B2. Hyperparathyroidism.

Hyperparathyroidism refers to the increased activity of the parathyroid glands, causing elevated levels of PTH. We distinguish primary, secondary, and tertiary hyperparathyroidism.

Primary hyperparathyroidism is caused by local parathyroid pathology, which is the most important cause of hyperparathyroidism overall. Secondary hyperparathyroidism occurs as a response to hypocalcaemia, causing the parathyroid glands to overproduce PTH. Tertiary hyperparathyroidism occurs due to long-standing secondary hyperparathyroidism, in which the parathyroid glands have been overstimulated for so long that they continue to overproduce PTH even if the original stimulus is removed.

Etiology

Parathyroid adenoma is the most common cause of primary hyperparathyroidism, accounting for around 80% of cases. It’s a benign tumour of the parathyroid glands, always occurs in only one of the four parathyroid glands. The remaining glands are normal in size or slightly smaller, due to feedback inhibition.

Parathyroid hyperplasia affects more than one glands, often affecting all four glands equally. It can be idiopathic or associated with multiple endocrine neoplasia. It accounts for approximately 15% of cases of primary hyperparathyroidism.

Parathyroid carcinoma is very rare (0,5% of cases). It is impossible to distinguish an adenoma from a carcinoma by histology; the diagnosis of carcinoma is based on the presence of metastasis and local invasion.

Secondary hyperparathyroidism is caused by chronic kidney disease, malnutrition, vitamin D deficiency. Tertiary hyperparathyroidism is caused by long-standing secondary hyperparathyroidism.

Pathology

Abnormalities in two specific genes are commonly associated with sporadic parathyroid adenoma, namely Cyclin D1 inversion and MEN1 mutations. 20-30% of parathyroid tumors not associated with MEN-1 syndrome have acquired/somatic mutations in both copies of MEN-1 gene.

Clinical features

Hyperparathyroidism is often asymptomatic (incidentally discovered hypercalcaemia), but it may cause severe features as well:

• Stones
  • Nephrolithiasis
  • Nephrocalcinosis
• Bones
  • Bone pain
  • Osteitis fibrosa cystica
• Abdominal groans (pain)
• Thrones
  • Polyuria
  • Constipation
• Psychiatric overtones
  • Lethargy
  • Depression
  • Psychosis
• Others
  • Peptic ulcers
  • Acute pancreatitis
  • Left ventricular hypertrophy

The symptoms of primary hyperparathyroidism are often remembered as “bones, stones, abdominal groans, thrones, and psychiatric overtones”.

Diagnosis and evaluation

For comparison of lab values in primary and secondary hyperparathyroidism, see the table:

	PTH level	Ca level	Phosphate level	ALP level
Primary PHT	Elevated	Elevated	Decreased	Elevated
Secondary PHT	Strongly elevated	Normal or decreased	Elevated	Elevated

X-ray is not performed for evaluation, but characteristic findings of PTH may be found incidentally on x-ray. Characteristic findings include cortical thinning of bone, especially prominent in the phalanges of the hand, salt-and-pepper skull (granular decalcification), and osteitis fibrosa cystica (bone cysts).

If primary PHT is evident on labs and surgery is indicated, studies should be performed to localise the pathology. This is important as the localisation of the glands shows a great variability between persons. This is done with ultrasonography or technetium-99m sestamibi scintigraphy.

Treatment

The treatment of primary hyperparathyroidism is surgery.

Surgical treatment of hyperparathyroidism

For primary hyperparathyroidism, surgery is the only definitive treatment. However, it’s not recommended for everyone. Surgery is generally indicated for:

• Serum calcium > 2,8 mM
• Deteriorating kidney function
• Young patient

If surgery is not indicated, the patient is monitored regularly for progression.

For patients with indication for surgery but who are unable to have surgery, medical therapy with cinacalcet is an option. See the internal medicine topic for details.

Surgery is successful in almost all cases. The specific surgical treatment depends on the etiology:

• Adenoma – extirpation (parathyroidectomy)
• Hyperplasia – subtotal parathyroidectomy or total extirpation with autotransplantation
• Carcinoma – extirpation + lymphatic block dissection

Autotransplantation refers to reimplantation of half of one of the resected glands in the forearm or neck muscle. This prevents total loss of PTH and allows for easy surgical access if this reimplanted gland causes problems later.

Secondary hyperparathyroidism is mostly treated conservatively, but surgery is indicated for severe refractory secondary hyperparathyroidism.

Pharmacological therapy

For patients with primary hyperparathyroidism and an indication for surgery but who are unable to have surgery, medical therapy is an option. The drug cinacalcet is used for this, which inhibits PTH release. Cinacalcet may also be used for parathyroid carcinoma.

Management for secondary hyperparathyroidism involves treating the underlying cause. Dietary restriction of phosphate and vitamin D supplements are also important. Phosphate binders may be used in case hyperphosphataemia remains despite dietary restriction. Cinacalcet may also be used.