The evolving landscape of managing hypoparathyroidism
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Approximately 77,000 people in the U.S. have hypoparathyroidism due to absent or subphysiological levels of parathyroid hormone.
About 75% of cases are the result of damage to parathyroid glands during neck surgery. The other 25% of cases are due to autoimmune disease or genetic causes or are idiopathic hypoparathyroidism of unknown etiology.
The calcium-conserving and phosphaturic effects of parathyroid hormone are lost in hypoparathyroidism. This manifests with a biochemical phenotype of hypocalcemia in the setting of inappropriately low parathyroid hormone. Hyperphosphatemia is also common. Urinary calcium excretion varies as a function of calcium and salt intake.
Symptoms and signs of hypoparathyroidism range on a spectrum and include paresthesia, muscle cramps, seizures, wheezing, fatigue, “brain fog,” cognitive dysfunction and QTc prolongation. Chronic hypocalcemia/hyperphosphatemia can lead to ectopic calcium depositions, such as basal ganglia calcifications, cataracts, nephrocalcinosis and nephrolithiasis, and chronic kidney disease.
These symptoms contribute to diminished quality of life for patients with hypoparathyroidism. Additionally, as symptoms of hypoparathyroidism overlap with symptoms of a variety of other health conditions, hypoparathyroidism may be misdiagnosed or diagnosed later in the course of the disease.
Challenges of hypoparathyroidism therapy
Conventional therapy, composed of calcium supplements (calcium citrate or calcium carbonate) and active vitamin D (calcitriol), is designed to raise albumin-adjusted serum calcium to the lower half of or just below the normal reference range. This is intended to alleviate symptoms of hypocalcemia while avoiding hypercalciuria and hyperphosphatemia. Magnesium supplementation and phosphate binders are also recommended in some cases. Calcium supplementation is often recommended in staggered doses and, in some cases, prescribed in high doses. Calcium supplementation may cause gastrointestinal side effects, such as constipation, interfere with absorption of other medications (eg, levothyroxine, iron) and, in high doses, may complicate the clinical phenotype of hypoparathyroidism with nephrolithiasis, nephrocalcinosis, CKD and ectopic calcifications.
Effectively raising serum calcium to physiologic or near-physiologic levels may be complicated by delay in diagnosing hypoparathyroidism, the need for high amounts of calcium supplementation, overall high pill burden, nonadherence with the prescribed regimen, and the lack of concordance between laboratory calcium values and patient symptoms. The following case study demonstrates the real-world challenges in diagnosing and managing hypoparathyroidism.
Case study
A 50-year-old man with gradually worsening vision was diagnosed with bilateral cataracts. Biochemical testing revealed hypocalcemia (7.8 mg/dL; reference, 8.4-10.2 mg/dL), hyperphosphatemia (5.2 mg/dL; reference, 2.7-4.5 mg/dL), low intact parathyroid hormone (12 pg/mL; reference, 15-65 pg/mL) and stage 1 CKD. Other biochemical assessments included 25-hydroxyvitamin D (26 ng/mL; reference, > 30 ng/mL) and 24-hour urinary calcium (< 300 mg/d).
Review of historical data of the past 6 years revealed persistent, mild and progressive hypocalcemia, but the patient reported no symptoms of hypocalcemia except infrequent muscle cramps. Further studies to assess end-organ effects of hypoparathyroidism showed nephrocalcinosis without nephrolithiasis; there was no basal ganglia calcification, and bone mineral density at the lumbar spine and total hip was normal.
The test results confirmed the diagnosis of hypoparathyroidism, but the challenge was to determine the cause in this patient with no prior neck surgery. The patient had no history of autoimmune or endocrine disorders, seizures or calcium abnormalities during childhood or young adulthood and no family history of calcium disorders. The clinical presentation did not suggest a genetic basis of hypoparathyroidism. Calcium-sensing receptor gene sequencing was considered, but was not considered medically necessary by the patient’s health coverage provider.
Treatment with conventional therapy initially resulted in an appropriate response based on laboratory assessments — but management challenges arose. The patient required relatively higher doses of calcium (2.4 g/day) despite the maximum recommended dose of calcitriol, and he started questioning the need for multiple doses, given that he was asymptomatic prior to treatment. Over time, the patient became nonadherent with the prescribed regimen, which made it difficult to establish an effective dose. Meanwhile, his CKD progressed to stage 3.
The patient eventually had multiple hospitalizations, for both hyper- and hypocalcemia, related to inconsistent intake of prescribed doses of calcium and vitamin D. He started experiencing frequent symptoms of hypocalcemia, and one of the hospitalizations was related to seizures with serum calcium as low as 6.4 mg/dL.
Treatment was switched to parathyroid hormone replacement therapy when it became available. Although he was not fully adherent to the recommended calcium and vitamin D intake, his calcium requirement reduced (1.2 g/day), serum calcium levels were relatively stable without wide excursions, CKD remained stable, and the patient remained asymptomatic during titration of parathyroid hormone dose.
However, the sudden unavailability of parathyroid hormone replacement in 2019 due to a product recall created a disruption in his hypoparathyroidism management. When conventional therapy was temporarily resumed, his inconsistent intake of recommended calcium and vitamin D once again led to intermittent, wide fluctuations in serum calcium levels and progression of CKD that required urgent hemodialysis during one of the hospitalizations.
Key learnings from this case study
Upon evaluation, the patient had an atypical presentation of hypoparathyroidism. This is an important reminder that the clinical presentation of hypoparathyroidism often varies depending on the duration and severity of hypocalcemia.
Patients with hypoparathyroidism may develop cataracts earlier in life due to ectopic deposition of calcium phosphate complexes in the eyes. Purported mechanisms include prolonged hypocalcemia with elevated calcium-phosphate product and membrane damage resulting from low levels of calcium in the aqueous humor of the eye. This patient’s ophthalmologist was an astute clinician who recognized that early-onset cataracts could be caused by abnormalities in mineral homeostasis and referred the patient for hormonal assessment. This underscores the importance of educating non-endocrinology-focused health care providers to recognize the signs/symptoms of hypoparathyroidism.
The spectrum of hypoparathyroidism symptomatology can make it difficult to diagnose, particularly in patients who are asymptomatic despite prolonged hypocalcemia. Lack of symptoms may reflect a longer chronicity of hypoparathyroidism, as patients lose the ability to sense the symptoms of hypocalcemia.
High pill burden can be a determining factor in nonadherence, which can lead to poor health outcomes and complicate management.
Parathyroid hormone replacement can reduce pill burden, improve adherence and prevent end-organ damage from complications related to high calcium supplementation.
Navigating the evolving management landscape
The potential for discordance between calcium levels and symptoms can make it challenging to determine what constitutes “adequate control.” Patients managed with conventional therapy may have normal calcium levels but still experience symptoms. Conversely, patients may be asymptomatic even with abnormal serum calcium levels. Titrating the dose of active vitamin D upward can help reduce the amount of calcium supplementation, which may improve adherence. Patients should be reminded to take their calcium supplements with food, as this helps to bind phosphate and manage hyperphosphatemia. Thiazide may be considered to treat hypercalciuria (except for patients with concomitant adrenal insufficiency in autoimmune polyglandular syndrome).
Regulating serum calcium is essential for managing hypoparathyroidism, but it should not be the only consideration — the patient’s quality of life and preference of treatment regimen are also important considerations. Patients who continue to experience symptoms despite normal calcium levels or those with a high pill burden may be interested in considering parathyroid hormone replacement, whereas a mostly asymptomatic patient with low pill burden may not want to switch to an injectable therapy.
Conclusions
Hypoparathyroidism is a rare disorder with limited therapeutic options. For clinicians managing patients with hypoparathyroidism, the 2022 international guidelines, which are based on the most up-to-date clinical evidence, serve as an excellent practice resource.
It is also important to stay up-to-date on the evolving treatment landscape. An FDA approval decision on a new parathyroid hormone replacement therapy for hypoparathyroidism is expected this year. If approved, consider how a new parathyroid hormone replacement therapy option may provide benefit to symptomatic patients who experience hypocalcemia, hyperphosphatemia, CKD, hypercalciuria and poor quality of life. Replacing the missing hormone may also be the preferred therapeutic option for patients with gastrointestinal disorders associated with calcium malabsorption and those with low adherence and/or intolerance of large doses of conventional therapy.
Endocrinologists should continue to educate themselves and their non-endocrinology colleagues about the latest hypoparathyroidism clinical evidence and treatment options with the goal of optimizing health outcomes for patients living with this condition.
Reference:
Khan AA, et al. J Bone Miner Res. 2022;doi:10.1002/jbmr.4691.
For more information:
Ruban Dhaliwal, MD, MPH, is associate professor of medicine in the division of endocrinology at University of Texas Southwestern. She can be reached at ruban.dhaliwal@utsouthwestern.edu; X (Twitter): @DrRubanDhaliwal.
Steven Ing, MD, MSCE, is clinical associate professor of internal medicine in the division of endocrinology, diabetes and metabolism at Ohio State University Wexner Medical Center. He can be reached at steven.ing@osumc.edu; LinkedIn: https://www.linkedin.com/in/steve-ing-951ab963/.
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