Secondary Hyperparathyroidism

In secondary hyperparathyroidism, there is a physiologically appropriate increase in parathyroid hormone secretion in response to a decrease in extracellular calcium. The most common cause of secondary hyperparathyroidism is renal failure. Less common causes are long term lithium usage, vitamin D deficiency, gastrointestinal malabsorption syndromes (when the intestines do not absorb vitamins and minerals properly), malnutrition, vitamin D-resistant rickets, or hypermagnesemia (abnormally high blood magnesium levels).

In the case of renal failure, the kidney is unable to clean the blood of phosphorus produced by the body and unable to make enough vitamin D (specifically calcitriol, the active form of vitamin D). The build-up of phosphorous leads to stimulation of the parathyroid glands through decreased calcium levels in the blood, as well as direct stimulation by the phosphorous itself. Continued stimulation of the parathyroid glands causes diffuse hyperplasia and eventually nodular hyperplasia. As the nodular hyperplasia becomes more advanced, vitamin D receptors and calcium sensing receptors are downregulated within the glands leading to a lack of normal response to blood calcium and vitamin D levels.

During early secondary hyperparathyroidism, the blood calcium levels are normal or low, but the PTH level is high. As the length of secondary hyperparathyroidism persists, patients may develop abnormally high levels of calcium in the blood. The change in biochemical profile could be due to some of the treatments for the kidney disease (vitamin D and calcium-containing phosphate binders), or it could be due to transformation to tertiary hyperparathyroidism, where there is autonomous secretion of PTH that is no longer responsive to blood calcium levels.  Large observational studies in the dialysis population have consistently shown that high PTH levels are associated with increased all-cause and cardiovascular mortality.  In addition, high PTH levels can lead to 1) weakening of the bones, 2) calciphylaxis (when calcium forms clumps in the skin and leads to ulcers and potentially death of surrounding tissue), 3) cardiovascular complications, 4) abnormal fat and sugar metabolism, 5) itching (pruritis), and 6) low blood counts (anemia).

Calciphylaxis is uncommon. These painful skin lesions begin as small nodules or plaques with a purplish color, mottling, or livedo reticularis in a stellate pattern. The ulcers grow, and surrounding tissue becomes necrotic (i.e., the tissue dies). They rarely heal with routine wound care measures. 

Treatment

Secondary hyperparathyroidism is usually treated with medical therapy, and surgery is generally performed if these fail. Overall, improvements in medical therapy have reduced the need for surgery in patients with chronic kidney disease.

Medical therapy

The main goals of medical treatment for the dialysis population based on the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines are to reduce hyperphosphatemia, avoid hypercalcemia, and control PTH levels. The goal parathyroid hormone level is 2x – 9x the normal reference PTH range. These goals are accomplished through dietary phosphate restriction, phosphate binders, vitamin D analogues, and calcimimetics. Vitamin D analogues reduce parathyroid hormone (PTH) levels, but may also increase the blood calcium levels and may contribute to calciphylaxis.  Phosphate binders reduce blood phosphorous levels.  Aluminum-based compounds are highly effective, but may cause aluminum toxicity leading to bone disease and are therefore generally not used anymore. Calcium-containing phosphate binders are less powerful, but can increase the blood calcium levels and may lead to soft tissue, blood vessel, and heart calcification.  Newer phosphate binders that are calcium-free polymer agents are more frequently used now, as they do not raise the blood calcium levels as much. Calcimimetics are medications that mimic the effect of calcium by binding to the parathyroid gland calcium sensing receptor to decrease the secretion of PTH.  By causing less PTH to be secreted, calcimimetics decrease the amount of calcium in the bloodstream. Cinacalcet is only FDA approved for treatment of secondary hyperparathyroidism and parathyroid carcinoma (see Alternatives to Surgery).  It can only decrease parathyroid hormone secretion to a certain extent. On average, patients with secondary hyperparathyroidism have a decrease in PTH levels by about 50%. Its main side effects are nausea and vomiting.  Taking cinacalcet will not cure the disease process, but it may allow bridging of patients to renal transplantation, which is the optimal treatment of their renal secondary hyperparathyroidism.

As of yet, there have been no randomized clinical trials comparing the efficacy of calcimimetics to parathyroidectomy.  Cinacalcet studies have shown mortality improvement in patients older than age 65 and improvement in bone disease.  Surgery studies have shown benefits in survival, bone fracture risk, erythropoietin resistant anemia, and quality of life.  It is important to note that surgery may still be appropriate in dialysis patients if they develop medically refractory hyperparathyroidism.[CU3]  

Surgery

Medical treatment of secondary hyperparathyroidism fails in up to 25% of patients.  Indications (reasons) for parathyroidectomy include high calcium and/or phosphorous levels in the blood which cannot be managed with dialysis or medical therapy, worsening bone density, intractable pruritus (itching), or calciphylaxis.  Since chronically elevated PTH levels may increase the risk of heart- and stroke-related death, surgery should also be considered for elevated PTH levels above 800 pg/mL (2017 KDIGO Guidelines).  Surgical options for the treatment of secondary hyperparathyroidism include subtotal parathyroidectomy, total parathyroidectomy WITH autotransplantation, and total parathyroidectomy WITHOUT autotransplantation.

Subtotal parathyroidectomy (removing 3-1/2 glands) and total parathyroidectomy (removing all four glands) with autotransplantation of parathyroid tissue have about the same rates of recurrent (3-40%) and persistent (5-25%) disease, postoperative hypocalcemia (2-73%), and improvement in symptoms (67-100%).  Total parathyroidectomy without autotransplantation has the least likelihood of recurrent disease but has the highest risk of permanent hypocalcemia.  This operation should only be considered in patients who are not kidney transplant candidates and who will require life-long dialysis.  Subtotal parathyroidectomy and total parathyroidectomy with autotransplantation both leave behind a small amount of parathyroid tissue.  The same process that caused the original parathyroid glands to become abnormal will cause the remaining parathyroid tissue to also become abnormal.  Therefore, unless these patients undergo kidney transplantation, they are at high risk for recurrent disease (5% to 80%). It is unclear if subtotal parathyroidectomy or total parathyroidectomy with autotransplantation is better for patients.  Ultimately, you will decide with your surgeon which operation to have.  Surgical skill and experience and proper patient selection appear to be more important to a successful outcome than which operation is performed.  The advantages and disadvantages of these two surgical procedures are:

Table

Surgical procedureAdvantagesDisadvantages
Subtotal parathyroidectomyPossible less postoperative hypocalcemia (low calcium levels)Re-operating in the neck has higher risks (if the patient needs a second operation)
Total parathyroidectomy with autotransplantationReoperation has fewer risks because the parathyroid autotransplant is usually placed in the forearm and not the neckPossible prolonged hypocalcemia (low calcium levels) while waiting for the autotransplant to work
Total parathyroidectomy without autotransplantationLeast likely to have recurrent disease and require reoperationHighest risk of permanent hypocalcemiaNot appropriate for kidney transplant candidates