Primary Hyperparathyroidism

PATHCHAT Edition No. 69
June 2020
Please contact your local Ampath pathologist for more information.

Author:

• Dr. Yashna Rampursat (Chemical Pathologist)

Introduction

✅ What is Primary Hyperparathyroidism (PHPT)?

• A disorder of mineral metabolism caused by excessive secretion of parathyroid hormone (PTH).
• PTH secretion is incompletely regulated and leads to hypercalcaemia.
• Usually identified through elevated serum calcium (corrected for albumin).

✅ Most Common Causes of PHPT:

• Single adenoma (80%).
• Multiple gland disease (20%).
• Parathyroid carcinoma (<1% of cases).

📌 PHPT is characterized by inappropriately high PTH levels despite hypercalcaemia.

Clinical Features of PHPT

✅ Symptoms Related to Hypercalcaemia:
✔ General:

• Polyuria, polydipsia.
• Constipation, anorexia, vomiting.
• Dehydration, arrhythmias.
• Altered mental status ("moans, bones, stones, and groans").

✔ Renal Involvement:

• Hypercalciuria.
• Nephrolithiasis (kidney stones).
• Nephrocalcinosis.
• Reduced renal function.

✔ Skeletal Involvement:

• Fragility fractures.
• Skeletal deformities.
• Bone pain (due to osteitis fibrosa cystica).

📌 Hypercalcaemia can present with a wide range of symptoms affecting multiple organ systems.

Risk Factors for PHPT

✅ Non-Modifiable Risk Factors:

• Gender: 2–3 times more common in women.
• Age: Most common in people aged ≥50–60 years.
• Genetic Factors (10% of cases):
  • Multiple Endocrine Neoplasia (MEN) Type 1 and 2A.

✅ Environmental & Modifiable Risk Factors:

• Chronic low calcium intake.
• Reduced physical activity.
• Higher body weight or BMI.
• External neck radiation.
• Lithium therapy.
• Thiazide diuretic therapy.

📌 A family history of hypercalcaemia or endocrine tumours should raise suspicion of genetic syndromes.

Laboratory Presentation of PHPT

✅ Classic Presentation (75% of Cases):

• Increased serum corrected calcium.
• Increased or inappropriately normal PTH.

✅ Other Presentations (25% of Cases):
✔ High calcium, normal PTH (20% of cases):

• May occur with lithium/thiazide use or familial hypocalciuric hypercalcaemia (FHH).

✔ Normocalcaemic Hyperparathyroidism (NPHPT) (<5% of cases):

• Elevated PTH with normal serum-corrected calcium and ionised calcium.
• Some patients progress to PHPT over time.
• Secondary causes (vitamin D deficiency, CKD, malabsorption, medications) must be excluded.

📌 A PTH level within the normal range, in the presence of hypercalcaemia, is still considered inappropriate and indicative of PHPT.

Evaluation of PHPT

✅ Recommended Laboratory Tests:
✔ Biochemical Markers:

• Serum corrected calcium or ionised calcium.
• Parathyroid hormone (PTH).
• Phosphate (often decreased in PHPT).
• Alkaline phosphatase (assesses bone turnover).
• 25-hydroxyvitamin D (to exclude deficiency).
• Renal function tests (urea, creatinine, eGFR).

✔ Urine Studies:

• 24-hour urinary calcium and creatinine excretion (to distinguish PHPT from FHH).
• Stone risk profile (if urinary calcium excretion >100 mmol/24h).

✔ Bone & Imaging Studies:

• Bone Mineral Density (DEXA scan) at the lumbar spine, hip, and distal radius.
• Vertebral spine assessment (radiography, CT, or vertebral fracture assessment by DEXA).
• Abdominal imaging (ultrasound, CT scan) for nephrolithiasis.

📌 Repeated calcium testing may be needed since PHPT patients may have fluctuating calcium levels.

Differential Diagnosis of Hypercalcaemia

✅ 1. Malignancy-Associated Hypercalcaemia:

• Marked hypercalcaemia (>3 mmol/L).
• Low or undetectable PTH.
• Often mediated by PTH-related protein (PTHrP).

✅ 2. Vitamin D Deficiency:

• Leads to reduced calcium absorption.
• Secondary increase in PTH secretion.

✅ 3. Chronic Kidney Disease (CKD):

• Secondary hyperparathyroidism due to:
  • Hyperphosphataemia.
  • Impaired renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D.
  • Hypocalcaemia.
• Tertiary hyperparathyroidism may develop due to chronic stimulation of the parathyroid glands.

✅ 4. Post-Gastric Bypass & Malabsorption Syndromes:

• Reduced calcium absorption stimulates secondary hyperparathyroidism.

📌 Low or undetectable PTH in hypercalcaemia suggests non-parathyroid causes, such as malignancy.

Genetic Testing for PHPT

✅ When to Consider Genetic Testing:

• Early-onset PHPT (<50 years).
• Family history of hypercalcaemia or endocrine tumours.
• Associated pituitary adenomas, pancreatic islet cell tumours, pheochromocytomas, or medullary thyroid cancer.

✅ Available Genetic Tests at Ampath:

• MEN 1 (Menin gene).
• MEN 2A (RET proto-oncogene).

📌 Genetic testing can help diagnose hereditary hyperparathyroidism and guide family screening.

Key Takeaways for Clinicians

✅ PHPT is the most common cause of PTH-dependent hypercalcaemia.
✅ Classic PHPT presents with hypercalcaemia and inappropriately high PTH.
✅ Urinary calcium excretion helps differentiate PHPT from familial hypocalciuric hypercalcaemia (FHH).
✅ Normocalcaemic PHPT (NPHPT) should be diagnosed after excluding secondary causes of elevated PTH.
✅ Genetic testing is indicated in early-onset or familial cases.
✅ Differentiating PHPT from malignancy-associated hypercalcaemia is crucial for management.

📌 Timely diagnosis and appropriate evaluation of PHPT can prevent complications such as fractures, nephrolithiasis, and chronic kidney disease.