What are the clinical features of hyperparathyroidism?

Clinical Features of Hyperparathyroidism

Hyperparathyroidism presents along a spectrum from asymptomatic biochemical abnormalities to severe multi-system disease affecting bone, kidneys, gastrointestinal, cardiovascular, neuromuscular, and neuropsychiatric systems, with the clinical presentation varying dramatically based on whether it is primary, secondary, or tertiary disease. 1, 2

Primary Hyperparathyroidism: Clinical Presentation

Modern Asymptomatic Presentation

• Up to 80% of primary hyperparathyroidism cases in Western countries now present as oligo-asymptomatic or completely asymptomatic disease, typically discovered incidentally on routine biochemical screening 1, 3
• The disease is characterized biochemically by hypercalcemia with elevated or inappropriately normal parathyroid hormone levels 4, 3
• Asymptomatic patients still have potential for disease progression with development of bone loss and kidney stones 3

Classical Symptomatic Manifestations

Skeletal manifestations:

• Generalized bone disease with decreased bone mineral density, particularly at cortical sites (distal radius) with relative preservation of cancellous bone 1, 5
• Increased fracture rate at peripheral sites and spine in untreated patients 5
• Brown tumors (rare in modern practice, must be differentiated from bone metastases, chondrosarcoma, and giant cell tumors) 6
• Diffuse bone pain 6

Renal manifestations:

• Kidney stones and nephrocalcinosis 1, 2
• Renal lithiasis 6
• Hypercalciuria 6

Gastrointestinal symptoms:

• Nausea, vomiting, and abdominal pain (particularly with moderate hypercalcemia) 4, 1

Cardiovascular manifestations:

• Bradycardia and hypotension (in severe hypercalcemia >14 mg/dL) 4
• General cardiovascular symptoms 1

Neuromuscular and neuropsychiatric features:

• Myalgia and muscle weakness 4
• Cognitive or psychiatric disorders 6
• Confusion (moderate hypercalcemia) progressing to altered mental status (severe hypercalcemia) 4
• Disturbance of consciousness 6

Metabolic features:

• Polyuria and polydipsia 4
• Severe dehydration and acute renal failure (in severe hypercalcemia) 4

Normocalcemic Variant

• A distinct variant exists where serum calcium remains within normal range but parathyroid hormone is persistently elevated in the absence of secondary causes 3
• This requires exclusion of vitamin D deficiency, renal insufficiency, malabsorption, insufficient calcium intake, and iatrogenic causes before diagnosis 6

Secondary Hyperparathyroidism: Clinical Features

Biochemical Presentation

• Secondary hyperparathyroidism presents with hypocalcemia or normal calcium (NOT hypercalcemia), distinguishing it from primary disease 4
• Elevated parathyroid hormone with low or low-normal calcium 7
• Inappropriately normal 1,25(OH)2D3 levels despite elevated PTH, contributing to defective feedback suppression 7

Bone Disease Manifestations

• Hyperparathyroid bone disease evident on bone biopsy even with modest PTH elevations in CKD Stage 3 patients 7
• High-turnover bone disease with increased bone resorption 7
• Histomorphometric features of hyperparathyroid bone disease despite only modest PTH elevations 7

Chronic Kidney Disease-Related Features

• Appears when GFR falls below 60 mL/min/1.73 m² (CKD Stage 3) 7
• Almost 90% of ESRD patients have hyperparathyroidism at time of transplantation 7
• Associated complications include refractory hyperphosphatemia, severe intractable pruritus, and progressive extraskeletal calcifications 7
• Calcium-phosphorus product persistently exceeding 70-80 mg/dL indicates severe disease 7
• Calciphylaxis (malignant calcinosis) in severe cases 7

Post-Transplant Persistence

• More than 30% of renal transplant recipients have persistent hyperparathyroidism up to 3 years post-transplant 7
• Hypercalcemia occurs in 10-22% of renal transplant recipients 7
• Associated with posttransplant renal dysfunction, bone disease, and possibly hypertension 7
• Hypophosphatemia occurs in 50-80% of patients in first 3 months post-transplant due to hyperphosphaturia 7

Tertiary Hyperparathyroidism

• Develops from autonomous parathyroid hormone secretion after prolonged secondary hyperparathyroidism 2
• Presents with hypercalcemia despite correction of underlying stimulus (typically after renal transplantation) 7
• Occurs in 1-5% of transplant recipients when parathyroid glands fail to involute sufficiently 7

Critical Diagnostic Pitfalls to Recognize

Common confounders that must be excluded:

• Vitamin D deficiency causes secondary hyperparathyroidism and must be ruled out before diagnosing primary disease 4, 6
• Renal insufficiency (measure eGFR) 6
• Malabsorption syndromes (inflammatory bowel disease, celiac disease, bariatric surgery) 6
• Insufficient calcium intake 6
• Iatrogenic causes: diuretics (especially thiazides and loop diuretics), lithium, corticosteroids, excessive vitamin D or calcium supplementation 4, 6

Atypical presentations requiring specific workup:

• Hypercalcemia with hypocalciuria suggests genetic causes (familial hypocalciuric hypercalcemia) 6
• Hypercalcemia with non-elevated PTH suggests malignancy, vitamin D excess, immobilization, or other endocrine causes 6
• Elevated PTH without hypercalcemia requires differentiation from normocalcemic hyperparathyroidism versus PTH resistance 6