Hyperparathyroidism

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Introduction

Hyperparathyroidism (HPT):

Primary Hyperparathyroidism (pHPT):

  • Elevated PTH and calcium levels.
  • Typically caused by parathyroid adenomas, hyperplasia, or, rarely, parathyroid carcinomas.
  • Can be asymptomatic but may present with symptoms like bone pain, gastric ulcers, and kidney stones.

Secondary Hyperparathyroidism (sHPT):

  • High PTH and low calcium levels.
  • Often a response to underlying conditions such as chronic kidney disease (CKD), vitamin D deficiency, low calcium intake, or malabsorption.
  • Sometimes called reactive HPT.
  • May progress to tHPT if left untreated.

Tertiary Hyperparathyroidism (tHPT):

  • Occurs when sHPT progresses, leading to high serum calcium levels.
  • Typically due to longstanding sHPT.

Diagnostics and Classification:

  • Involves evaluating calcium, PTH, and phosphate levels.
  • Identifying the underlying cause, such as CKD, in the case of sHPT.

Treatment:

  • Primary and Tertiary HPT: Surgery to remove affected parathyroid tissue is the primary treatment. Alternatively, calcimimetics or bisphosphonates may be used.
  • Secondary HPT: Focus on treating the underlying cause, like CKD or vitamin D deficiency. Dietary changes, supplements, or medications may be prescribed.

 

Primary Hyperparathyroidism:

Epidemiology:

  • Lifetime incidence: 1 in 80 people
  • Sex: More common in females (3:1 female-to-male ratio)
  • Age: Most cases occur after the age of 50
  • Prevalence: Approximately 0.1% to 0.5%

Etiology:

  • Most common cause: Parathyroid gland adenoma (about 85% of cases) – a benign tumor of the parathyroid glands
  • Less common causes (about 15%): Hyperplasia or multiple adenomas
  • Rare cases (about 0.5%): Carcinomas of the parathyroid glands
  • Other etiologies: Idiopathic cases, Multiple endocrine neoplasia type 1 or 2, and certain medications like lithium or thiazide diuretics

Pathophysiology:

  • Hyperparathyroidism results from excessive parathyroid hormone (PTH) production by parathyroid chief cells.
  • PTH effect on bones: It increases bone resorption, leading to the release of calcium and phosphate into the bloodstream, thereby elevating calcium levels.
    • PTH induces the expression of RANKL in osteoblasts, which binds to RANK on osteoclasts, resulting in the activation of osteoclasts responsible for bone resorption.
    • PTH also triggers the production of IL-1 in osteoblasts, further contributing to osteoclast activation.

PTH effect In the kidneys: PTH leads to increased phosphate excretion, a phenomenon known as phosphaturia.

 

Clinical Features:

  • Most patients with pHPT are asymptomatic.
  • Symptomatic patients often display clinical manifestations of hypercalcemia.
  • General symptoms may include weakness.

Cardiovascular System:

  • Left ventricular hypertrophy.
  • Arterial hypertension.
  • Shortened QT interval.

Urinary Tract:

  • Nephrolithiasis (kidney stones) and nephrocalcinosis.
  • Abdominal or flank pain.
  • Increased urination (polyuria) and excessive thirst (polydipsia).

Musculoskeletal System:

  • Pain in bones, muscles, and joints.
  • Pseudogout, a condition resembling gout but without the presence of uric acid crystals.

Digestive Tract:

  • Reduced appetite leading to weight loss.
  • Nausea and constipation.
  • Gastric or duodenal ulcers.
  • Occasional acute pancreatitis.

Psychological Symptoms:

  • Depression.
  • Fatigue.
  • Anxiety.
  • Sleep disorders.

Diagnostics:

Laboratory Studies:

  • Diagnostic Confirmation:
    • ↑ Serum calcium levels
    • ↑ Serum intact PTH (or inappropriately normal levels)
  • Additional Studies for Confirmed pHPT:
    • Serum creatinine and estimated GFR to evaluate renal function
    • Assessment of 25-hydroxyvitamin D levels for deficiency
    • Possible ↓ phosphate levels
    • ↑ ALP levels due to increased bone turnover
    • 24-hour urinary calcium and creatinine:
      • ↑ Ca/Cr clearance ratio (>0.02) suggests pHPT and is a risk factor for nephrocalcinosis and nephrolithiasis.
      • ↓ Ca/Cr clearance ratio (<0.01) may suggest familial hypocalciuric hypercalcemia, which can mimic pHPT.

Routine Imaging Studies:

  • Recommended for all confirmed pHPT patients to assess renal and skeletal manifestations.
  • Skeletal Evaluation:
    • Assess for osteoporosis, osteopenia, and fragility fractures.
    • Preferred modality: dual-energy x-ray absorptiometry (DXA).
  • RenalImaging:
    • Assess for nephrolithiasis and nephrocalcinosis.
    • Options include abdominal CT without contrast, renal ultrasound, and abdominal x-ray.

Additional Imaging Studies:

  • Neck Imaging:
    • Used for surgical planning to locate abnormal glands and assess for concomitant thyroid disease.
    • Options include neck ultrasound and nuclear imaging with Tc-99m sestamibi scans.
  • X-ray:
    • While not typically a primary diagnostic tool, it may reveal findings such as:
      • ↓ BMD
      • Cortical thinning, especially in hand phalanges (acroosteolysis)
      • “Salt and pepper” appearance on skull imaging, indicating granular decalcification in the calvarium, which are features of osteitis fibrosa cystica.
  • Parathyroid imaging is primarily used for surgical planning and is not usually employed for the initial diagnosis of pHPT.

Management:

Immediate Hypercalcemia Treatment:

  • Start immediate treatment for patients with a serum calcium level > 14 mg/dL (> 3.5 mmol/L).

Surgical Approach

Indications for Surgery:

  • Surgical intervention is recommended for the following groups:
    • Symptomatic patients.
    • Asymptomatic patients who meet any of the subsequent criteria:
      • Age below 50 years.
      • Hypercalcemia: serum calcium level > 1 mg/dL above the ULN.
      • Renal involvement.
        • Estimated GFR < 60 mL/minute.
        • Hypercalciuria.
        • Nephrolithiasis or nephrocalcinosis on imaging.
      • Skeletal involvement:
        • Reduced BMD (T-score ≤ -2.5 at any site) or the 
        • Presence of a vertebral fracture.

Procedures for Surgery:

  • Solitary adenoma: Minimally invasive parathyroidectomy of the affected gland.
  • Hyperplasia: Total parathyroidectomy (removal of all four glands) with reimplantation of half a gland in easily accessible muscle.
  • Carcinoma: Tumor resection, involving the removal of the ipsilateral thyroid lobe and enlarged lymph nodes

Pharmacotherapy:

Calcimimetics (e.g., cinacalcet):

  • Mechanism of action: Enhances the responsiveness of calcium-sensing receptors in parathyroid glands to circulating Ca2+, resulting in the inhibition of parathyroid hormone (PTH) release.
  • Indications:
    • Parathyroid carcinoma with hypercalcemia.
    • Primary hyperparathyroidism (pHPT) and severe hypercalcemia in patients not undergoing parathyroidectomy.
    • Secondary hyperparathyroidism (sHPT) in patients with chronic kidney disease (CKD) who are on dialysis.
  • Adverse effects: May lead to hypocalcemia, and patients may experience symptoms like nausea, vomiting, and diarrhea.
  • Contraindications: Not recommended in the presence of hypocalcemia.

Bisphosphonates:

  • Usage: These medications are employed for individuals with osteopenia or osteoporosis.

Complications:

Osteitis Fibrosa Cystica (OFC):

  • OFC is an infrequent skeletal disorder observed in advanced hyperparathyroidism. It is distinguished by the substitution of calcified bone with fibrous tissue.
  • Although most commonly associated with primary hyperparathyroidism, it can also manifest in cases of secondary hyperparathyroidism.
  • The pathophysiology involves an increase in parathyroid hormone (PTH) levels, which subsequently enhances the expression of RANK ligand, leading to the activation of osteoclasts. This results in bone resorption, cortical bone degradation, and the deposition of fibrous tissue.
  • Clinical features of OFC encompass bone pain, subperiosteal thinning, and the development of bone cysts. In cases of multiple skull cysts, a radiographic appearance resembling a “salt and pepper skull” can be observed.
  • In advanced stages of OFC, sizable cystic cavities with a tumor-like appearance are evident on X-rays. These cavities often exhibit a brown hue due to the deposition of hemosiderin and are referred to as “brown tumors.”

Hungry Bone Syndrome:

  • This syndrome is defined as a complication of parathyroidectomy, which is characterized by a notable drop in calcium levels despite normal or elevated PTH levels.

Secondary and Tertiary Hyperparathyroidism

Secondary Hyperparathyroidism:

  • Chronic kidney disease is the most common cause.
  • Other contributing factors include malnutrition, vitamin D deficiency (resulting from reduced sunlight exposure, nutritional deficits, or liver cirrhosis), and cholestasis.

Tertiary Hyperparathyroidism:

  • This condition is induced by persistent secondary hyperparathyroidism (sHPT). usually as a result of chronic kidney disease. tHPT causes reactive hypercalcemia in response to long term elevation of PTH

Pathophysiology of secondary and tertiary hyperparathyroidism:

Secondary Hyperparathyroidism:

  • Decreased calcium and/or increased phosphate blood levels ➔ reactive hyperplasia of the parathyroid glands ➔ ⬆️ elevated parathyroid hormone (PTH) secretion.
    • In cases of chronic kidney disease (CKD), impaired renal phosphate excretion causes higher phosphate blood levels, which, in turn, stimulate PTH secretion.
    • Furthermore, CKD reduces the biosynthesis of active vitamin D. This affects both intestinal calcium resorption and renal calcium reabsorption, resulting in hypocalcemia and further elevating PTH secretion.

Tertiary Hyperparathyroidism:

  • Chronic renal disease leads to refractory and autonomous PTH secretion, resulting in hypercalcemia.

Both secondary and tertiary hyperparathyroidism associated with renal disease contribute to a condition called renal osteodystrophy, characterized by various bone lesions.

Clinical Features of secondary and tertiary hyperparathyroidism

  1. Underlying Cause-Related Symptoms:
    • Manifestations may be related to the underlying cause of sHPT or tHPT, which is often chronic kidney disease (CKD).
  2. Clinical Features of Hypocalcemia or Hypercalcemia:
    • Patients may exhibit symptoms of either hypocalcemia (low blood calcium) or hypercalcemia (high blood calcium) depending on the stage and severity of the condition.
  3. Bone Pain and Increased Fracture Risk:
    • Patients are at an increased risk of bone pain and may be prone to fractures due to the bone changes associated with sHPT and tHPT.
  4. Osteitis Fibrosa Cystica:
    • Osteitis fibrosa cystica is a characteristic feature, especially in cases of advanced hyperparathyroidism. It involves the replacement of calcified bone with fibrous tissue.
  5. Rugger-Jersey Spine Sign:
    • The Rugger-Jersey spine sign is a radiological finding associated with certain bone changes in the spine, often seen in patients with advanced hyperparathyroidism.

Diagnostic Studies of secondary and tertiary hyperparathyroidism

Diagnostic Confirmation:

  • sHPT: ↑ PTH and ↓ calcium
  • tHPT: ↑ PTH (or inappropriately normal) and ↑ calcium: 
  • Additional Studies:
    • Phosphate levels:
      • ↓ Phosphate: sHPT not caused by CKD
      • Normal or ↑ phosphate: sHPT caused by CKD
      • ↑ Phosphate: tHPT
    • ↑ ALP (Alkaline Phosphatase): Sign of bone turnover

Treatment of secondary and tertiary hyperparathyroidism

  • Address the Underlying Cause:
    • Treat the primary condition (e.g., chronic kidney disease) effectively.
  • Vitamin D Supplementation:
    • In cases of vitamin D deficiency, supplement with vitamin D analogues such as ergocalciferol.
  • Management of Complications:
    • Hyperphosphatemia:
      • Implement dietary phosphorus restriction (e.g., avoiding soft cheese or nuts).
      • Consider using phosphate binders if dietary restrictions alone are ineffective.
    • Hypercalcemia:
      • Management may involve:
        • Intravenous (IV) fluids.
        • Diuretics.
        • Calcitonin.
        • Bisphosphonates.
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