The Curbsiders podcast

#443 Primary Hyperparathyroidism: Stones, bones, and almost certainly some groans

June 11, 2024 | By

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Don’t just sit on that borderline calcium!  Learn how to approach hypercalcemia and work up primary hyperparathyroidism.  In this episode, we learn who goes to surgery, how to work them up, and some variants of typical primary hyperparathyroidism. We’re joined by Dr. Lindsay Kuo @lindsaykuo (Temple University Hospital)

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Show Segments

  • 00:00 Intro
  • 03:31 Understanding Primary Hyperparathyroidism
  • 09:03 Handling Mistakes and Complications in Surgery
  • 11:44 Case Discussion: Hypercalcemia and Elevated PTH Levels
  • 22:41 Symptoms of Primary Hyperparathyroidism
  • 25:06 The Role of Vitamin D in Primary Hyperparathyroidism
  • 28:07 Testing Considerations for Parathyroid Hormone (PTH) Levels
  • 46:02 Considerations for Parathyroid Carcinoma
  • 49:19 Parathyroid Imaging in Primary Hyperparathyroidism
  • 52:23 The Surgical Procedure for Primary Hyperparathyroidism
  • 57:45 Intraoperative Parathyroid Hormone Monitoring
  • 01:00:15 Post-Operative Monitoring for Hypocalcemia
  • 01:04:38 Normocalcemic Primary Hypoparathyroidism and Normohormonal Primary Hyperparathyroidism

Primary Hyperparathyroidism Pearls

  1. Repeated serum calcium levels at or above the upper limit of normal should prompt evaluation
  2. Thiazide diuretics are a common cause of hypercalcemia; if suspected, the thiazide should be held prior to three months to assess if it is a contributing factor
  3. If both calcium and PTH are elevated, primary hyperparathyroidism is the most likely diagnosis
  4. 24 hour urine calcium should be done to differentiate between familial hypocalciuric hypercalcemia from primary hyperparathyroidism
  5. Primary hyperparathyroid patients with hypovitaminosis D should  undergo repletion to a level of at least 30 ng/dL
  6. All patients undergoing work-up for primary hyperparathyroidism should undergo DEXA of the femoral head, lumbar spine, and distal radius
  7. Indications for parathyroidectomy for primary hyperparathyroidism include serum calcium >1 mg/dL above upper limit of normal, skeletal involvement, renal involvement, and age <50 years
  8. After parathyroidectomy, patients are typically sent home with supplemental calcium and counseled regarding symptoms of hypocalcemia
  9. Normocalcemic hyperparathyroidism and normohormonal hyperparathyroidism both carry the same surgical indications as primary hyperparathyroidism

Primary Hyperparathyroidism- Notes 

Initial Evaluation

Initial presentation and work-up

Dr. Kuo states that any time the serum calcium is at or above the upper limit of normal multiple times should prompt further evaluation.  Patients are often asymptomatic at presentation, and hypercalcemia is discovered during routine labs.  The three most common causes of hypercalcemia she considers would be medication-related, primary hyperparathyroidism, and malignancy.  In terms of medications, thiazide diuretics are the most common culprits and lead to mild hypercalcemia (Lecoq 2021).  Dr. Kuo recommends holding the thiazide for three months to determine if it is a causative agent.  Lithium can also lead to hypercalcemia.  

Parathyroid carcinoma is rare but should be considered in patients with extremely high calcium levels, often leading to hospitalization, in the setting of significantly elevated PTH.  The onset is comparatively abrupt.  

Laboratory work-up

Dr. Kuo begins her work-up by checking a parathyroid hormone (PTH).  If the PTH is elevated, primary hyperparathyroidism is the most likely diagnosis.  If PTH is suppressed, it is worth considering other diagnoses.  Dr. Kuo notes that 25-hydroxy vitamin D is typically low-normal or slightly low with primary hyperparathyroidism since parathyroid hormone helps convert 25-hydroxyvitamin D to 1,25 dihydroxyvitamin D, and these patients by definition have elevated parathyroid hormone (Bilezikian 2018).  It is recommended to replete these patients to at least 30 ng/mL (Bilezikian 2022).

Some lab considerations to bear in mind.  Corrected calcium is passé these days, so ionized calcium should be checked if you need confirmation.  This lab is typically kept on ice for processing.  The calcium and parathyroid hormone levels should be checked at the same time, and biotin supplementation can potentially interfere with PTH (Oncul 2022).

Evaluating for symptoms

Kidney stones and osteoporosis with fracture are the two classic symptoms of primary hyperparathyroidism, but there are a myriad of other potential symptoms that can be seen.  Patients may mention polydipsia and polyuria (Walker 2022).  She will ask about bone pain (not joint pain) as well as weakness.  Additionally, patients may report abdominal pain, constipation, or heartburn.  These patients may have peptic ulcer disease, pancreatitis, or constipation that leads to abdominal pain.  Patients may report fatigue, dysphoria, or short-term memory issues as well.

Complications of untreated primary hyperparathyroidism

Primary hyperparathyroidism can lead to a decrease in renal function over time.  In addition to kidney stones, patients can develop nephrocalcinosis (calcium deposition in the renal parenchyma).  Patients may develop osteoporosis and subsequent vertebral compression fractures or, less commonly, brown tumors (a bony lesion caused by excess osteoclast activity).

Surgical considerations

Indications for surgery

Any patient with primary hyperparathyroidism and symptoms in the form of kidney stones or significant bony involvement should be considered for surgery.  Osteoporosis, GFR <60 mL/min/1.73 m2, serum calcium >1 mg/dL above normal, and nephrocalcinosis are also indications for surgery.  Twenty-four-hour urinary calcium >250 mg/day (6.25 mmol/day) in women and >300 mg/day (7.5 mmol/day) in men also constitute an indication for surgery, as does age less than 50 years (Bilezikian 2022).  Dr. Kuo states that many endocrine surgeons would consider operating if osteopenia is present.  Patients with some of the less concrete constitutional symptoms like fatigue or memory issues may also benefit from surgery (expert opinion).

24-Hour urine collection

When considering sending a patient for definitive surgery, a 24-hour urine calcium is collected to evaluate patients for familial hypocalciuric hypercalcemia (FHH), which can present with mild serum calcium and PTH elevations.  Importantly, FHH is a benign condition and is not corrected by surgery.  FHH is distinguished from primary hyperparathyroidism by the presence of low urine calcium and low calcium/creatinine clearance ratio.

Imaging

All patients with primary hyperparathyroidism should have a DEXA scan at three sites–the femoral head, lumbar spine, and distal radius (Bilezikian 2022).  The distal radius is not always included in standard DEXA scans but is often more affected than the other sites due to the presence of cortical bone.  The American Association of Endocrine Surgery guidelines recommend that all patients undergoing evaluation for surgery for primary hyperparathyroidism should undergo thyroid ultrasound to evaluate for concurrent thyroid nodular disease (Wilhem 2016).  Importantly, neck ultrasound would not significantly impact the decision to proceed to surgery.

In terms of parathyroid imaging, surgeons often have their own preferences, which can include 4-dimensional CT scanning or SPECT CT.  This type of imaging can be coordinated with your friendly neighborhood endocrine surgeon.

The surgery

Typically, this parathyroidectomy is done under full anesthesia with an endotracheal tube placed.  A baseline parathyroid hormone is drawn, and the surgeon may use preoperative imaging to guide their initial incision.  Approximately 80% of patients with primary hyperparathyroidism have a single abnormal gland (Kebebew 1998).  Seven to ten percent have two adenomas, and another seven to ten percent have four abnormal glands.  The abnormal glands are removed, and a series of PTH levels are checked following this.  The general rule is that the PTH should decrease by 50% and into the normal range.

Post-operative considerations

Patients generally go home on the day of their surgery, and most do not need postoperative opioid analgesia.  Patients may report a sore throat but can go back to eating and drinking normally as soon as they feel able.

Patients are sent home on a course of calcium supplementation to prevent postoperative hypocalcemia, which typically occurs over a period of about 48 hours (Wilhem 2016).  Symptoms of hypocalcemia include perioral and digital paresthesias, which can progress to muscle cramping, weakness, and eventually tetany.  Patients are advised to take extra calcium if they note symptoms and to seek prompt medical attention if the symptoms do not promptly resolve.

Primary hyperparathyroidism variants

Normocalcemic hyperparathyroidism

Normocalcemic hyperparathyroidism is characterized by a normal serum calcium level in the setting of an elevated PTH.  This can be challenging to differentiate from secondary hyperparathyroidism, which is also characterized by a normal calcium level and which must be ruled out before a diagnosis of normocalcemic hyperparathyroidism can be made.  This means ruling out secondary causes such as hypovitaminosis D, renal insufficiency, and malabsorption.  It can be helpful to work with an endocrinologist if you are considering this diagnosis.

Once the diagnosis of normocalcemic hyperparathyroidism is made, the same surgical criteria and approach apply as those in primary hyperparathyroidism.  These patients have a higher likelihood of multiple involved glands, which means the potential for operative failure is higher (Kulkarni 2024).

Normohormonal primary hyperparathyroidism

Normohormonal primary hyperparathyroidism is defined by an elevated serum calcium and inappropriately normal PTH level.  In the setting of hypercalcemia, PTH should be suppressed, so even a level at the lower end of the normal reference range is abnormal because it is not appropriately suppressed.  As with normocalcemic hyperparathyroidism, the same surgical guidelines apply as they would for classic primary hyperparathyroidism (Nabata 2023). 

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Goal

Listeners will develop a framework for the diagnosis and evaluation of primary hyperparathyroidism.

Learning objectives

After listening to this episode listeners will…  

  1. Develop an initial differential for hypercalcemia
  2. Perform an appropriate laboratory work-up for hypercalcemia
  3. Recognize the common presentations of primary hyperparathyroidism
  4. Appropriately evaluate patients for potential complications of hyperparathyroidism
  5. Outline the indications for surgical intervention for hyperparathyroidism
  6. Recognize common variants of typical primary hyperparathyroidism

Disclosures

Dr. Kuo reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Kuo, L, Williams PN, Watto MF. “334 Hyperparathyroidism with Dr. Lindsay Kuo”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast June 10, 2024

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Episode Credits

Written and produced by: Paul Williams, MD, FACP
Show Notes: Paul Williams, MD, FACP
Infographic and Cover Art: Paul Williams, MD, FACP
Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP
Reviewer: Fatima Syed, MD
Showrunners: Matthew Watto MD, FACP; Paul Williams MD, FACP
Technical Production: PodPaste
Guest: Lindsay Kuo, MD

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