Hyperparathyroidism

Snapshot

• 55-year-old woman presents to the clinic for an annual well exam. Routine laboratory tests demontrates elevated levels of hypercalcemia. The patient reports some mild diffuse abdominal pain over the past 2 weeks but otherwise denies any chest pain, palpitations, or fatigue. A follow up PTH level is high. 

Introduction

• Clinical definition
  • disorder characterized by the over secretion of parathyroid hormone (PTH) by one or more of the parathyroid glands
  • high levels of PTH leads to increase in serum calcium levels, causing hypercalcemia
  • can be of primary, secondary, or tertiary causes  
• Epidemiology
  • demographics
    • occurs in 0.1% of the population and 90% of cases result from a single adenoma
  • risk factors
    • severe, prolonged calcium or vitamin D deficiency
    • menopause
    • neck radiation
    • lithium use
• Pathogenesis
  • PTH leads to
    • activation of osteoclasts leading to increased Ca²⁺ and phosphate reabsorption at the bone
      • stimulates osteoclasts by binding to its receptor on osteoblasts, inducing RANK-L and M-CSF synthesis 
    • increased reabsorption of Ca²⁺ in the distal convoluted tubule at the kidney
• stimulation of kidney 1α-hydroxylase in the proximal convoluted tubule to increase calcitriol production

Classification

• Primary hyperparathyroidism 
  • most commonly results from parathyroid adenoma or hyperplasia 
  • associated conditions
    • osteitis fibrosa cystica
      • high osteoclast activity at bone resulting in cystic bone spaces with brown fibrous tissue
      • commonly occurs at the jaw
    • multiple endocrine dysplasia (MEN) 1 and 2A
• Secondary hyperparathyroidism  
  • secondary parathyroid hyperplasia as a result of low Ca²⁺  absorption and/or high phosphate levels
  • associated conditions
    • chronic renal disease
      • renal disease causes hypovitaminosis D
        • leads to ↓ Ca²⁺ absorption 
    • renal osteodystrophy
      • bone lesions due to secondary hyperparathyroidism 
• Tertiary hyperparathyroidism
  • dysregulation of parathyroid glands following chronic renal disease
    • will secrete PTH regardless of Ca²⁺ levels
  • associated conditions 
    • chronic renal disease 

• renal osteodystrophy 

Serum Ca	Serum Phos	Serum PTH
Primary	↑	↓	↑
Secondary	normal or ↓	↑	↑
Tertiary	↑	↑	↑

Presentation

• Symptoms
  • asymptomatic (most common)
  • weakness
  • kidney stones (“stones”)
  • bone pain (“bones”)
  • constipation (“groans”)
  • abdominal/flank pain
  • depression (“psychiatric overtones”)
  • uncommon cause of secondary hypertension  
• Physical exam
• hypertension

Imaging

• Bone mineral density test
  • dual energy X-ray absorptiometry (DEXA) is the most common test to measure bone mineral density
  • allows for measurement of bone reabsorption 
• Computed tomography (CT)
  • abdominal CT may be indicated to determine if kidney stones or other abnormalities are present
• Radiograph
  • cystic bone spaces (“salt and pepper”) most common at the skull
  • loss of phalange bone mass with increased concavity 
  • subperiosteal thinning (cortical resorption) 
• Sestamibi parathyroid scan
  • allows for visualization of the parathyroid glands
• indicated if surgery is expected

Studies

• Serum calcium test 
  • best initial test
  • primary hyperparathyroidism
    • hypercalcemia
  • secondary/tertiary hyperparathyroidism
    • hypocalcemia/normocalcemia   
• Serum PTH
  • best initial test
  • levels will be elevated in all forms of hyperparathyroidism
• 24-hour urinary calcium  
  • routinely measured in patients to assess risk of renal complications
  • helps to distinguish hyperparathyroidism from familial hypocaloric hypercalcemia (FHH)  
  • hypercalciuria/normocalciuria
• Serum 25-hydroxyvitamin D
  • helps in differentiating from FHH
  • guides management
• Genetic testing
• may be indicated in patients suspected of MEN 1 or MEN 2A

Differential

• Paraneoplastic syndrome (e.g., squamous cell cancer of the lung)
  • distinguishing factors
    • serum PTH levels will be low due to negative feedback
• Familial hypocalciuric hypercalcemia (FHH)
  • distinguishing factors
• urine calcium will be low

Treatment

• Acute hypercalcemia
  • IV fluids
  • loop diuretics
• Asymptomatic patients
  • first-line
    • observation with follow-up
  • second-line
    • surgical intervention indicated in select patients with abnormal studies indicating skeletal and renal damage
• Symptomatic patients (e.g., nephrolithiasis)
  • first-line
    • parathyroid surgery is the only definitive therapy
      • complications include post-op hypocalcemia (e.g., numbness, tingling, and muscle cramps)
      • treat with IV calcium gluconate
  • second-line
    • cinacalcet indicated in patients who are unable to have surgery 
• decreases PTH levels by sensitizing Ca²⁺ – sensing receptors at the parathyroid gland

Complications

• Peptic ulcer disease
  • ↑ gastrin production stimulated by ↑ Ca²⁺
• Acute pancreatitis
  • ↑ lipase activity stimulated by ↑ Ca²⁺
• CNS dysfunction
  • anxiety, confusion, and coma
  • result of metastatic calcification of the brain