the JBMR, and we completed a systematic review and meta-analysis of the literature looking at PTH therapy in comparison to the standard of care and what are the desirable and the undesirable consequences. We took a great approach and we felt that there were 6 studies that met our eligibility criteria. If we look at the meta-analysis, what was the bottom line comparing PTH and the standard of care? Well, with PTH therapy, we demonstrated reductions in phosphorus. This was a very positive outcome. We've also demonstrated reductions in the pill burden with reductions in the doses of calcium and active vitamin D. That's also a very positive outcome. What we did see, however, was an increase in hypercalcemia episodes. This was really reflective of the study design of the studies that have been completed to date. To conclude, PTH therapy is effective in decreasing phosphate, and it may have important benefits in decreasing long term complications of chronic hypoparathyroidism. This requires further study. Our graded recommendation is that in patients with chronic hypoparathyroidism, we suggest conventional therapy as first line therapy. This is a weak recommendation based on low quality evidence. We recommend that when conventional therapy is deemed unsatisfactory, the panel considers the use of PTH. But clearly, we need longer and larger studies with patient important outcomes.

Dr Clarke: Thank you, Aliya. This is great. One of the questions obviously our members or our audience will think about is what's new in this particular disorder, and can you tell us something about emerging therapy, specifically for ADH?

Dr Khan: Absolutely. Bart, you and I have been involved in the development of new molecules which are being evaluated currently, and these are the calcilytics. The calcilytics are antagonists of the calcium-sensing receptor. When we bind to the calcium-sensing receptor, a calcimimetic agent will decrease PTH, but a blocker will increase PTH. So, a calcilytic would be the ideal drug for patients who have autosomal dominant type of hypocalcemia, which is an association with gain of function mutations in the calcium-sensing receptor. We do have a number of molecules which have been as calcilytic options. The calcilytic molecule NPSP795 was evaluated in the animal model and showed a dose-dependent rise in PTH and was able to ameliorate the hypocalcemia in the mouse model. But it needs further evaluation, obviously. Encaleret has been evaluated in phase 2 clinical trials and has been demonstrated to increase blood calcium and PTH in patients with autosomal dominant hypocalcemia. This is a fairly small study, but you can see the baseline blood calcium. Then this is mean serum calcium on day 5. These patients were given 180 mg of encaleret twice daily, and we can see over here that these patients demonstrated a rise in serum calcium. In association with this was a dramatic decline in urine calcium and a rise in PTH. You can see the initial value and following encaleret therapy. It appears that we are able to reverse the abnormality that is present in patients who have autosomal dominant hypocalcemia because of gain of function mutations in the calcium-sensing receptor gene. Here we can see that encaleret treatment normalized mean blood and urine calcium levels. We can see the rises in serum calcium and reductions in urine calcium. And we saw rises in PTH and reductions in phosphate. We are correcting the underlying biochemical abnormality, which suggests that encaleret may be an effective treatment for autosomal dominant hypocalcemia type 1. Another piece of good news is that it has been granted Fast Track designation by the FDA and organ drug status in the US and EU approval will be expedited for our patients who suffer from rare disease. Having this granted Fast Track designation is very beneficial. Back to you, Bart.

Dr Clarke: All right. Aliya, very interesting data and certainly opens the door to future excellent therapies for these rare of patients.

What about study limitations of the phase 2 study that you've just gone over? This clearly was a small study. There are a lot of variants that cause calcium-sensing receptor mutations to cause this condition. Tell us a little bit more about that.

Dr Khan: Yes, absolutely, Bart. You're a hundred percent right. It is a small study and there is no control group and it is also open label. As you've mentioned, there are more than 100 variants of the calcium-sensing receptor, and we have only studied 9 reported variants. We're not certain if it will be reflective of all the variants. And where will this fit? Well, it could certainly become standard of care for autosomal dominant hypocalcemia type 1 to prevent end organ damage. But this is clearly very optimistic and very encouraging data.

Dr Clarke: All right. Aliya, I'd like to thank you for this great discussion and presentation of various aspects of this rare disorder. Are there any key takeaways you'd like to provide to our audience?

Dr Khan: Yes, Bart. I want to emphasize that hypoparathyroidism requires careful evaluation. It is associated with significant morbidity and we need to monitor our patients closely, especially when we're adjusting the doses of the calcium and the active vitamin D. Remember, long term complications are significant, and we want to avoid these long-term complications. If our patients are not doing well with active therapy, active vitamin D, and calcium supplements, then we should consider PTH therapy. And for autosomal dominant hypocalcemia, which is a challenging clinical situation, targeted therapy is very promising.

Dr Clarke: Great. Aliya, thank you so much for this overview and of the recent clinical trials, the developing emerging evidence that we have for specific targeted therapies in this condition. I'll just leave a few concluding remarks as well to close out this session. ADH1, to remind you again, is a rare genetic disorder are causing hypoparathyroidism. Hypoparathyroidism itself is a rare disorder, but this is a subset of the total and a very specific subset because of the issues that Aliya has mentioned. This condition is characterized biochemically by hypocalcemia, hyperphosphatemia, low PTH levels, and normal or increased urine calcium. This is the population in which you might think a patient could have ADH1. This is caused by autosomal dominant heterozygous activating calcium-sensing receptor mutations with a prevalence rate estimated somewhere between about 4 and 6 per 100,000. It's important to recognize that these patients who have hypoparathyroidism due to ADH1 should be treated carefully with conventional therapy so as to minimize hypercalciuria and consequent kidney calcifications and nephrolithiasis. Also, just to remind you, new therapies are underway that are being developed that hopefully will give us more options to treat these patients more specifically in a targeted, specific manner that will not aggravate their particular condition. With that, I'd like to thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.

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