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Life Cycle Considerations in Hypoparathyroidism
Hypoparathyroidism and Aging
Hypoparathyroidism and Aging
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The second part of my presentation is about potential long-term consequences of hypoparathyroidism. Again, I want to thank Endocrine Society for the opportunity to talk to you about this subject. I don't have any relevant disclosures. As we know, hypoparathyroidism is a multisystem disease. The second international hypoparathyroidism workshop performed a systemic review to identify symptoms and complications associated with hypoparathyroidism. Ninety-three studies enrolling more than 18,000 patients were reviewed, and if a symptom or complication was reported in at least three studies and had significantly higher estimates in comparison with individuals with normal parathyroid function, they were considered to be caused by chronic hypoparathyroidism. Using these criteria, they arrived at eight most common complications that you can see listed in this table. They also identified 51 potential symptoms and complications that were reported by one to two studies, such as basal ganglia calcification. Overall, depending on which individual complication we're looking at, there are certain risk factors that are reported to be associated with increased risk of developing that specific complication. Longer duration of hypoparathyroidism and non-surgical cases of hypoparathyroidism are often associated with higher frequency of symptoms or complications. It's unclear if this increased risk in non-surgical cases is related to longer duration of exposure because non-surgical cases are usually diagnosed at a young age or if there are other factors involved. In the studies that we will be reviewing in this module, all or almost all patients were treated with conventional therapy and patients who were on PTH or PTH analogs, if present, were excluded. Focus of this module will be on renal complications and cardiovascular complications. Neuropsychiatric complications are also a major source of morbidity, but their association with aging and duration of disease is less clear. Here we're looking at a retrospective chart review of 120 patients with hypoparathyroidism of diversity allergies that were treated within the Harvard system. Most patients were seen at least twice. Two of them were seen only once but had extensive documentation of outside data, including lab results which were available to authors. This first graph here shows the distribution plot of the most recently recorded serum calcium in panel A, serum phosphorus in panel B, and serum calcium phosphate product in panel C for each of the patients in the cohort. Eighty-eight percent of these patients had post-surgical hypoparathyroidism and 79 percent of them were female. Majority of them were taking calcium supplements with a median frequency of three times daily and majority were also prescribed calcitriol. No patient was on a phosphinder. Renal imaging and 24-hour urine collection were not done systematically but only at discretion of the treating physician. Recommended goal of serum calcium was lower half of reference range or just below, which here was 7.5 to 9.5 milligrams per deciliter, and the goal for calcium phosphorus product was less than 55 milligrams square per deciliter square. So in figure one, we can see that majority of cases had serum calcium, phosphorus, and calcium phosphorus product within normal limit. Specifically, looking at serum calcium, we can see that it was within target in 71 percent of patients and that average most recently measured calcium phosphorus product was about 35. Because serum calcium and phosphorus levels were obtained at variable intervals, the authors computed time-weighted average values. And in the figure two, we can see that the estimated proportion of time spent with serum calcium levels within in green, below in yellow, and orange above target range, and we can see that overall about 86 percent of time, as can be seen in the green, serum calcium was within target range. So overall, these patients were very well controlled and majority of them were able to have their biochemical parameters at goal. Despite that, when we look at the renal complications in this cohort, we see a relatively high frequency of hypercalciuria. So 38 percent of those that had a 24-hour urine calcium measured had at least one 24-hour value of more than 300 milligrams per 24 hours, which is striking. Again, as we noted, 86 percent of the time, these patients had serum calcium values within the target range. In figure B, we're looking at 44 patients who had a 24-hour urine calcium measured within 24 hours of a serum calcium measurement. And here, the thiazide users were excluded. As expected, higher serum calcium levels were associated with higher urine calcium values. However, you can see that there's a lot of scatter here. Of the seven individuals who had a 24-hour urine calcium level over 300 milligrams per day, five actually had low normal serum calcium values. And here, we can see that 41 percent of the individuals had a GFR of 60 or below, which is consistent with chronic kidney disease stage 3 or higher. And this is also significantly higher than the rate of renal impairment in healthy controls. In addition, authors also reported high healthcare usage in this cohort as compared with controls. So, 33 percent of these individuals required at least one emergency department visit or hospital admission for complications of hypoparathyroidism. So, for example, after excluding the first 30 days after diagnosis, 21 percent of them required ED visits for emergency treatment of hypocalcemia. Eight percent of patients had a report of a hypocalcemic seizure, including eight patients who suffered a seizure after diagnosis and initiation of therapy. One patient also had dilated cardiomyopathy, which was attributed to chronic hypocalcemia. Here, we're looking at a retrospective cohort study using a managed care claims database in the U.S. spanning over 10 years from 2007 to 2017. The cohort included more than 8,000 patients with chronic hypoparathyroidism and, again, excluded those who were receiving PTH therapy. They compared these individuals with about 40,000 randomly selected controls who did not have hypoparathyroidism with a ratio of 1 to 5, and they followed the cohort for five years. In graph A, we can see that patients with chronic hypoparathyroidism in blue had a significantly increased risk of developing incident CKD stage 3 or higher. In graph B, we can see that patients with hypoparathyroidism had a significantly increased risk of progression to a higher CKD stage. And in graph C, we can see that patients with hypoparathyroidism, again in blue, had a significantly increased risk of progression to end-stage kidney disease. In multivariable analysis adjusted for baseline characteristics, hazards ratio for incident CKD was 2.9, for CKD progression was 1.5, and for progression to end-stage kidney disease was 2.1. And here, we're looking at data from a Danish cohort of patients with hypoparathyroidism. These data were extracted from their National Herd Service, which is a nationwide coverage of public and private hospital with an almost 100% completeness and high precision of diagnosis. Using this database, the authors identified more than 1,800 patients with post-surgical hypoparathyroidism and assessed their mortality as well as their renal and cardiovascular complications. So in this table here, we see that compared with controls, patients had almost five times increased risk of renal stones and renal insufficiency, which remains significant after adjustment for prior renal disease or for prior diabetes. And using the same national registry, 180 patients were identified with non-surgical hypoparathyroidism based on ICD. 21% of this cohort had a genetic diagnosis, for example, DeGeorge syndrome or autosomal dominant hypocalcemia, and they were compared with age and gender-matched controls. In this image here, we see the risk of any renal disease, which was about three times higher than controls with a hazard ratio of 3.39. And specifically, there was a six-fold increase in risk of renal insufficiency, although the risk of nephrolithiasis was not increased in this cohort. Now moving on to cardiovascular complications, we know that hypocalcemia can lead to electrocardiographic abnormalities, including prolongation of the corrected QT interval. And we know that based on case reports in patients with hypoparathyroidism, cardiomyopathy and congestive heart failure are rare, but they have been reported. Data from Danish study of patients with non-surgical hypoparathyroidism showed an increased risk for any cardiovascular disease with hazard ratio of 1.9, ischemic heart disease with hazard ratio of 2. And we can also see that cardiac arrhythmias and stroke showed a trend towards increased hazard ratio. In this cohort, mortality was not increased. In this Danish case-control study, which evaluated association between biochemical findings and risk of different complications, they noted an increased risk of cardiovascular disease in the lowest tertile of serum calcium and also in individuals with four or more episodes of hypercalcemia. And they also noted that these individuals with four or more episodes of hypercalcemia also had an increased risk of renal disease. They also showed that disease duration was associated with an increased risk of both cardiovascular and renal disease. A 3.7-fold increased risk of cardiovascular disease is noted in individuals who had suffered from hypoparathyroidism for more than 20 years, compared with disease duration of less than 7.2 years after adjustment for other studied exposures. And a similar result for renal disease can also be noted. There is a 3.3-fold increased risk in patients with more than 20 years disease duration, compared with individuals whose duration of disease was less than 7.2 years. Trials evaluating the use of PTH replacement have shown promising results in decreasing pill burden and improving quality-of-life parameters. Effect of PTH therapy on 24-hour urine calcium has also been reported. In this graph here, we can see renal outcomes that were reported in 24 patients with hypoparathyroidism after eight-year use of recombinant human parathyroid hormone 184 therapy. Serum creatinine and GFR remained stable. And overall, the urinary calcium excretion declined by 38%. Decreased renal excretion of calcium was not seen in a similar study of shorter duration of 24 weeks. As we know, in 2019, the FDA recalled recombinant human PTH 184 due to the possibility of presence of rubber particles in the solution. In this graph here, we can see the effect of 26 weeks of palopectaryparotide, which was developed as transcon PTH on 24-hour urinary calcium. Palopectaryparotide is a prodrug consisting of PTH-134 transiently conjugated to a polyethylene glycol carrier molecule. The carrier blocks the parent drug from binding to the PTH receptor and decreases renal clearance and enzymatic degradation of the drug. Following subcutaneous injection with exposure to physiologic pH and temperature, the linker is cleaved, releasing PTH-134 in a controlled manner. In phase three of the pathway trial, which was a double-blind placebo-controlled trial, 84 participants were randomized to palopectaryparotide versus placebo. The mean 24-hour urine calcium levels decreased from 392 in patients who received the palopectaryparotide, to 220 as compared to 329 at baseline for the patients who received placebo to 292 mg per 24 hours. Overall, 60.7% of participants were treated with palopectaryparotide compared with placebo. Overall, 60.7% of participants who were treated with palopectaryparotide compared with 28.6% of participants on placebo achieved normal 24-hour urinary calcium, which was defined as less than 250 mg per 24 hours, which was statistically significant. In conclusion, chronic hypoparathyroidism is a multisystem disease and can be associated with renal, skeletal, neuropsychiatric, ocular, and cardiovascular complications. Increased disease duration with aging can be associated with increased risk of a number of complications. Patients on conventional therapy should be carefully monitored to minimize the risk of complications. And PTH replacement therapies have shown promising results in curbing some neuropsychiatric and renal complications. Thank you for your attention.
Video Summary
This presentation delves into the long-term consequences of hypoparathyroidism, highlighting its multisystem nature and the associated risks of renal and cardiovascular complications. A systemic review revealed common complications linked to this condition. Notably, hypoparathyroidism patients, particularly with prolonged and non-surgical cases, face heightened risks of renal issues, such as hypercalciuria and increased progression towards chronic kidney disease (CKD). Cardiovascular risks, including arrhythmias and ischemic heart disease, are also significant. Evidence from various studies indicates worsening complications with disease duration. While conventional therapies necessitate continuous monitoring to mitigate risks, PTH replacement therapies offer promising outcomes, notably reducing neuropsychiatric and renal complications, with studies showing improved biochemical control and decreased urinary calcium excretion. Despite these advancements, comprehensive patient care and vigilant monitoring remain crucial in managing hypoparathyroidism.
Keywords
hypoparathyroidism
renal complications
cardiovascular risks
PTH replacement therapy
chronic kidney disease
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