Introduction
Secondary hyperparathyroidism (SHPT) is a consequence of the decreased concentration of ionized calcium in the blood, which may have many causes. SHPT is characterized by increased compensatory parathyroid hormone (PTH) secretion due to the malabsorption of intestinal calcium mainly caused by chronic renal disease. For this reason, SHPT is often referred to as renal SHPT, but it may be due to other chronic conditions that result in low serum calcium. Increased parathyroid function is stimulated by calcium deficiency (presenting with normocalcemia or hypocalcemia); thus the parathyroid gland has no functional autonomy. Other causes of SHPT include long-term lithium therapy, osteomalacia, rickets, malabsorption diseases, severe Crohn disease, celiac disease, and vitamin D deficiency. Gastric bypass or weight reduction (bariatric) surgery may also result in SHPT. Renal SHPT is initially treated medically, although parathyroidectomy (PTX) remains an efficient and definitive treatment option for this condition, since it may bridge the time until kidney transplantation can be performed.
In theory, if the feedback mechanism involving the level of blood calcium and PTH is interrupted, it could result in regression of the parathyroid glands. For patients with chronic kidney disease–mineral and bone disorder (CKD-MBD), the feedback mechanism is interrupted by successful renal transplantation. The hypertrophic gland transformation occurs over years of progressive kidney disease. The sustained hypersecretion of PTH is associated with an increase in the size of the parathyroid gland, leading to diffuse parathyroid hyperplasia. Subsequently, some cells inside the parathyroid gland can proliferate in a monoclonal growth pattern, which results in an advanced type of nodular hyperplasia. During the process of parathyroid hyperplasia, both calcium-sensing receptors (CaSRs) and vitamin D receptors (VDRs) are progressively downregulated. As a result, the parathyroid glands with nodular hyperplasia become increasingly unresponsive to active treatment with vitamin D.
Whether a regression of parathyroid hyperplasia can occur after medical treatment with calcitriol or vitamin D3 remains uncertain. Also, regression of parathyroid hyperplasia has been reported in rare cases of spontaneous infarction of the glands. Also, enhanced apoptosis of parathyroid cells has been observed in diffuse hyperplasia following kidney transplantation, which suggests the possibility of the long-term regression of an individual gland.
The use of a new generation of vitamin D analogues and calcimimetics as well as changes in diet and modified dialysis techniques has led to a reduction in fractures and PTX for renal SHPT in patients with CKD-MBD. However, the required medications can be expensive, and the cost of 9 months of calcimimetic treatment may exceed that of surgical therapy.
The elevation of PTH takes time; when it reaches values higher than 495 pg/mL, there is a 25% increased risk of mortality. The response to vitamin D is reduced by 50% at PTH levels above 750 pg/mL. Therefore early surgery can potentially offer an improved quality of life and possibly a higher long-term rate of survival.
Key Operative Learning Points
- 1.
The surgical strategy should focus on a correct balance between the extent of parathyroid resection with prevention of recurrence while also minimizing permanent hypoparathyroidism.
- 2.
The common surgical procedures are subtotal parathyroidectomy (SPTX) and total parathyroidectomy (TPTX). SPTX and TPTX can be coupled with parathyroid autotransplantation (AT) and bilateral cervical thymectomy (BCT) ( Table 85.1 ). The surgeon’s preference and transplantation status influence the type of operation performed.
TABLE 85.1
Acceptable Surgical Procedures for Secondary Hyperparathyroidism and Outcomes
Procedure
Recurrence/Persistence (%)
Hypoparathyroidism (%)
Reference/Type Study/Level of Evidence
SPTX with or without BCT
20
0
Rothmund et al. (1991)/RCT/1b
SPTX with or without BCT and with AT
4.8
2.4
Gasparri et al. (2001)/CRS/3
SPTX with or without BCT and without AT
0
0
Schnierder (2012)/CRS/3
AT, Autotransplantation; BCT, bilateral cervical thymectomy; SPTX, subtotal parathyroidectomy.
- 3.
BCT is considered an essential part of any effort to remove supernumerary glands or ectopic parathyroid nests, thus reducing persistent and recurrent SHPT.
- 4.
Proper timing of the decision for surgery is essential in order to avoid a procedure done too early in the development of renal SHPT, which would prove unnecessary, or one that is done too late, which would pose increasing risks and complications due to the patient’s worsening comorbidities. Therefore integrated, multidisciplinary care is vital to detect the best surgical timing as well as careful postoperative care to control for metabolic alterations.
- 5.
A comprehensive approach to the treatment and prevention of progressive renal SHPT is crucial, starting with early monitoring for biomarkers (PTH, Ca, and phosphorus), dietary modifications, mode of renal replacement therapy, and drug therapy.
Preoperative Period
History
- 1.
History of present illness
- a.
Many patients with renal SHPT may be asymptomatic but may present with nonspecific symptoms, such as bone or joint pain, cutaneous itching, and fatigue. However, abnormalities may be already detectable by laboratory or radiographic studies. Patients may present with elevated serum phosphate levels, reduced vitamin D production, and low or normal serum calcium levels; as a result, PTH levels would be markedly elevated.
- b.
What serologic parameters indicate changes in renal SHPT, and is it possible to avoid progressive PTH elevation?
At the beginning of CKD stage III (estimated glomerular filtration rate [GFR] <60 mL/min), PTH levels start to increase. According to the recommendations of the kidney disease outcomes quality initiative (KDOQI), PTH should be kept between 150 and 300 pg/mL to avoid the complete suppression of osteoclasts and prevent adynamic bone disease ( Table 85.2 ). Current therapeutic strategies include the modification of calcium and phosphorus balance by restricting the intake of dietary calcium and phosphorus and their removal during hemodialysis as well as the administration of phosphate binders, vitamin D receptor activators (calcitriol and newer vitamin D analogues), and a calcimimetic. When PTH levels cannot be maintained within the target ranges, the surgical option should be considered so as to avoid the progression of ectopic calcification.
TABLE 85.2
Target Ranges for Monitoring of Secondary Hyperparathyroidism
Stage of CKD
GFR
Corrected Calcium (mg/dL)
Phosphorus (mg/dL)
iPTH (pg/mL)
Monitoring of iPTH
Monitoring of Calcium and Phosphorus
3
30–60
Normal limits
2.7–4.6
35–70
1 year
1 year
4
15–29
Normal limits
2.7–4.6
70–110
3 months
3 months
5
<15
8.4–9.5
3.5–5.5
150–300
3 months
1 month
CKD, Chronic kidney disease; GFR, glomerular filtration rate; iPTH, intact parathyroid hormone.
- c.
Why do PTH levels continue to increase despite dietary restriction and the administration of phosphate binders, calcimimetics, and vitamin D analogues?
As the process of low-level secretion of extracellular Ca-stimulating PTH continues, the parathyroid glands are gradually transformed from normal glands into glands manifesting diffuse hyperplasia, then nodular hyperplasia, and finally multiple adenomas. The glandular growth/hyperplasia is hyperactive, irregular, asymmetrical, and asynchronous; this process is related to the time on dialysis until the parathyroid gland finally becomes autonomous. At that point there is no longer any response to medical treatment. This is an important part of disease progression, because even after kidney transplantation the hypersecretion of PTH and hypercalcemia can persist. This condition, called tertiary hyperparathyroidism, can jeopardize the transplant surgery and long-term viability of the transplanted kidney.
Although PTH levels can be suppressed by continuous treatment with phosphate binders, vitamin D analogues, and/or calcimimetics, a progressive reduction in the expression of CaSRs and VDRs can occur. This can ultimately result in resistance to medical management, at which point PTX might be required.
- d.
Which patients may benefit from PTX?
Surgical intervention should be considered in symptomatic patients who present with bone or muscle pain, muscle weakness, irritability, pruritus, bone loss, the exacerbation of anemia due to resistance to erythropoietin, or worsening cardiomyopathy. There are patients who develop resistance or intolerance to medical therapy; they too should be considered candidates for surgical intervention.
Patients may present with painful pink or purple firm nodules or plaques surrounded by livedo reticularis that progress to deep painful ulcers covered with black eschar; such patients must be screened for surgery immediately. Sepsis from infections in skin ulcers can cause up to 80% mortality.
This condition is known as calciphylaxis, which may be bilateral and symmetrical, affecting the thighs, abdomen, and buttocks. It occurs in only 4% of patients undergoing surgery. Where it appears that vascular calcification is driven by PTH, calcimimetic (as cinacalcet) is the preferred treatment for the control of PTH levels, as demonstrated by the evaluation of cinacalcet hydrochloride therapy to lower cardiovascular events (EVOLVE) trial. PTX is a surgical option for controlling elevated PTH levels and has been effective in isolated cases. In patients with calciphylaxis who have received urgent surgical treatment with TPTX, median survival was significantly prolonged. However, the risks associated with surgery, especially in medically complicated patients, make this a second-line treatment following failed medical management. Calciphilaxis is more commonly observed in women, patients with diabetes mellitus, obesity, hypoalbuminemia, and/or liver cirrhosis as well as in patients taking warfarin and those with a systemic inflammation or malignant disease.
- e.
What PTH level indicates the need for surgical intervention?
Intact PTH levels should be higher than 500 pg/mL and refractory to medical treatment.
- a.
- 2.
Past Medical History
- a.
Most of these patients have significant worsening of the CKD; therefore the following questions must be addressed:
- 1)
Is this patient on dialysis? If so, how long has this been the case?
- 2)
What is the patient’s general state of health?
- 3)
Has the patient had any previous hospitalizations related to SHPT?
- 1)
- b.
Medical illness
The following must be investigated as they may influence surgery: anemia, heart disease, hypertension, diabetes mellitus, hyperlipidemia, previous thrombosis, gastrointestinal malabsorption, and voice changes.
- c.
Surgery
- 1)
Evaluation of any previous neck surgery or thyroid/parathyroid surgery is mandatory. Postoperative complications are higher and success rates lower if there was previous cervical exploration.
- 1)
- d.
Family history
- 1)
There are some studies showing that the loss of heterozygosity (LOH) in 3q was detected more frequently in uremic parathyroid hyperplasia in comparison with LOH in 11q13 and 1q in parathyroid adenomas and LOH in 1q and 6q in familial hyperparathyroidism. It has been reported that LOH in 11q13 and the X-chromosome is present in uremic parathyroid hyperplasia.
- 1)
- e.
Medications
- 1)
The use of anticoagulants or antiplatelet medication should be discontinued several days prior to surgery to reduce complications from bleeding.
- 2)
Prolonged diuretic (especially thiazides) or lithium use is a cause of SHPT, which can lead to hyperplasia or persistent hypercalcemia.
- 1)
- a.
Physical Examination
- 1.
Head and Neck
- a.
Inspection of the neck and thyroid gland to evaluate
- 1)
Symmetry, size, firmness, fixation, and associated lymph nodes as well as evidence of previous neck surgery
- 1)
- b.
Laryngoscopic evaluation
Vocal fold function should be assessed, especially in repeat surgery or in the case of associated thyroid masses.
- a.
Laboratory
- 1.
Patients may present with elevated serum phosphate, reduced vitamin D, and low or normal serum calcium levels and, as a result, elevated PTH levels.
- 2.
The KDOQI of the National Kidney Foundation recommends the following target levels for renal SHPT patients who are on dialysis:
- a.
Serum calcium level between 8.4 and 9.5 mg/dL
- b.
Serum phosphate level of 3.5 to 5.5 mg/dL
- c.
Intact PTH (iPTH) of 150 to 300 pg/mL
- a.
- 3.
Although there are no specific indications for PTX listed in the KDOQI guidelines, PTX is considered in severe renal SHPT refractory to medical treatment. PTX effectively and quickly lowers calcium, PTH, and phosphorus levels and also helps to prevent cardiovascular complications and ectopic calcifications. Postoperative bone biopsy has shown suppression of bone resorption and initiation of bone formation. Up to 32% of patients with prolonged renal failure require PTX despite expensive medical treatment.
Imaging
- 1.
Preoperative routine evaluation includes the following:
- a.
Ultrasonography (US) of the neck
- 1)
To localize the parathyroid as well as to evaluate any concomitant thyroid disease or nodules that may point to the presence of an intrathyroidal parathyroid gland ( Fig. 85.1 )
- 1)
- a.
