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Hyperparathyroidism Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Classification

Classification of hyperparathyridism
Features	Primary hyperparathyroidism	Secondary hyperparathyroidism	Tertiary hyperparathyroidism
Pathology	Hyperfunction of parathyroid cells due to hyperplasia, adenoma or carcinoma.	Physiological stimulation of parathyroid in response to hypocalcaemia.	Following long term physiological stimulation leading to hyperplasia.
Cause
Associations	May be associated with multiple endocrine neoplasia.	Usually due to chronic renal failure or other causes of Vitamin D deficiency.	Seen in chronic renal failure.
Serum calcium	High	Low/Normal	High
Serum phosphate	Low/Normal	High	High
Management	Usually surgery if symptomatic. Cincacalcet can be considered in those not fit for surgery.	Treatment of underlying cause.	Usually cinacalcet or surgery in those that don't respond.

Causes

Overview

Hyperparathyroidism is caused by an increase in concentration of parathyroid hormone in serum. There are three type of hyperparathyroidism including primary, secondary and tertiary hyperparathyroidism. The are an array of different causes for all types of hyperparathyroidism.

Causes of Primary hyperparathyroidism

Causes of primary hyperparathyroidism are as follows:

Common causes

• Parathyroid adenoma
  • Usually single gland affected
  • Sometimes multiple gland affected

Less common causes

• Parathyroid hyperplasia
• Parathyroid carcinoma
• Familial isloated hyperparathyroidism
• Radiation exposure (due to development of parathyroid adenoma or parathyroid hyperplasia)
• Celiac disease

Genetic causes

• HRPT2 gene mutations:
  • HRPT2 gene code for parafibromin protein.
  • HRPT2 gene mutations are found in a type of familial hyperparathyroidism, hyperparathyroidism-jaw tumor (HPT-JT) syndrome.
  • HRTP2 gene mutations increases risk of parathyroid carcinoma.
• Cyclin D1 gene (CCND1)/PRAD1 gene:
  • PRAD1 (parathyroid adenoma 1) is a protooncogene located on chromosome 11q13.
  • Cyclin D1 gene translocation and oncogene action observerd in 8% of adenomas
  • Cyclin D1 gene overexpression is pbserved in 20% to 40% of parathyroid adenomas
• MEN1 gene:
  • MEN1 is a tumor supressor gene on chronosome 11q13.
  • Somatic loss of single MEN1 allele is observed in 25% to 40% of sporadic parathyroid adenomas.

Causes of secondary hyperparathyroidism

Causes of secondary hyperparathyroidism are as follows:

Common causes

• Chronic renal failure (leading to parathyroid hyperplasia)
• Vitamin D deficiency

Less common causes

• Severe calcium deficiency
• Gastric bypass surgery, particularly roux-en-Y gastric bypass (RYGBP)
• Malabsorption syndrome

Causes of tertiary hyperparathyroidism

Causes of tertiary hyperparathyroidism are as follows:

Common causes

• Chronic renal failure (leading to parathyroid hyperplasia)
• Renal transplant patients

Less common cause

• Long standing celiac disease

Pathogenesis

Associated conditions

• Hypercalcemia
• Chronic renal failure
• Osteitis fibrous cystica
• Osteoporosis
• Osteomalacia
• Osteoarthritis
• Brown tumor
• Multiple endocrine neoplasia type 1, type 2A, and type 4
• Familial isolated hyperparathyroidism
• Neonatal severe hyperparathyroidism
• Familial hypocalciuric hypercalcemia
• Hyperparathyroid-jaw tumor syndrome
• Pancreatitis

Natural history, Prognosis and Complications

Natural history

• Primary hyperparathyroidism usually develops in the fifth decade of life, in post-menopausal women and starts as asymptomatic hypercalcemia in presence of increased parathyroid hormone.
• If left untreated, some of patients with primary hyperparathyroidism may commonly develop marked hypercalcemia, marked hypercalciuria, cortical bone demineralization and nephrolithiasis.

• Secondary hyperparathyroidism arise in the early course of chronic renal failure. As renal failure progress, secondary hyperparathyroidism becomes more notable.
• Secondary hyperparathyroidism leads to vascular calcification due to elevated calcium and phosphorus levels. This is strongly associated with increase in morbidity and mortality.
• If left untreated, secondary hyperparathyroidism carries an increased risk of vascular calcification with increasing age and duration of dialysis in patients.

• Tertiary hyperparathyroidism usually develops in post renal transplant patients.
• If left untreated, tertiary hyperparathyroidism in post renal transplant patients may carry the risk of amyloid deposition, calciphylaxis, destructive or erosive spondyloarthropathy, osteonecrosis, and musculoskeletal infections.

Complications

Primary hyperparathyroidism

Majority of complications of primary hyperparathyroidism are due to hypercalcemia. Common complications of primary hyperparathyroidism include:

• Bone related complication:
  • Brown tumor
  • Osteitis fibrous cystica
  • Osteoporosis
• Cardiac complications:
  • Aortic and mitral valve calcification
  • Calcific deposits in the myocardium
  • Left ventricular hypertrophy
• Endocrine complications:
  • Pancreatitis
• Gastrointestinal complications:
  • Peptic ulcer disease
• Metabolic complications:
  • Hypercalcemic crisis
  • Osteomalacia
• Neuromuscular complications:
  • Neuropathic muscle disease
• Pregnancy related complications:
  • Neonatal hypoparathyroidism
• Psychiatric complications:
  • Anxiety
  • Cognitive dysfunction including verbal memory and nonverbal abstraction
  • Depression
  • Irritability
  • Lack of concentration
  • Sleep disturbances
• Renal complications:
  • Hypercalciuria
  • Nephrolithiasis
  • Nephrocalcinosis
  • Renal insufficiency (impairement of GFR)
• Rheumatologic complications:
  • Gout
  • Osteoarthritis
  • Pseudogout

Secondary hyperparathyroidism

Complications of secondary hyperparathyroidism includes:

• Cardiovascular complications:
  • Impaired left ventricular diastolic function
  • Left ventricular hypertrophy
• Hematologic complication:
  • Platlet function inhibition
• Metabolic complicattions:

• • Metabolic syndrome
• Musculoskeletal complications:
  • Renal Osteodystrophy
    • Brown cysts
    • Osteitis fibrosa cystica
    • Osteoporosis
    • Osteosclerosis
• Neurologic complications:
  • Electroencephalogram abnormalities
  • Uremic neuropathy
• Neuromuscular complications:
  • Neuropathic muscle disease
• System non-specific complications:
  • Metastatic calcifications

Tertiary hyperparathyroidism

Complications of tertiary hyperparathyroidism post renal transplantation includes:

• Metabolic complications:
  • Calciphylaxis
• Musculoskeletal complications:
  • Musculoskeletal infections
  • Osteonecrosis
• Neuromuscular complications:
  • Neuropathic muscle disease
• Renal complications:
  • Nephrolithiasis
• Rheumatologic complications:
  • Destructive or erosive spondyloarthropathy
• System non-specific complications:
  • Amyloid deposition
  • Metastatic calcifications

Prognosis

• Prognosis of primary hyperparathyroidism is generally excellent after parathyroidectomy.
• The complications of primary hyperparathyroidism resolves after the treatment.
• Untreated complication of primary hyperparathyroidism may be fatal.

• Effective treatment can reduce morbidity and mortality associated with uncontrolled secondary hyperparathyroidism.
• Hyperphosphatemia and metastatic calcification results due elevated product of serum calcium and serum phosphorus. Both conditions are present in patients with secondary hyperparathyroidism in presence of end stage renal disease. This leads to a significant increase in morbidity and mortality. Aggressive control of hyperphosphatemia may improve prognosis.

• Prognosis of tertiary hyperparathyroidism is generally good after resection of abnormal hyperplastic gland.

ECG

There are no CT scan findings associated with hyperparathyroidism. However, a CT scan may be helpful in the diagnosis of cardiac complications of hyperparathyroidism. Findings on ECG are due to hypercalcemia and includes:

• ST segment - ST segment is short in patients with hyperparathyroidism when compared to normocalcemic patients. This represents a decrease in systolic interval.
• QRS complex - QRS complex has an increased amplitudein patients with hyperparathyroidism when compared to normocalcemic patients. This represents an increase in ventricular muscle mass.
• T wave - T wave is prolonged in patients with hyperparathyroidism when compared to normocalcemic patients.

X-ray

Finding in primary hyperparathyroidism includes: Subperiosteal bone resorption Classically affects the radial aspects of the proximal and middle phalanges of the 2nd and 3rd fingers Medial aspect of tibia, femur, humerus Phalyngeal tuft erosion (acro-osteolysis) Lamina dura around teeth (floating teeth) Endoosteal bone resorption Widening of medullary cavity Thinning of the inner cortex Subchondral resorption Lateral end of the clavicles Symphysis pubis Sacroiliac joints Subligamentous resorption Ischial tuberosity Humeral tuberosity Trochanters Inferior surface of calcaneus Inferior margin of lateral clavicle Intracortical resorption: cigar/oval-shaped or tunnel-shaped radiolucency in the cortex Osteopaenia Brown tumours Salt and pepper sign in the skull (pepper pot skull) Chondrocalcinosis X-ray is the preferred imaging for diagnosis of secondary hyperparathyroidism as majority of findings are radiological. Findings in secondary and tertiary hyperparathyroidism are often associated with the osteosclerosis of renal osteodystrophy, and the osteomalacia of vitamin D deficiency: Subperiosteal bone resorption Radial aspect of middle phalanges of index and long fingers are involved. Subchondral resorption Hands, hips, shoulders, patellofemoral and sacroiliac joints are involved. Hands are involves in the ulnar side. Distal interphalangeal and metacarpophalangeal joints are involved. Subchondral resorption is very severe. It may lead to bony collapse. Subligamentous resorption Retrocalcaneal bursa and insertion of planter aponeurosis may be involved. Severe osteopenia, may be complicated by pathologic fractures Osteosclerosis, e.g. rugger-jersey spine Brown tumor Amyloid deposition May be manifested as lytic bone lesion on radiograph Soft tissue and vascular calcification Superior and inferior rib notching Osteonecrosis may be often observed in patients in whom steroid is administered for prevention of renal transplant rejection.
Subperiosteal bone resorption - Source:Radiopedia	Brown tumors - Source:Case courtesy of A.Prof Frank Gaillard, Radiopedia
Normal skull compared to Salt & pepper appearance of skull - Source:Radiopedia	Acro-osteolytis, terminal tufts erosion - Source:Case courtesy of Dr Andrew Dixon, Radiopedia

CT scan

• Good quality preoperative evaluation favors post operative results.
• 4-Dimentional CT scan is an investigation for preoperative localizing of hyperfunctioning pituitary gland.
• 4D-CT may be used for preoperative localization of hyper-functioning parathyroid glands in hyperparathyroidism. 4D-CT is significantly more sensitive than sestamibi imaging and ultrasound for precise (quadrant) localization of hyper-functioning parathyroid glands.
• The name 4D-CT refers to 3-dimensional CT scanning plus additional dimension of changes observed with respect to time as perfusion of contrast occurs. The principle is similar to CT angiography.
• 4D-CT provides extremely detailed images of neck in multiple planes and enables the visualization of difference in hyper-functioning parathyroid gland compared with normal parathyroid glands and other structures in the neck on the basis on perfusion characteristics ( rapid uptake and washout).
• 4D-CT has a sensitive of 88% in preoperative lateralizing hyper-functioning parathyroid glands to one side of neck when compared to sestamibi imaging (68% to 86% sensitive) and ultrasound (61% to 88% sensitive).
• 4D-CT has a sensitive of 79-88% in preoperative localizing the hyper-functioning parathyroid gland to the correct quadrant of the neck (right inferior, right superior, left inferior, or left superior) when compared to sestamibi imaging (33% to 40% sensitive) and ultrasound (29% to 48% sensitive).
• 4D-CT has a specificity of 75-100% in preoperative localizing the hyper-functioning parathyroid gland.
• 4D-CT enables an improved planning preoperativively, particularly in case of reoperation.
• A modified technique of 4D-CT/Ultrasound (Mod 4D-CT/US) has a sensitivity of 94% and specificity of 96% for lateralizing the hyperfunctioning parathyroid glands to one side of the neck. Mod 4D-CT/US has a sensitivity of 82% and specificity of 93% for localizing the hyper-functioning parathyroid gland to the correct quadrant of the neck (right inferior, right superior, left inferior, or left superior). Mod 4D-CT/US has a positive predictive vaue of 92% for single-gland disease and 75% for multi-gland disease.Mod 4D-CT/US has a negative predictive value of 73% for single-gland disease and 92% multi-gland disease.
• The major disadvantage of 4D-CT is significant radiation exposure associated with scanning the patient multiple times.

MRI

MRI may be helpful in the preoperative evaluation of hype-functioning parathyroid glands.

Sestamibi scintigraphy

• Technetium-99m-methoxyisobutylisonitrile (99mTc-sestamibi or MIBI) scintigraphy is the most popular investigation for preoperative localization of hyper-functioning parathyroid glands.
• Most of the sestamibi is retained in mitochondria of thyroid and abnormal parathyroid tissue and is a function of mitochondrial activity.
• The basis of this "single-isotope, double-phase technique" is that sestamibi washes out of the thyroid more rapidly than from abnormal parathyroid tissue.
• As all parathyroid lesions does not retain sestamibi nor all thyroid tissue washes out quickly, subtraction imaging may be beneficial.

Factors influencing Sestamibi-SPECT scan
Biological factors			Sensitivity
Biochemical factors	Serum calcium	Higher calcium	Increased
	Serum Parathyroid hormone	Higher	Increased
	Vitamin D