Introduction

Primary hyperparathyroidism is the most common cause of hypercalcaemia in outpatients.

The condition is characterised by a raised serum parathyroid hormone (PTH) and calcium levels, however normocalcaemic variations have been identified. It is relatively common, disproportionately affecting women and the elderly. Primary hyperparathyroidism is typically caused by parathyroid hormone secreting adenomas within the parathyroid gland itself.

Primary hyperparathyroidism can be managed conservatively or surgically. Parathyroidectomy is preferred due to the high cure rates (up to 98%) and reduced risk of drug side effects. Medical therapies involve drugs, such as calcitonin and bisphosphonates. These reduce the release of calcium into circulation from the bones, kidneys and gut.

Epidemiology

  • Incidence: 40.00 cases per 100,000 person-years
  • Peak incidence: 70+ years
  • Sex ratio: more common in females 3:1
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Aetiology

Primary hyperparathyroidism is caused by excess secretion of PTH resulting in hypercalcaemia. In 85% of cases a parathyroid adenoma is responsible, however other aetiologies are recognised. Multiple adenomas or diffuse enlargement of all 4 parathyroid glands is less common and are associated with inherited forms of primary hyperparathyroidism.

These inherited forms occur in approximately 15% of cases. Inherited disorders responsible for primary hyperparathyroidism include:
  • Multiple endocrine neoplasia (MEN)
  • Hyperparathyroidism jaw tumour syndrome
  • Familial isolated primary hyperparathyroidism

Another 1% of cases is cause by parathyroid malignancies. While another small proportion is caused by other factors such as lithium therapy or neck irradiation.

Risk factors for primary hyperparathyroidism include:
  • Female sex
    • Woman are 2-3 times as likely to develop primary hyperparathyroidism
    • Post-menopausal woman are at the highest risk
  • Older age
    • Prevalence increases with age
    • Most common from ages 45-75
    • All ages can be diagnosed
  • Family history
    • Increases risk of multi-gland disease
    • May suggest multiple endocrine neoplasia (MEN)

Pathophysiology

Primary hyperparathyroidism is driven by dysregulation of normal calcium homeostasis.
  • Normally, PTH is secreted in response to low serum calcium levels.
  • Here, PTH acts on the bones, kidneys and, indirectly, the bowels to move calcium into the blood stream to increase the serum calcium concentration back within the normal range.
  • This normal concentration of calcium doesn't stimulate PTH secretion and the level of PTH drops.

Reduced serum calcium → PTH secretion by the parathyroid gland → PTH binds to receptors within the bones and kidneys → calcium is moved from the bones and kidneys into the bloodstream → calcium re-enters the normal range → PTH levels drop.

However, in primary hyperparathyroidism a region of cells within the parathyroid glands cease to respond to this negative feedback loop. These cells continuously secrete PTH irrespective of the serum calcium concentration. This results in hypercalcaemia.
  • Over time, the region of cells secreting excess parathyroid hormone grows and the levels of PTH and therefore calcium slowly rise.
  • As the hypercalcaemia worsens the patient will begin to develop symptoms.

Clinical features

Patients with primary hyperparathyroidism are most commonly asymptomatic. In these cases, patients are often identified incidentally when a raised calcium level is identified after a serum calcium is investigated for another reason. These patients may report mild fatigue, weakness, depression and cognitive impairment if questioned, however. Over time, these patients may begin to develop symptoms as their calcium levels increase.

Symptomatic patients typically present with signs and symptoms of hypercalcaemia which can be remembered with the mnemonic 'stones, bones, abdominal groans and psychic overtones':
  • 'Stones' - increased risk of kidney stones (17%)
  • 'Bones'
    • Bone pain (35%)
    • Osteopenia and osteoporosis (40%)
  • 'Abdominal groans'
  • 'Psychic overtones'
    • Fatigue
    • Depression (10%)
    • Memory impairment (18%)
Other features include polyuria, paresthesia and muscle cramps. As calcium levels rise more serious symptoms develop. In severe cases, cardiac and metabolic disturbances, delirium or even coma may occur. The history should also screen for symptoms of malignancies, including but not limited to unexplained weight loss, night sweats and pain.

On examination, fluid status should be assessed due to the increased risk of dehydration as a result of polyuria and reduced oral intake. As hypercalcaemia in the elderly can mimic dementia or depression, cognitive impairment should be screened. Finally, signs of a malignancy should be examined. This includes neck, respiratory, abdominal, breast and lymphoreticular examinations.

Investigations

In patients with suspected primary hyperparathyroidism, a diagnosis is made by measuring serum adjusted calcium and parathyroid hormone (PTH) levels at the same time. Typically, both calcium and PTH should be raised, although a raised serum calcium and a normal PTH is also indicative of primary hyperparathyroidism. This is because the PTH levels are inappropriately high in the context of a raised calcium.
  • Serum calcium
    • Hypercalcaemia is defined as a serum adjusted calcium >2.6mmol/L
    • Raised levels suggest disease, however high-normal results should be further investigated if there is high clinical suspicion
    • Duration and pattern of hypercalcaemia may suggest a cause. Primary hyperparathyroidism progresses slowly over years and is typically mild
  • Serum PTH
    • Raised in primary and tertiary hyperparathyroidism
    • Inappropriately normal results indicate disease too
    • Reduced in malignant and PTH independent causes of hypercalcaemia
Findings of raised serum adjusted calcium and PTH indicate the presence of a parathyroid-dependant hypercalcaemia. This limits the cause to a small number of conditions. To differentiate these the following investigations should be considered:
  • 24-hour urinary calcium to exclude familial hypocalciuric hypercalcaemia
    • High-normal in primary hyperparathyroidism, but low in familial hypocalciuric hypercalcaemia

Additional investigations should be used to rule out differential diagnoses, assess viability for surgery and identify evidence of complications. Some common additional investigations include:
  • Estimated glomerular filtration rate (eGFR) and creatinine to assess hydration status, risk of acute kidney injury and presence of chronic kidney disease
  • Serum and urine protein electrophoresis, including testing for urine Bence-Jones protein to exclude myeloma
  • Full blood count (FBC) to exclude haematological malignancy
  • Liver function tests (LFTs) to exclude liver metastasis and some systematic diseases
  • Dual energy x-ray absorptiometry (DEXA) to assess bone health and risk of osteopenia/osteoporosis

Imaging may be indicated to identify lesion if a surgical intervention is desired. The most commonly used imaging used in primary hyperparathyroidism is ultrasound, but CT and MRI are sometimes indicated.

Differential diagnosis

Malignancy is the most common differential and therefore should be excluded in all patients. Hypercalcaemia of malignancy has 2 main mechanisms:
  • PTH-related-protein (PTHrP) secreting tumours (e.g. lung, breast and kidney)
  • Osteolytic lesions (e.g. bone metastasis and multiple myeloma)
A full history and examination should be conducted. This may elicit symptoms and signs of malignancy such as fatigue, weight loss, pain, malaise and unexplained masses. Hypercalcaemia of malignancy typically causes a much faster rise in calcium than primary hyperparathyroidism and generally produces a more severe hypercalcaemia. Additionally, serum PTH is low in hypercalcaemia of malignancy.

Familial hypocalciuric hypercalcaemia (FHH) is a rare autosomal domination condition in which there is reduced renal excretion of calcium. Patients are asymptomatic and are characterised by raised serum adjusted calcium and normal-raised PTH levels similar to primary hyperparathyroidism. These patients generally do not require treatment, so differentiation from primary hyperparathyroidism is important.
  • Differentiated with a 24-hour urinary calcium
    • FHH results in a hypocalciuria
    • Primary hyperparathyroidism results in high or normal urinary calcium
  • A diagnosis of FHH can be confirmed with genetic testing

Some medications can result in hypercalcaemia too. The drugs most often associated with hypercalcaemia are:
  • Thiazide diuretics (e.g. bendroflumethiazide, indapamide)
    • These increase renal reabsorption of calcium resulting in a PTH-independent hypercalcaemia
  • Vitamin D supplements
    • Vitamin D toxicity is a result of too much supplemental vitamin D
  • Calcium supplements
These causes can be ruled out with a thorough drug history. Additionally, these result in a hypercalcaemia with a reduced PTH level.

Other differentials to consider include: secondary and tertiary hyperparathyroidism, sarcoidosis, thyrotoxicosis, immobilisation and Paget's disease of bone.

Management

Most patients diagnosed with primary hyperparathyroidism can be initially managed by their GP and then referred to a surgeon for parathyroidectomy. These patients who are asymptomatic or only have mild symptoms will not need to be admitted to hospital for medical management.

However, patients with severe hypercalcaemia or severe symptoms will need to be managed within the hospital.
  • Severe hypercalcaemia is defined as a serum adjusted calcium of 3.40 mmol/L.
  • Severe symptoms include:
    • Electrocardiogram (ECG) changes (e.g. shortened QT interval) and cardiac arrhythmia
    • Impaired consciousness
    • Fractures
    • Pancreatitis and peptic ulcers
Management for these patients will involve medications to reduce the calcium levels and treatment for the complications. Once stabilised, these patients may be given the option of surgery.

The 2019 NICE guidelines recommend parathyroidectomy for most patients with diagnosed primary hyperparathyroidism due to the high cure rates (up to 98%) and reduced risk of drug side effects. Conservative therapies are available and effective for some patients, however. Surgery is indicated for those with one or more of:
  • Symptomatic disease
    • Symptoms of hypercalcaemia
    • Osteoporosis and/or fragility fractures
    • Renal stones or nephrocalcinosis
  • Age <50 years
  • Serum adjusted calcium of 2.85 mmol/L or above
  • Estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m²
However, those unfit for surgery or with mild hypercalcaemia and symptoms may be recommended alternative management.

When parathyroid surgery is not acceptable, NICE recommends specialist management of hypercalcaemia with either:
  • Calcitonin which reduces serum calcium concentrations by inhibiting bone and kidney resorption of calcium
  • Cinacalcet which is a calcimimetic and acts to reduce serum calcium concentrations while not affecting bone density or urinary calcium concentrations
  • Desunomab which also impairs calcium resorption
  • Bisphosphonates

Complications

The complications of primary hyperparathyroidism result from either untreated hypercalcaemia or the treatment options. They can be minimised with effective diagnosis and treatment.

Complications of untreated hypercalcaemia include:
  • Osteoporosis and fragility fractures
  • Kidney stones and kidney injury
  • Hypertension and heart disease
  • Numerous gastrointestinal disorders including peptic ulcer disease, pancreatitis and gall stones

Complications of parathyroidectomy:
  • General surgical complications (reduced risk with good surgical practice)
    • Infection
    • Thrombosis
    • Scarring
  • Procedure specific complications
    • Damage to the recurrent or superior laryngeal nerves
    • Post operative hypocalcaemia can result after the removal of too much parathyroid tissue
  • Failure to identify adenoma or persistence of disease post-surgery