What causes elevated Parathyroid Hormone (PTH) levels?

Causes of Elevated PTH

Elevated PTH occurs primarily due to secondary hyperparathyroidism from chronic kidney disease, vitamin D deficiency, or primary hyperparathyroidism from parathyroid adenoma or hyperplasia. 1, 2

Primary Hyperparathyroidism

Primary hyperparathyroidism is defined by hypercalcemia with elevated or inappropriately normal PTH levels, most commonly caused by adenoma or hyperplasia of one or more parathyroid glands. 1 This represents autonomous PTH secretion independent of calcium regulation. 3

• The condition leads to calcium removal from bones, increasing osteoporosis risk, and promotes kidney stone formation through hypercalciuria. 1
• Parathyroidectomy is the only curative treatment and is indicated for symptomatic patients, those ≤50 years old, serum calcium >1 mg/dL above normal, osteoporosis, creatinine clearance <60 mL/min/1.73 m², nephrolithiasis, nephrocalcinosis, or hypercalciuria. 3

Secondary Hyperparathyroidism

Chronic Kidney Disease (Most Common Cause)

CKD is the most common cause of secondary hyperparathyroidism, with nearly all patients developing parathyroid gland hyperplasia as kidney function declines. 2 The pathophysiology involves multiple interconnected mechanisms:

• Phosphate retention occurs early in CKD and is the fundamental initiating factor, triggering the cascade even before hyperphosphatemia develops. 4 High phosphate intake can directly provoke secondary hyperparathyroidism in early CKD stages. 4
• Phosphate retention directly lowers ionized calcium by forming calcium-phosphate complexes in serum, reducing bioavailable calcium. 2
• Decreased 1,25-dihydroxyvitamin D production results from failing kidneys, reducing intestinal calcium absorption and causing hypocalcemia. 1, 2
• High serum phosphate interferes with calcitriol production and secretion, further impairing calcium absorption. 2
• Skeletal resistance to PTH's calcemic action contributes to persistent hypocalcemia despite elevated PTH. 2
• PTH levels begin rising when GFR falls below 60 mL/min/1.73 m². 5

Vitamin D Deficiency

Vitamin D insufficiency (25-hydroxyvitamin D <30 ng/mL) is extremely prevalent (80-90%) in CKD patients but also common in the general population, leading to reduced intestinal calcium absorption, hypocalcemia, and compensatory PTH elevation. 2

• Vitamin D deficiency causes secondary hyperparathyroidism independent of kidney disease. 3, 6
• PTH reference values are 20% lower when established in vitamin D-replete individuals compared to those with unknown vitamin D status. 1

Malabsorption Syndromes

Gastrointestinal conditions that impair calcium absorption can cause secondary hyperparathyroidism, though this is less common than CKD or vitamin D deficiency. 3

Post-Bariatric Surgery

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

Tertiary Hyperparathyroidism

Tertiary hyperparathyroidism results from long-standing, severe secondary hyperparathyroidism that has become autonomous after the original cause has been removed or corrected. 6 This most commonly occurs in CKD patients, with approximately 10% of dialysis patients requiring parathyroidectomy after 10 years, increasing to 30% after more than 20 years. 2

Physiological and Demographic Factors Influencing PTH

Several factors affect PTH concentrations independent of disease:

• Race: PTH is higher in Black individuals compared to White individuals. 1
• Age: PTH increases with age, possibly due to steady decline in GFR, leading to higher concentrations in people over 60 years old. 1
• BMI: PTH correlates positively with body mass index, with higher levels in obese patients. 1
• Biological variation: Within-subject PTH variation is ~20% in healthy people and up to 30% in hemodialysis patients, requiring >54% change in healthy individuals or >72% in dialysis patients to confirm true change beyond biological variation. 1

Pre-Analytical and Assay-Related Factors

PTH measurement can be influenced by biotin supplements, which may cause underestimation or overestimation depending on assay design. 1 PTH is most stable in EDTA plasma rather than serum. 1

Different PTH assay generations (second vs. third generation) measure overlapping but distinct molecular forms, with second-generation assays overestimating biologically active PTH by detecting inactive fragments like 7-84 PTH. 5 This can affect clinical decisions, particularly in CKD management. 5

Critical Pitfalls to Avoid

• Do not focus solely on PTH levels without evaluating calcium, phosphorus, and vitamin D status, as this can lead to misdiagnosis. 2
• Overlooking vitamin D insufficiency (levels 16-30 ng/mL) is a common error that perpetuates secondary hyperparathyroidism. 2
• Attempting to maintain PTH in the "normal" range in CKD patients can cause adynamic bone disease; stage-specific targets should be used instead. 5
• In post-parathyroidectomy patients, normocalcemic PTH elevation occurs in 28% and may indicate dietary calcium/vitamin D deficiency rather than residual disease. 7
• Normal or low PTH in ESRD may indicate adynamic bone disease, which is also problematic and requires different management. 4