Secondary & Tertiary Hyperparathyroidism

Secondary Hyperparathyroidism (SHPT)

Fig. 1: The enlargement of all glands in secondary HPTThis is where parathyroid hormone (PTH) levels are raised due to any disease process which causes low calcium levels, thus stimulating the parathyroids to become overactive. Thus the disease is secondary to another underlying problem, rather than being directly caused by an abnormality in a single (or multiple) parathyroid(s). 

It is usually associated with the pathology of parathyroid hyperplasia (see webpage on Hyperparathyroidism), where all parathyroids are affected (though often not necessarily uniformly) and treatment requires more than a single gland to be removed.

Causes

The main causes of secondary hyperparathyroidism are:

1. Renal (kidney) failure

This is by far the most common cause of secondary hyperparathyroidism in Australia. There are more than 30,000 patients on renal replacement therapy (dialysis) in this country.

With the withdrawal of cinacalcet from the Pharmaceutical Benefits Scheme in 2016, this medical management option is no longer available to control the secondary HPT, making surgery more necessary (it is thought to be more cost-effective than long term drugs as well, hence the withdrawal of the drug from the PBS).

The mechanism of secondary HPT in renal disease is the failing kidney's inability to handle phosphate excretion. This causes chronic hypocalcaemia, and in addition the kidney fails to convert 25-cholecalciferol into 1,25-dihydroxycholecalciferol, the active form of vitamin D. This means that the intestine absorbs less calcium from the diet, further contributing to a low blood calcium. 

Both of these factors (high serum phosphate and low Vitamin D synthesis) lead to chronic parathyroid stimulation and an increase in secretion of parathyroid hormone, often to very high levels. The serum calcium levels will usually be low normal or relatively normal however, at least in the early stages (cf. primary hyperparathyroidism). Almost all patients with chronic renal failure will have secondary HPT to some degree.

The metabolic abnormalities will result in high-turnover bone disease, osteitis fibrosa cystica, which results in more fibrotic bone of decreased strength. This can lead to pain in the bones and joints, and pathological fractures in advanced cases.

Extraskeletal manifestations are common with ectopic calcifications in subcutaneous tissues, muscles, joints, heart valves, and widespread calcifications in blood vessels. Calciphylaxis is a rare condition of accelerated calcifications in vessels which can lead to tissue necrosis, gangrene, sepsis and a mortality rate approaching 50%. This is an indication for an urgent (life-saving) parathyroidectomy.

2. Malabsorption

Any disorder where there is a generalised malabsorption of nutrients from the diet can result in a low blood calcium and a subsequent increase in parathyroid hormone production. This is managed by dietary manipulaton to prevent the calcium deficiency.

3. Vitamin D and calcium deficiency

A diet deficient in calcium or vitamin D (required to absorb calcium) leads to low blood calcium and increased parathyroid hormone release. This is a common cause in patients found to have a normal calcium but a mild rise in PTH (usually less than double the upper limit of normal). Correction of the Vitamin D deficiency by regular oral supplementation will reverse the rise in PTH, although it can take some time to correct. Further information on Vitamin D can be found on webpage Vitamin D.

4. Lithium therapy

Long term use of lithium for control of bipolar psychiatric illness can result in secondary HPT in 15-60% of patients. Hypercalcaemia tends to be mild, and typically only develops after years of treatment. In contrast, patients who develop hypercalcaemia soon after the lithium is started will generally have an underlying single gland adenoma of primary HPT, which is unmasked by the lithium.

The condition is often reversible if the lithium can be stopped, but surgery may be needed to control the hypercalcaemia, and is usually managed surgically in the same way as patients with renal failure.

Investigation

In general, patients with secondary HPT do not undergo localisation studies as they will always have a 4-gland bilateral exploration of their neck. However, ultrasound can be useful to locate the enlarged glands in selected cases, but sestamibi nuclear scanning has a low success rate in localising patients with hyperplastic glands and so is less useful.

Treatment

Secondary hyperparathyroidism is essentially treated by targeting the underlying cause of the hypocalcaemia driving the excess PTH secretion. In the case of the less common causes such as malabsorption, Vitamin D deficiency and lithium therapy, treatment is generally medical manipulation of the diet, or cessation of the drug in the case of lithium, if possible.

Renal hyperparathyroidism

Patients with renal failure, on chronic dialysis, will generally be managed by the nephrologist with medical therapies such as phosphate binders and high dose vitamin D. Drugs such as cinacalcet (a calcium receptor agonist) can be given to lower the PTH levels, however recently this drug has been withdrawn from the Pharmaceutical Benefits Scheme in Australia, as it was not thought to cost effective.

The best long term solution is kidney transplantation if possible, which will reverse the secondary hyperparathyroidism in most patients.

The indications for surgery in renal hyperparathyroidism are: 

  • calciphylaxis
  • poor compliance with medical management
  • patient preference
  • remote location
  • failed medical therapy, especially developing hypercalcaemia
  • osteoporosis
  • symptoms (especially skeletal pain) 

The choice of operation depends on surgeon experience and preference, hospital nephrology protocols, the operative findings, patient compliance and isolation, patient comorbidities and life expectancy, and finally the likelihood of a renal transplant.

The two main operations performed in this case (see webpage on Details of Surgery) are:

  • subtotal parathyroidectomy (leaving part of one parathyroid intact, usually a lower gland)
  • total parathyroidectomy, and auto transplantation of part of one gland into a neck or forearm muscle

Postoperatively, approximately 10% of patients will develop a condition called 'hungry bone syndrome', caused by the depletion of calcium in the bones over many years by the hyperparathyroidism. This is managed by high dose calcium replacement (often intravenously), so a central IV line is usually inserted as part of the operation. The patients at high risk for this syndrome are usually male, younger, with greater body weight, and have a lower preop calcium level, and a higher serum ALP level.

The aim is for a 90% success rate of controlling the HPT, with <5% recurrence, but it is salient to remember that 9-13% of dialysis patients die each year.

Tertiary Hyperparathyroidism (THPT)

If the causes of secondary hyperparathyroidism persist for some time, one or more parathyroid glands may become autonomous. The cells start producing excessive amounts of PTH even once the stimulus of low calcium is removed (e.g. after medical treatment). This is known as tertiary hyperparathyroidism.

This is thought to be due to the evolution over time from polyclonal parathyroid cells to more monoclonal nodules, resulting in the failure of medical treatment controlling the hyperparathyroidism. It can also occur when excessive PTH secretion continues after renal transplantation (which is sometimes known as quaternary HPT). Again this is thought to be due to monoclonal nodular parathyroid disease, with 20% of affected patients having a single or double adenoma, rather than hyperplasia affecting all glands.

In tertiary hyperparathyroidism, the main indications for surgery are:

  • calciphylaxis
  • severe hypercalcaemia
  • persistent hypercalcaemia
  • osteoporosis
  • symptoms, especially bone pain

In these rare circumstances parathyroid surgery is necessary to correct the autonomous parathyroid abnormality. The exact type of operation performed depends on the patient’s individual clinical situation, but the two main operations performed in this case are:

  • 4-gland exploration with removal of a single or double adenoma
  • subtotal parathyroidectomy (leaving part of one parathyroid intact, usually a lower gland)
  • total parathyroidectomy and auto transplantation of part of one gland in neck or forearm muscle

Which operation is performed depends on the exact state of the parathyroid glands when they are inspected at operation, the expertise of the surgeon and the protocol normally followed by the hospital and nephrology unit.