Hyperparathyroidism

Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Primary hyperparathyroidism is an inherent disease of parathyroid glands associated with abnormal secretion of PTH. Secondary hyperparathyroidism results from abnormalities of calcium metabolism, which, if left untreated, can progress to tertiary hyperparathyroidism, which is associated with hypertrophy of the parathyroid gland and oversecretion of PTH even if the primary cause is eliminated. Diagnosis is based on biochemical parameters, which include serum PTH, calcium, and phosphate levels as well as urinary calcium. Management relies mostly on surgical parathyroidectomy for primary and tertiary hyperparathyroidism. Management of secondary hyperparathyroidism is focused on treatment of the underlying disease.

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Overview

Definition

Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH).

Etiology

  • Primary hyperparathyroidism:
    • Most common cause of hypercalcemia
    • Can be associated with MEN 1
    • Adenomas of the parathyroid gland (85% of cases, mostly solitary)
    • Hyperplasia of the parathyroid glands (15%)
    • Parathyroid carcinoma (1%)
  • Secondary hyperparathyroidism: 
    • Secondary elevation of PTH caused by hypocalcemia
    • Most common cause of secondary PTH:
      • Chronic renal failure (CRF)
      • Vitamin D deficiency
      • ↓ Enteral Ca absorption
      • Liver cirrhosis
  • Tertiary hyperparathyroidism: 
    • Due to long-standing secondary hyperparathyroidism
    • Usually associated with end-stage kidney disease
    • Hypertrophy of parathyroid gland and oversecretion of PTH due to long-standing chronic stimulation

Parathyroid adenoma involving the left upper parathyroid gland
The other three glands are prominently displayed, but normal parathyroids are smaller than these appear to be (normal size, 3–5 mm; 30–60 mg each).

Image: “Blausen 0533 Parathyroid adenoma” by BruceBlaus. License: CC BY 3.0

Epidemiology

  • Primary hyperparathyroidism:
    • 66 per 100,000 person-years in females
    • 25 per 100,000 person-years in males
    • Mean age at diagnosis: 52–56 years
  • Secondary hyperparathyroidism:
    • Vitamin D deficiency affects up to 40% of adults in the United States.
    • Secondary hyperparathyroidism is present in up to 90% of patients with severe CRF who are approaching dialysis.
  • Tertiary hyperparathyroidism:
    • Develops in some CRF patients with long-standing secondary hyperparathyroidism
    • Persists after kidney transplantation

Pathophysiology

Normal physiologic effects of PTH

  • Secreted by parathyroid glands in response to decreasing serum calcium (Ca) levels sensed by the Ca-sensing receptor
  • Stimulates osteoclast activity → ↑ bone resorption with Ca and phosphate release in the blood
  • ↑ Ca reabsorption in kidney
  • ↑ Phosphate elimination in kidney
  • ↑ 1-hydroxylation of vitamin D in kidney
  • ↑ Intestinal absorption of Ca from diet via ↑ production of active vitamin D

Pathophysiology

Primary hyperparathyroidism:

  • In parathyroid adenomas, the expression of the Ca-sensing receptor is reduced, leading to unregulated PTH secretion.
  • In parathyroid hyperplasia, the hypersecretion is due to the simple increase in the number of secreting cells.
  • ↑ PTH → effects on kidneys and bones
  • ↑ Ca and ↓ serum phosphate levels

Secondary hyperparathyroidism:

  • ↓ Ca2+ and ↑ phosphate stimulate PTH secretion
  • Hypocalcemia and hyperphosphatemia can result from:
    • CKD:
      • ↓ Calcitriol
      • ↓ Ca reabsorption
      • ↓ Phosphate secretion
    • Vitamin D deficiency (nutritional, liver disease)
    • Vitamin D resistance (Fanconi’s syndrome, vitamin D–receptor defects)
    • PTH resistance (pseudohypoparathyroidism, hypomagnesemia)
    • Drugs: 
      • Ca chelators (citrated blood transfusions, phosphate from cow’s milk)
      • Inhibitors of bone resorption (bisphosphonates, calcitonin, plicamycin)
      • Altered vitamin D metabolism (phenytoin, ketoconazole)
    • Miscellaneous:
      • Acute pancreatitis
      • Acute rhabdomyolysis
      • Massive tumor lysis
      • Osteoblastic metastases (prostate or breast carcinoma)
      • Toxic shock syndrome

Tertiary hyperparathyroidism:

  • Chronic hyperstimulation of parathyroid gland
  • Parathyroid hypertrophy and autonomous hypersecretion of PTH
  • Hypercalcemia develops in the setting of hyperphosphatemia from CRF.
  • Dangerous: can result in diffuse calcinosis

Parathyroid hormone has only one function: to correct hypocalcemia and maintain the serum level of calcium within narrow limits.
If the serum calcium is low, the four parathyroid glands secrete PTH, which is made and stored in the glands. When released, PTH works with and through vitamin D to restore the calcium level to normal.

Image by Lecturio.

Clinical Presentation

Primary hyperparathyroidism (PH)

Over 50% of patients are asymptomatic or present with nonspecific symptoms.

Mnemonic for PH: Stones, bones, groans, and moans:

  • Nephrolithiasis (calcium phosphate or calcium oxalate stones)
  • Can progress to nephrocalcinosis (deposition of Ca in renal tubules)
  • Three skeletal abnormalities seen in untreated PH:
    • Osteoporosis:
      • Mostly in cortical bone (subperiosteal resorption) of the phalanges, vertebrae, and proximal femur
      • Salt-and-pepper skull refers to diffuse, lytic foci in the calvarium
      • Overall increased risk of fractures
    • Brown tumors: masses of reactive fibrous tissue with macrophages
      • Due to brisk osteoclast activity
      • Producing microfractures
      • Associated with increased vascularity, hemorrhage, and hemosiderin deposition
    • Osteitis fibrosa cystica (von Recklinghausen’s disease of bone): from severe hyperparathyroidism, due to cystic degeneration of many brown tumors
  • GI tract:
    • Obstipation
    • Meteorism
    • Nausea
    • Loss of appetite
    • Weight loss
    • Gastric and duodenal ulcers
    • Pancreatitis
  • Neuropsychiatric symptoms:
    • Depression
    • Personality changes
    • Lethargy
    • Coma

Other symptoms include:

  • General muscle weakness, rapid muscle fatigue
  • Electrocardiogram changes (atrioventricular (AV) block, bradycardia, short QT interval, left ventricular hypertrophy)
  • Polyuria, polydipsia
  • Hyperparathyroid crisis (rare):
    • Polyuria, polydipsia
    • Nausea/vomiting
    • Loss of consciousness, somnolence, and coma

Secondary hyperparathyroidism

  • No unique clinical presentation
  • CRF patients can present with bone pain
  • Cases associated with vitamin D deficiency present with related symptoms:
    • Osteomalacia, increased fractures
    • Myopathy

Hand radiograph in a 64-year-old woman with mild secondary hyperparathyroidism and a long history of knitting, showing subperiosteal bone resorption at both terminal thumb phalanges.
Bone resorption due to hyperparathyroidism is usually seen at the phalangeal tufts and the radial aspects of the middle phalanges of the second and the third fingers. The unusual location in the thumbs in this patient may be due to a combination of repetitive trauma and hyperparathyroidism.

Image: “Unusual hand radiographic presentation in a patient on hemodialysis” by Pipili C, Grapsa E, Tzanatos H. License: CC BY 2.0, edited by Lecturio.

Tertiary hyperparathyroidism

  • Bone pain
  • Pruritus
  • Fatigue/lethargy
  • Increased risk of fractures

Diagnosis

Primary hyperparathyroidism

  • Laboratory tests:
    • Serum Ca2+:
      • Measure total serum Ca2+ if normal albumin
      • Measure ionized Ca2+ if low albumin
    • ↑ PTH level
    • 24-hour urinary Ca2+:
      • Elevated or normal
      • Helps to differentiate from familial hypocalciuric hypercalcemia (FHH)
    • ↓ Or near-normal serum phosphate
    • ↑ Alkaline phosphatase
    • Normocalcemic variant:
      • Normal total and ionized serum Ca2+ in the presence of ↑ PTH
      • Usually an early or mild presentation of primary hyperparathyroidism
      • Diagnosis is made if secondary hyperparathyroidism is excluded.
  • Imaging:
    • Not routinely used for diagnosis
    • Can be used prior to surgery for localization of parathyroid tumors
    • X-rays may show bone disease: 
      • Subperiosteal bone resorption
      • Brown tumors of the long bones
      • Tapering of distal clavicles
      • Salt-and-pepper skull
      • Bone cysts

X-rays of left lower limb in two orthogonal views showing osteitis fibrosa cystica presenting as a cystic/lytic bone space filled with brown fibrous tissue (arrows) known as a “brown tumor”:
Brown tumors are less commonly seen in hyperparathyroidism today because the disease is usually diagnosed at an earlier stage.

Image: “Case 2: x-ray: extensive osteolytic lesion in proximal end of tibia (arrows)” by Waldemar Misiorowski et al. License: CC BY 4.0

Secondary hyperparathyroidism

  • ↓ Serum Ca2+
  • ↑ Or normal phosphate levels
  • ↑ PTH level
  • 25-hydroxyvitamin D level may be low in vitamin D deficiency.

Tertiary hyperparathyroidism

  • ↑ PTH level
  • Serum Ca2+
  • ↑ Or normal phosphate levels

Management

Primary hyperparathyroidism

Medical management:

  • Indications:
    • For asymptomatic patients
    • For patients who are poor surgical candidates
  • Calcimimetic agents (activate Ca2+-sensing receptor)
  • Osteoporosis prophylaxis with bisphosphonates
  • Encourage physical activity to decrease bone resorption.
  • Encourage adequate hydration (to prevent kidney stones).
  • Avoid certain medications (lithium, thiazide diuretics).
  • Maintain adequate vitamin D intake.

Surgery:

  • Indications:
    • All symptomatic cases
    • Asymptomatic cases with certain criteria:
      • Impaired kidney function, nephrolithiasis, or nephrocalcinosis
      • Reduced bone density
      • Serum Ca > 0.25 mmol/L
      • > 50 years of age
  • Preoperative localization:
    • Not required if total parathyroidectomy is planned
    • Needed for:
      • Minimally invasive/unilateral approach
      • Reoperation for recurrent/persistent hyperparathyroidism
    • Imaging methods:
      • Sestamibi (technetium-99m methoxyisobutylisonitrile) scan
      • Ultrasound
      • 4-dimensional CT scan
      • MRI
    • Invasive methods:
      • Selective venous sampling
      • Selective arteriography
  • Surgical procedures:
    • Total parathyroidectomy with forearm transplantation of parathyroid fragment:
      • In cases of parathyroid hyperplasia
      • If adenoma cannot be reliably identified preoperatively or intraoperatively
    • Removal of a specific parathyroid gland if tumor is reliably identified
    • Parathyroid carcinoma: parathyroidectomy with ipsilateral thyroidectomy and en bloc resection of all tissue invaded by the tumor

Secondary and tertiary hyperparathyroidism

Medical management:

  • Management of underlying disease
  • Vitamin D supplementation
  • Phosphorus dietary restriction and phosphate binders
  • Calcimimetics
  • Tertiary hyperparathyroidism: total or subtotal parathyroidectomy

Differential Diagnosis

  • Malignancy: Hypercalcemia is not uncommon in malignant disease, especially in more advanced stages. Malignancy is usually more severe and symptomatic than the hypercalcemia caused by hyperparathyroidism. Malignancy is often clinically evident when hypercalcemia is discovered. Management relies mostly on treatment of underlying disease.
  • Familial hypocalciuric hypercalcemia (FHH): an autosomal dominant disorder characterized by mild hypercalcemia, mild PTH elevation and low urine Ca: Familial hypocalciuric hypercalcemia is caused by an inactivating mutation of the Ca-sensing receptor in the parathyroid glands and kidneys. This condition usually presents with mild asymptomatic hypercalcemia and is distinguished from primary hyperparathyroidism by low urine Ca. This benign condition usually does not require treatment.
  • Drugs: Certain drugs can affect Ca metabolism and cause hypercalcemia, most notably lithium and thiazide diuretics. Lithium decreases parathyroid gland sensitivity to Ca and also decreases renal Ca excretion and may be associated with mild PTH elevation. Thiazide diuretics reduce urine Ca excretion. Hypercalcemia usually resolves following drug discontinuation.

References

  1. Bilezikian JP, et al. (2014). Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab 99:3561–3569. https://pubmed.ncbi.nlm.nih.gov/25162665/
  2. Fuleihan GE, Silverberg SJ. (2020). Primary hyperparathyroidism: diagnosis, differential diagnosis, and evaluation. Retrieved February 6, 2021, from https://www.uptodate.com/contents/primary-hyperparathyroidism-diagnosis-differential-diagnosis-and-evaluation
  3. Fuleihan GE, Silverberg SJ. (2019). Primary hyperparathyroidism: clinical manifestations. Retrieved February 6, 2021, from https://www.uptodate.com/contents/primary-hyperparathyroidism-clinical-manifestations
  4. Fuleihan GE, Arnold A. (2020). Pathogenesis and etiology of primary hyperparathyroidism. Retrieved February 6, 2021, from https://www.uptodate.com/contents/pathogenesis-and-etiology-of-primary-hyperparathyroidism
  5. Kim L. (2020). Hyperparathyroidism. Retrieved February 6, 2021, from https://emedicine.medscape.com/article/127351-overview#a4
  6. Silverberg SJ, Fuleihan GE. (2019). Primary hyperparathyroidism: management. Retrieved February 6, 2021, from https://www.uptodate.com/contents/primary-hyperparathyroidism-management
  7. Maitra A. (2020). Hyperthyroidism. In Kumar V, Abbas AK, Aster JC (Eds.). Robbins & Cotran Pathologic Basis of Disease, 10th ed., pp. 354–355.

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