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Understanding Secondary Hyperparathyroidism: Causes, Symptoms, Diagnosis, and Treatment Options

Renal secondary hyperparathyroidism is a condition more common than primary hyperparathyroidism, often seen in chronic kidney disease, particularly in dogs and occasionally in cats. As kidney function declines, the blood phosphate levels rise (hyperphosphatemia), causing a decrease in blood calcium levels. This is due to the formation of phosphate-calcium complexes in the blood, reducing the amount of free, ionized calcium. Additionally, impaired kidney function hinders the production of calcitriol (active vitamin D3), further exacerbating the problem.


The body responds to the low calcium levels and reduced calcitriol by increasing the production of parathyroid hormone (PTH) from the parathyroid glands. Fibroblast growth factor 23, a compound produced in the bones, is also increased in response to high phosphate levels and interferes with the activation of vitamin D3. The lack of sufficient calcitriol also impairs the usual negative feedback mechanism that regulates PTH secretion.


As kidney disease progresses and the glomerular filtration rate drops, PTH levels continue to rise, leading to the symptoms and complications associated with renal secondary hyperparathyroidism. Unlike primary hyperparathyroidism, this condition is not autonomous but rather a secondary response to chronic kidney failure and its effects on calcium, phosphate, and vitamin D metabolism.


Clinical Signs of Renal Secondary Hyperparathyroidism

 

In dogs with renal insufficiency, several primary symptoms such as vomiting, dehydration, excessive thirst and urination, and depression are indicative of kidney issues. This condition also causes various bone-related problems that worsen as the kidney disease advances. Initial stages might reveal slight bone alterations, but later stages can result in serious bone diseases like fibrous osteodystrophy. Young dogs may develop swelling in their faces due to bone irregularities, while older dogs often maintain normal bone mass because of slower disease progression and decreased bone metabolism.


In fibrous osteodystrophy, bones often appear less dense or softer than normal due to mineral imbalances.
In fibrous osteodystrophy, bones often appear less dense or softer than normal due to mineral imbalances.

Bone symptoms are common and differ in their severity. Certain parts, such as the skull's spongy bones, exhibit early and more pronounced damage. Early signs include the loss of alveolar bone, which can lead to teeth loosening, chewing difficulties, and possibly tooth loss. In extreme cases, the jawbones soften and become flexible, leading to alignment issues, drooling, and the tongue sticking out. This is referred to as "rubber jaw" syndrome. The mandible, extremely demineralized, is susceptible to fractures and teeth shifting. Yet, the long bones in the limbs are not as significantly impacted, though increased bone resorption may cause lameness, stiff movements, and fractures from slight injuries.

Typically, all parathyroid glands are enlarged in these dogs, and their parathyroid hormone (PTH) levels may exceed those seen in primary hyperparathyroidism. From a histological perspective, there's an uptick in osteoclast activity, bone marrow fibrosis, and a greater presence of disorganised bone tissue (woven osteoid). In the latter stages of the disease, severe imbalances in calcium and phosphate levels may occur, leading to osteosclerosis.

Osteosclerosis, an uncommon condition, is characterized by heightened bone density, resulting in the bones becoming stiff and hardened. The symptoms experienced can differ based on the specific form of sclerosis.

Diagnosis of Renal Secondary Hyperparathyroidism

 

Renal secondary hyperparathyroidism is identified through lab tests indicating kidney dysfunction and elevated blood levels of parathyroid hormone (PTH). For accurate diagnosis, a species-specific radioimmunoassay of PTH, available for most pets and horses, is necessary. It's important to avoid assays that measure only parts of the PTH molecule, as these can be misleading due to the rise in biologically inactive PTH metabolites in cases of renal failure.

A Clinical Case Example

Max, an otherwise energetic Labrador, had become a shadow of his former self. Each morning, his once eager barks for breakfast had turned into lethargic whimpers. He'd approach his water bowl with an unquenchable thirst, yet even the smallest drink would send him outside, urinating more frequently than ever. As the days passed, his once lustrous coat dulled and his eyes lost their sparkle, often gazing into the distance in a daze of depression.


As the vet, I noticed the subtle changes first. Gently palpating Max's abdomen, I observed his discomfort. But it was the X-rays that revealed the truth: Max's bones told a story of hidden suffering. The normally dense and structured bones of his skull now appeared porous and fragile, particularly around his jaw. When I probed gently, Max's jaw seemed to give way slightly – a classic sign of what I knew as "rubber jaw" syndrome, a severe consequence of advanced renal insufficiency.


As Max lay on the examination table, his limbs stretched out, I noted their frailty. Unlike his skull, the long bones in his legs hadn't suffered as much demineralisation, but there was a definite stiffness in his movements. I recalled a recent incident when Max yelped in pain from a simple leap off the porch – a minor jump that would have been effortless months ago, now a risky endeavour for his weakened bones.


Turning to Max's recent blood tests, I pointed out to his owner the abnormally high levels of parathyroid hormone (PTH), far exceeding the normal range. This hormonal imbalance was silently orchestrating a destructive process within Max's body, leading to an overactive breakdown of bone tissue, leaving behind a chaotic array of unorganised bone tissue.


As I explained the progression of renal insufficiency and its impact on Max's skeletal structure, I emphasised the importance of early intervention. The imbalance in calcium and phosphate levels in Max's body was not just a number on a lab report; it was a ticking clock, gradually leading towards osteosclerosis, a condition that would further limit his mobility and quality of life.


Treatment of Renal Secondary Hyperparathyroidism

 

Treatment options for renal secondary hyperparathyroidism include:


1. Dietary modifications:

  1. Managing phosphorus intake:

  2. Adequate calcium intake:

2. Medications (Supplements):

a. Calcimimetics: 

Drugs like cinacalcet (Sensipar) can be prescribed to lower PTH levels by increasing the sensitivity of the parathyroid glands to calcium.


b. Vitamin D analogs: 

In some cases, vitamin D supplements may be prescribed to help regulate calcium and PTH levels. These can either be calcitriol or paricalcitol.


Calcitriol (active form of vitamin D):

Calcitriol prevents and treats low calcium levels in cases of kidney disease. It is also used in cases of parathyroid gland conditions. It works by increasing the amount of calcium in the body. It also helps regulate parathyroid hormone levels. In some cases, calcitriol supplementation may be necessary to help regulate calcium and PTH levels. Treating hyperparathyroidism caused by chronic kidney disease has been successful with oral calcitriol at doses of 1.5–3.5 ng/kg/day, but its use is not recommended if there is hyperphosphatemia or hypercalcemia. (Note that calcitriol requires custom preparation since the doses needed for clinical use are much smaller than what is commonly available in the market.).


Paricalcitol

Illustration showing the extensive positive effects of paricalcitol, an activator of the vitamin D receptor (VDR). Beyond its primary function in reducing parathyroid hormone (PTH) levels for treating secondary hyperparathyroidism and chronic kidney disease (CKD)-related mineral bone disorder, paricalcitol offers additional cardiac and renal benefits. These are achieved largely through the downregulation of the renin-aldosterone-angiotensin system (RAAS), which in turn reduces oxidative stress, inflammation, and fibrosis. Cardiac protection is further enhanced by blocking the calcineurin signaling pathway, which regulates the nuclear factor of activated T cells (NFAT), leading to reduced myocardial hypertrophy. Additionally, paricalcitol contributes to renal protection by lessening proteinuria and maintaining podocyte health, again through RAAS inhibition.
Illustration showing the extensive positive effects of paricalcitol, an activator of the vitamin D receptor (VDR). Beyond its primary function in reducing parathyroid hormone (PTH) levels for treating secondary hyperparathyroidism and chronic kidney disease (CKD)-related mineral bone disorder, paricalcitol offers additional cardiac and renal benefits. These are achieved largely through the downregulation of the renin-aldosterone-angiotensin system (RAAS), which in turn reduces oxidative stress, inflammation, and fibrosis. Cardiac protection is further enhanced by blocking the calcineurin signaling pathway, which regulates the nuclear factor of activated T cells (NFAT), leading to reduced myocardial hypertrophy. Additionally, paricalcitol contributes to renal protection by lessening proteinuria and maintaining podocyte health, again through RAAS inhibition.(Freundlich,2017).

Paricalcitol is a synthetic vitamin D analog. It has been used to reduce parathyroid hormone levels. Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure.


Phosphate binders:

  1. Medications like aluminum hydroxide or calcium-based binders may be prescribed to reduce the absorption of dietary phosphorus.

  2. Vitamin D supplements may be given in specific cases, but only under the guidance of a veterinarian, as excessive vitamin D can be harmful.


3. Managing the underlying renal (kidney) disease:

The primary cause of secondary hyperparathyroidism in dogs is often chronic kidney disease (CKD). Managing CKD is essential, and this may include dietary changes, medication, and supportive care as recommended by a veterinarian. It is essential to ensure that the dog has access to clean drinking water at all times to help maintain hydration.


4. Surgery (parathyroidectomy):

In rare and severe cases where medical management is unsuccessful, surgical removal of one or more parathyroid glands may be considered. However, this is generally a last resort and is not commonly performed in dogs.


Prognosis

 

Prognosis of Renal Secondary Hyperparathyroidism in animals If untreated, secondary hyperparathyroidism results in irreversible hypertrophy of the parathyroid glands, a condition also known as tertiary hyperparathyroidism. In this stage, hyperparathyroidism becomes unresponsive to treatment and requires surgical extirpation of the hypertrophic parathyroid glands.


Monitoring:

 

Periodic blood tests are recommended and crucial for regular monitoring of blood levels of PTH, calcium, phosphorus, and vitamin D to assess the effectiveness of treatment and necessary adjustments made to medications and diet based on these results.


References

 

Freundlich, M., Abitbol, C.L. Oral paricalcitol: expanding therapeutic options for pediatric chronic kidney disease patients. Pediatr Nephrol 32, 1103–1108 (2017). https://doi.org/10.1007/s00467-017-3675-7


Cortadellas O, Fernandez del Palacio M T, Talavera J, Bayon A (2010) Calcium and phosphorus homeostasis in dogs with spontaneous chronic kidney disease at different stages of severity. JVIM 24 (1), 73-79 PubMed.


Roudebush P, Polzin D J, Adams L G, Towell T L, Forrester S D (2010) An evidence-based review of therapies for canine chronic kidney disease. JSAP 51 (5), 244-252 PubMed.


Stillion J R, Ritt M G (2009) Renal secondary hyperparathyroidism in dogs. Compend Contin Educ Vet 31 (6), E8 PubMed.

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