What is Secondary Hyperparathyroidism and How is it Treated?

Introduction

Over the years I have seen a fair amount of confusion from patients (and from doctors as well) concerning the concept of secondary hyperparathyroidism and how it is different from primary parathyroid disease.  The distinction between the two is an important one, and in this article I will discuss what secondary hyperparathyroidism is, how it compares with primary hyperparathyroidism, the most common causes of secondary hyperparathyroidism, and finally how it is treated. 

What is Secondary Hyperparathyroidism?

Patients with primary hyperparathyroidism have one or more parathyroid glands that are diseased.  These diseased, or abnormal, glands over-secrete parathyroid hormone (PTH) leading to a number of symptoms and end-organ complications. Learn more about primary hyperparathyroidism.

Patients with secondary hyperparathyroidism do NOT have diseased parathyroid glands.  Rather, they have perfectly normal parathyroid glands that are secreting more PTH than they normally do to try and compensate for other things going on in their bodies.  There are a number of conditions that can lead to a secondary elevation of a patient’s PTH levels.

Why is it important to distinguish between primary and secondary hyperparathyroidism?

When evaluating patients with a possible diagnosis of hyperparathyroidism, it is important to determine if they have primary hyperparathyroidism or a secondary PTH elevation.  This is important because the treatment for primary and secondary hyperparathyroidism is very different (in most cases – more on this later).  For patients with primary hyperparathyroidism, the only effective treatment requires surgical removal of one or more diseased parathyroid glands causing the problem. Learn more about the treatment of primary hyperparathyroidism. In the majority of cases of secondary hyperparathyroidism, medical treatment to correct the problem influencing the normal parathyroid glands is all that is required.  Surgical removal or one or more parathyroid glands in these cases typically has no benefit for the patient and in some cases can cause harm to them. 

What are the most common causes of secondary hyperparathyroidism?

As mentioned above, there are a number of conditions that can influence the function of our parathyroid glands.  Once again, these conditions cause NORMAL parathyroid glands to secrete increased amounts of PTH as a way of compensating for what they are doing to the body.  The following sections will discuss the most common causes of secondary PTH elevation and how they should be treated. 

Renal Failure

How does renal failure cause secondary hyperparathyroidism?

One of the most common causes for secondary hyperparathyroidism is seen in patients with end-stage renal disease.  When a patient’s kidneys fail, several alterations in their physiology cause a great deal of stimulation to the parathyroid glands.  The kidneys are involved in activating vitamin D, which is involved with absorption of calcium from the GI tract into the bloodstream.   When the kidneys fail, this no longer occurs leading to low calcium levels from malabsorption, which in turn stimulates the parathyroid glands to secrete more PTH.  Additionally, in patients with renal failure their phosphorus levels become elevated, something that also significantly stimulates PTH secretion.

How is secondary hyperparathyroidism caused by renal failure treated?

As described above, the reason for secondary PTH elevation in patients with renal failure is a combination of low calcium and vitamin D levels as well as elevated phosphorus levels.  The primary treatment for this is medical, involving supplementation with calcium, vitamin D and vitamin D alanogs, as well as reducing phosphorus levels with phosphate binding medications.  In recent years the addition of calcimimetic medications like cinacalcet (Sensipar) have made medical management of renal failure-mediated secondary hyperparathyroidism effective in most cases.  There are, however, instances when medical management fails to control PTH hypersecretion and subtotal resection (removal of three and part of the fourth parathyroid glands) is required.  These patients are not in general considered failures of medical therapy until the PTH values are 1,000pg/ml or higher.   In reality, these patients should be referred for surgical therapy sooner, as when PTH values climb into the 500 to 1000pg/ml range, patients can begin to develop the same symptoms that patients with primary disease.  Additionally, the argument has been made that surgical treatment is more cost-effective than treatment with long-term cinacalcet, which is an expensive medication. 

Malabsorption

How does malabsorption cause secondary hyperparathyroidism?

Another common etiology of secondary hyperparathyroidism is malabsorption syndromes.  The common thread in these syndromes is poor absorption of calcium and vitamin D, which in turn leads to increased secretion of PTH to compensate for this.  The most common examples of this include long-standing celiac disease, Crohn’s disease, and patients who have had roux-en-y gastric bypass operations.   In celiac disease (gluten sensitive enteropathy) and Crohn’s disease, inflammation of the small intestine interferes with absorption of nutrients (including calcium and vitamin D) from the intestines into the bloodstream.  In patients who have had roux-en-y gastric bypass for obesity, the portion of the small intestine that is most responsible for calcium and vitamin D absorption is bypassed. 

How is secondary hyperparathyroidism caused by malabsorption treated?

The treatment for these collective malabsorption syndromes is medical, involving aggressive supplementation with calcium and vitamin D.   Surgery is not an effective treatment option for secondary hyperparathyroidism due to malabsorption.  Even performing a sub-total resection (removing three of the four parathyroid glands) does not typically lower PTH levels, at least not for very long.  This is because the reason for the PTH elevation – the malabsorption – has not been corrected and will continue to stimulate the remaining gland to overproduce PTH.  Additionally, surgery can be harmful in these patients.  They already have low calcium levels, and removing parathyroid glands takes away the body’s ability to compensate for this, leading to even lower calcium levels, which can be dangerous. 

Vitamin D Deficiency

How does vitamin D deficiency cause secondary hyperparathyroidism?

While vitamin D deficiency was mentioned as part of the previous sections on renal failure and malabsorption syndromes, there are patients with normal kidney function and who do not have a malabsorption syndrome who are simply vitamin D deficient.  This is most commonly due to a combination of poor dietary intake of vitamin D and having little exposure to sunlight.  Our vitamin D comes from a combination of dietary intake and a portion that is synthesized in our skin – a reaction initiated by UV radiation.  Severe vitamin D deficiency can cause a secondary elevation of PTH levels, as the reduced vitamin D limits absorption of calcium from the intestines, lowering calcium levels.  The parathyroid glands then do their job – secrete more PTH to try and compensate for the low calcium levels. Here's a detailed explanation of how the parathyroid glands maintain calcium levels.

How is secondary hyperparathyroidism caused by vitamin D deficiency treated?

Treatment of secondary hyperparathyroidism due to severe vitamin D deficiency involves increasing dietary intake, taking vitamin D supplements, and increasing exposure to sunlight.  A very important distinction to remember with respect to vitamin D deficiency is that this NEVER causes high calcium levels. Patients with primary hyperparathyroidism usually also have low vitamin D levels. The critical difference is that patients with secondary hyperparathyroidism due to vitamin D deficiency have LOW calcium, LOW vitamin D, and HIGH PTH levels, while patients with primary hyperparathyroidism have HIGH calcium, LOW vitamin D, and HIGH PTH levels.  Vitamin D deficiency NEVER causes high calcium levels. 

Renal Calcium Leak Syndrome

How does renal calcium leak cause secondary hyperparathyroidism?

Renal calcium leak syndrome is caused by a defect in the kidney which interferes with their ability to keep calcium in the blood stream.  As a consequence of this, increased amounts of calcium ends up being excreted in the urine then normal and blood levels of calcium go down.  Once again, the parathyroid glands try to do their job and compensate for this by secreting more PTH.  These patients typically have low calcium levels, high PTH levels, high urinary calcium levels, and produce numerous kidney stones. 

How is renal calcium leak treated? 

Treatment for this is medical, involving calcium supplementation along with the use of a thiazide diuretic.  These diuretics work by forcing more sodium ions into the urine in exchange for calcium ions, leading to more calcium remaining in the bloodstream.  This action, along with calcium supplementation usually return calcium levels and consequently PTH levels to normal.   The figure below summarizes the relationship between calcium and PTH levels in the various forms of secondary hyperparathyroidism and primary hyperparathyroidism. 

Summary

Secondary hyperparathyroidism can sometimes be confused with primary parathyroid disease by doctors.  It is an important distinction to make, as secondary hyperparathyroidism is in the vast majority of cases treated medically while primary parathyroid disease requires surgery to treat. Find more information about all things parathyroid disease.

Additional Resources:

• Learn more about the Norman Parathyroid Center.
• Read more on the Parathyroid blog.
• Become our patient.
• Check out our sister surgeons at the Clayman Thyroid Center, the Scarless Thyroid Surgery Center and the Carling Adrenal Center. We are now united under one roof, operating at the Hospital for Endocrine Surgery.