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Optimizing outcomes for the approximately 77,000 people in the US who have hypoparathyroidism due to absent or sub-physiologic levels of parathyroid hormone.

Approximately 77,000 people in the US have hypoparathyroidism (HypoPTH) due to absent or sub-physiologic levels of parathyroid hormone (PTH). HypoPTH most commonly (75%) results from damage to all four parathyroid glands during neck surgery but may have infiltrative, radiation-induced, genetic, or idiopathic causes. Because of insufficient levels of PTH, the calcium conserving and phosphaturic effects of PTH are lost, resulting in a biochemical phenotype of hypocalcemia, and commonly hyperphosphatemia and hypercalciuria. The signs and symptoms of HypoPTH are shown in Table 1 and key HypoPTH laboratory values are shown in Table 2. It should be noted that cataracts, kidney stones, and chronic kidney disease (CKD) may occur in patients taking high doses of calcium supplements.

Diagnosing HypoPTH

As post-surgical HypoPTH is the most common etiology in adults, it is important to follow a patient for onset of HypoPTH after neck surgery. Patients with genetic forms of HypoPTH may have been diagnosed as children. Timely and accurate diagnosis for other patients may be challenging because HypoPTH symptoms often overlap with those of other conditions. Physicians may not consider or test for HypoPTH as part of the differential diagnosis for other suspect causes of the symptoms. Additionally, in patients with minimal symptoms, HypoPTH may not be considered, especially in patients without prior neck surgery.

Diagnosis of HypoPTH requires low albumin-adjusted calcium (or low ionized calcium) along with a concomitantly measured PTH level that is low or “inappropriately normal.”  Confirmation of a HypoPTH diagnosis requires this finding on repeat laboratory measurements (at least a few weeks apart). Given that acute hypocalcemia is observed in hospital settings, it is important to repeat these assessments once the acute episode has passed to confirm a HypoPTH diagnosis.

Treating HypoPTH

Conventional therapy for HypoPTH typically includes calcium supplements and active Vitamin D (calcitriol). Magnesium supplements and phosphate binders may also be used in some patients. Conventional therapy for HypoPTH aims to increase albumin-adjusted serum calcium levels to the lower half or just below the normal reference range to alleviate hypocalcemia symptoms without causing hypercalciuria.

Challenges in managing patients with HypoPTH

Treatment adherence is a key challenge to effective management of HypoPTH. Calcium supplementation may require multiple daily doses; may cause gastrointestinal side effects (eg, constipation, bloating), may hinder absorption of concurrent medications (eg, levothyroxine). Additionally, calcium supplementation in high amounts may lead to other complications, including hypercalciuria, nephrolithiasis, CKD, and ectopic calcifications (eg, nephrocalcinosis). Given these challenges, patient education is essential for adherence to therapy and balancing symptom control versus adverse outcomes.

In some cases, even patients who adhere to their treatment regimens may need additional calcium doses if they have symptoms of hypocalcemia. Like people living with asthma carrying rescuer inhalers and patients with diabetes responding in real-time to symptoms of hypoglycemia, patients with HypoPTH should be counseled to keep calcium supplement pills with them in their workplace, car, purse, or pocket. Patients should also be educated that hypocalcemia may occur during some viral illnesses, presumably due to calcium malabsorption. In these instances, calcium supplement doses can be adjusted if calcium levels are destabilized, but patients must return to their regular supplement regimen once symptoms have resolved.

It is important to educate patients that calcium and calcitriol are essential for therapeutic benefit and serve a different purpose than other vitamin/mineral supplements. Physicians should also inform patients of the difference between calcium’s recommended daily allowance (RDA) and the therapeutic dosage intended to treat HypoPTH. Given the similarity in names, patients should be aware that calcium and calcitriol are different medications that serve different purposes (calcitriol, an active form of vitamin D, facilitates calcium absorption in the digestive tract). Building trusted relationships with patients is essential for ensuring the open and effective communication needed to manage HypoPTH in evolving circumstances.

Adherence can also be improved by prescribing a regimen that fits each patient’s lifestyle and preferences. In some patients, calcium forms other than tablets (eg, gelcaps, gummies, dissolvable tablets, dissolvable powders, and liquid forms) may be necessary. Special considerations should be taken for patients with concomitant gastrointestinal conditions such as gastroesophageal reflux disease. Given the acid-blocking effects of proton pump inhibitors or H2 blockers, patients taking these agents should be counseled to use calcium citrate instead of calcium carbonate supplements, as the latter is not fully absorbed without an acidic environment. Patients may not include over-the-counter calcium or vitamin D in their medication list, so proactively inquiring about the use of these supplements should be a part of medication reconciliation during clinical encounters.

Case study: The importance of considering and documenting HypoPTH as a cause of patient symptoms

A 46-year-old woman presented in the ICU with a past medical history that included a remote T10 spinal cord injury from a motorcycle accident complicated by spastic paraplegia, sensory loss, neurogenic bowel/bladder s/p suprapubic catheter, chronic contractures, chronic decubiti ulcer of the perineum, chronic sacral osteomyelitis. She was transferred from another institution over concerns of a urinary tract infection (UTI). She reported some typical symptoms as she had with prior UTI (weakness, fever, chills, feeling “woozy”) as well as new and different symptoms of visual disturbance and numbness.

In the month before transfer, she was hospitalized for metabolic encephalopathy attributed to hypovolemia and polypharmacy (including gabapentin, fentanyl patch, baclofen). The infectious work-up was negative and was treated empirically with cefepime/linezolid.

The hospitalists and consultants in urology, infectious disease, and gastroenterology did not identify specific diagnoses.

Once admitted to the ICU, endocrinology was consulted due to hypocalcemia and abnormal thyroid function tests. Upon further questioning, she reported a new symptom of perioral and hand paresthesia, muscle twitching, and jerking involving the eyes. Laboratory assessment found calcium 4.6 (reference range, 8.6-10.5 mg/dl), albumin 2.4 (3.5-5.0 g/dl), phosphate 6.3 (2.2-4.6 mg/dl), Mg 1.6 (1.6-2.6 mg/dl), intact PTH 16.3 (14-72 pg/ml), 25 hydroxy-vitamin D 14.4 (30-100 ng/ml), 1,25 dihydroxy-vitamin D 26.4 (20-79 pg/ml), TSH 49.445 (0.550-4.780 mcg/ml), free T4 0.45 (0.89-1.76 ng/dl). She was treated with continuous IV calcium infusion for 3 days while oral calcium, calcitriol, vitamin D, and levothyroxine were initiated.

At the time of her discharge from the ICU, she had iCa 4.93 (4.6-5.3 mg/dl) on calcium (as carbonate) 500mg TID with meals, calcitriol 0.25mcg TID, ergocalciferol 50,000 units weekly, and levothyroxine 88mcg daily. She was scheduled for an endocrinology follow-up two weeks later but was re-hospitalized due to “malaise” and elevated ALP 1100. A liver biopsy showed autoimmune hepatitis with primary biliary cholangitis (PBC) overlap, and she started prednisone and ursodiol. Autoimmune etiology would tie together primary hypothyroidism, hepatitis/PBC, and hypoparathyroidism.

Key Takeaways: This case study underscores the importance of evaluating calcium levels, managing severe hypocalcemia, and documenting hypoparathyroidism as the cause of symptoms. Proper documentation is essential to improving downstream care by making it clear to all patient care teams in the future that a symptomatic hypocalcemia episode occurred. It also facilitates follow-up to confirm the diagnosis and further evaluate the etiology.

Optimizing outcomes for patients with HypoPTH

A key step in optimizing outcomes for patients with HypoPTH is enabling accurate and timely diagnosis. HypoPTH should be considered as a possible cause of hypocalcemia, even in patients without prior neck surgery. Physicians should consider consulting with an endocrinologist to confirm a diagnosis of HypoPTH, assess etiology for nonsurgical HypoPTH, and make treatment recommendations. Utilizing the 2022 HypoPTH Clinical Practice Guidelines, an evidence-based practice resource, can help standardize and improve outcomes for patients with HypoPTH. Providing optimized care for patients with HypoPTH also depends on staying current with the evolving HypoPTH treatment landscape. The first new PTH replacement therapy for HypoPTH is expected to receive FDA approval in 2024, providing patients with a new treatment option. Most importantly, physicians need to maintain honest and open communication with patients to enable timely and effective responses to changes in symptoms or adherence to therapy.