What are the causes of an elevated parathyroid hormone level?

Causes of Elevated Parathyroid Hormone

Elevated PTH is most commonly caused by primary hyperparathyroidism (autonomous parathyroid adenoma), chronic kidney disease, or vitamin D deficiency—and distinguishing between these requires simultaneous measurement of serum calcium, 25-hydroxyvitamin D, and renal function. 1

Primary Hyperparathyroidism (Autonomous PTH Secretion)

Primary hyperparathyroidism presents with elevated or inappropriately normal PTH in the presence of hypercalcemia (corrected calcium >10.2 mg/dL). 1, 2

• A single parathyroid adenoma accounts for approximately 80% of cases, making it the most common etiology of elevated PTH with hypercalcemia. 3, 4
• Multiple adenomas or parathyroid hyperplasia affect 15-20% of patients (multigland disease). 3
• Parathyroid carcinoma is rare (<1% of cases). 3
• Hereditary syndromes (multiple endocrine neoplasia types 1 and 2A, familial hyperparathyroidism) should be suspected in younger patients or those with family history. 3, 4

Critical diagnostic point: The parathyroid glands autonomously secrete PTH despite elevated calcium—this failure to suppress PTH below 20 pg/mL in the setting of hypercalcemia is the hallmark of primary disease. 2

Secondary Hyperparathyroidism (Appropriate Physiologic Response)

Secondary hyperparathyroidism is characterized by elevated PTH with normal or low serum calcium, representing an appropriate compensatory response to a stimulus. 1, 5

Chronic Kidney Disease

• CKD is the most common cause of secondary hyperparathyroidism, with nearly all patients developing parathyroid gland hyperplasia as kidney function declines. 1, 4
• PTH levels begin rising when eGFR falls below 60 mL/min/1.73 m². 1, 2
• Phosphate retention is the fundamental initiating factor, triggering the cascade even before overt hyperphosphatemia develops—high phosphate intake directly provokes secondary hyperparathyroidism in early CKD stages. 1, 4
• Decreased 1,25-dihydroxyvitamin D production results from failing kidneys, reducing intestinal calcium absorption and causing hypocalcemia. 1, 4

Vitamin D Deficiency

• Vitamin D insufficiency is extremely prevalent and leads to reduced intestinal calcium absorption, hypocalcemia, and compensatory PTH elevation. 1
• PTH reference values are 20% lower when established in vitamin D-replete individuals (>20 ng/mL) compared to those with unknown vitamin D status—this means vitamin D deficiency can falsely suggest primary hyperparathyroidism. 1, 2
• The Endocrine Society recommends vitamin D measurement in all patients with elevated PTH to exclude this reversible cause. 1

Malabsorption and Nutritional Deficiencies

• Chronic intestinal malabsorption (celiac disease, inflammatory bowel disease, short bowel syndrome) impairs calcium and vitamin D absorption. 6
• Severe dietary calcium deficiency (<1000 mg/day) can stimulate PTH secretion. 2
• Hepatobiliary disease impairs vitamin D metabolism. 6

Post-Bariatric Surgery

• Patients who have undergone bariatric surgery may develop secondary hyperparathyroidism due to impaired calcium and vitamin D absorption, requiring regular monitoring. 1

Tertiary Hyperparathyroidism (Autonomous After Prolonged Secondary)

Tertiary hyperparathyroidism results from long-standing, severe secondary hyperparathyroidism that has become autonomous, characterized by lack of PTH suppression despite rising serum calcium levels. 1, 4, 7

• This typically occurs in CKD patients, with approximately 10% of dialysis patients requiring parathyroidectomy after 10 years, increasing to 30% after more than 20 years. 1, 4
• The hypertrophied parathyroid tissue fails to involute after renal transplantation and continues to oversecrete PTH despite normal or elevated calcium. 7, 5
• These glands may become resistant to calcimimetic treatment. 7

Normocalcemic Primary Hyperparathyroidism

Normocalcemic primary hyperparathyroidism (NPHPT) is defined by persistently elevated PTH with consistently normal albumin-corrected serum calcium, after exclusion of all secondary causes. 2, 8

• Vitamin D status must be >20 ng/mL (>50 nmol/L) to exclude secondary hyperparathyroidism. 2
• Adequate dietary calcium intake (1000-1200 mg/day) should be confirmed. 2
• Renal function should be normal (eGFR ≥60 mL/min/1.73 m²). 2
• NPHPT is not benign—it carries a risk profile comparable to hypercalcemic primary hyperparathyroidism, including bone loss and neuropsychiatric symptoms. 2

Physiologic and Demographic Factors

• PTH increases with age, possibly due to steady decline in GFR, leading to higher concentrations in people over 60 years old. 1, 2
• PTH is higher in Black individuals compared to White individuals—racial differences must be considered in interpretation. 1, 2
• PTH correlates positively with body mass index, with higher levels in obese patients. 1, 2

Pre-Analytical and Assay-Related Factors

• PTH should be measured in EDTA plasma rather than serum, as PTH is most stable in EDTA plasma at 4°C. 2
• Biotin supplementation can interfere with PTH immunoassays, causing under- or over-estimation depending on assay design—the Endocrine Society recommends avoiding biotin supplements before PTH measurement. 1, 2
• Different PTH assay generations measure overlapping but distinct molecular forms—second-generation assays overestimate biologically active PTH by detecting inactive fragments, and results can vary by up to 47% between assays. 1, 2
• Biological variation of PTH is substantial (20% in healthy individuals), so differences must exceed 54% to be clinically significant. 2
• Sampling site matters: central blood has higher PTH concentrations than peripheral blood. 2

Diagnostic Algorithm to Distinguish Causes

Step 1: Measure serum calcium (corrected for albumin or ionized calcium) simultaneously with PTH. 2

• If calcium is elevated (>10.2 mg/dL) with elevated or inappropriately normal PTH → Primary hyperparathyroidism. 1, 2
• If calcium is normal or low with elevated PTH → Secondary hyperparathyroidism or normocalcemic primary hyperparathyroidism. 1, 5

Step 2: Measure 25-hydroxyvitamin D and assess renal function (eGFR). 1, 2

• If 25-OH vitamin D <20 ng/mL → Vitamin D deficiency is causing or contributing to elevated PTH; supplement and recheck. 1, 2
• If eGFR <60 mL/min/1.73 m² → CKD-related secondary hyperparathyroidism. 1, 2

Step 3: If vitamin D is replete (>20 ng/mL) and eGFR is normal, measure 1,25-dihydroxyvitamin D to differentiate causes. 2

• Both 25-OH and 1,25-(OH)₂ vitamin D low → Vitamin D deficiency or malabsorption. 2
• 25-OH vitamin D low but 1,25-(OH)₂ vitamin D elevated → Granulomatous disease (sarcoidosis) with increased 1α-hydroxylase activity. 2
• 1,25-(OH)₂ vitamin D low in CKD → Impaired renal conversion. 2

Step 4: Assess dietary calcium intake and medication history. 2

• Confirm adequate calcium intake (1000-1200 mg/day). 2
• Review for medications that impair calcium absorption or vitamin D metabolism. 2

Step 5: If all secondary causes are excluded and PTH remains elevated with normal calcium, consider normocalcemic primary hyperparathyroidism. 2, 8

Critical Pitfalls to Avoid

• Never focus solely on PTH levels without evaluating calcium, phosphorus, and vitamin D status—this leads to misdiagnosis. 1, 4
• Overlooking vitamin D insufficiency is the most common error that perpetuates secondary hyperparathyroidism and can mimic primary disease. 1, 4
• Do not order parathyroid imaging before confirming biochemical diagnosis—imaging is for surgical planning in confirmed primary hyperparathyroidism, not for diagnosis. 2
• Attempting to maintain PTH in the "normal" range in CKD patients can cause adynamic bone disease—stage-specific targets are required. 1
• Normal or low PTH in end-stage renal disease may indicate adynamic bone disease, which is also problematic and requires different management. 1
• Always use assay-specific reference ranges because PTH measurements can vary by up to 47% between different assay generations. 1, 2