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Secondary and Tertiary Hyperparathyroidism

OVERVIEW Primary hyperparathyroidism is the overproduction of parathyroid hormone (PTH) by abnormal parathyroid glands, and secondary hyperparathyroidism (2°HPT) refers to the excess secretion of serum PTH by normal parathyroid glands in response to perturbations in calcium homeostasis. The most common pathologic process that affects normal calcium metabolism, and thus stimulates increased parathyroid gland function, is chronic renal failure. Other causes of 2°HPT include vitamin D deficiency, inadequate calcium ingestion, calcium malabsorption, and idiopathic hypercalciuria. 2°HPT is common; population studies suggest a prevalence rate as high as 6.6% in some cases. Reversibility is an implicit feature of this disorder, and correction of the underlying abnormality should result in disease resolution. Cases in which this does not occur either represent misdiagnosis (e.g., primary hyperparathyroidism) or indicate development of tertiary hyperparathyroidism (3°HPT). 3°HPT occurs when chronically stimulated parathyroid tissue in a patient with 2°HPT becomes autonomous, producing elevated and unsuppressed levels of PTH even after correction of abnormal calcium metabolism. The development of 3°HPT therefore represents an additional pathologic event, superimposed on a background of 2°HPT, that produces autonomous parathyroid gland function. The most common clinical scenario in which this develops is in a patient with 2°HPT and chronic renal failure who undergoes renal transplantation. Despite a functional kidney in such cases, and therefore normalization of calcium metabolism, the parathyroid glands continue to overproduce PTH, which results in a condition similar to primary hyperparathyroidism. Chronic renal failure (CRF) is the most important cause of 2°HPT, and 2°HPT develops in the majority of patients with CRF. Most 2°HPT cases are successfully managed medically; surgical treatment for 2°HPT (parathyroidectomy) is almost always reserved for those cases in which medical management fails. Medical treatment in these cases is complex, however, and unlike most other causes of 2°HPT, parathyroidectomy can play a therapeutic role. In this chapter, we review the pathophysiology and current treatment strategies for CRF-associated 2°HPT and 3°HPT, including medical and surgical approaches. PATHOPHYSIOLOGY The pathologic mechanisms resulting from renal failure that lead to hyperparathyroidism are complex and incompletely understood. The primary known stimulus for PTH secretion is low serum ionized calcium, and persistently low serum calcium measurements may well be expected in patients with 2°HPT. Interestingly, patients with CRF and 2°HPT often have serum calcium levels in the normal (or low normal) range, which indicates that more complex biochemical interactions are at play. At least four interdependent factors that affect calcium homeostasis contribute to the development and progression of 2°HPT: hypocalcemia, impaired vitamin D activation, hyperphosphatemia, and parathyroid resistance to fibroblast growth factor 23 (FGF23; Box 1). In the absence of renal disease, absorption of urinary calcium is extremely efficient, reaching 98% in individuals with eucalcemia. As renal failure progresses, however, absorption of urinary calcium is correspondingly impaired and hypocalcemia develops. Renal failure progression also results in impaired vitamin D activation. In normal circumstances, the kidneys convert 25-hydroxyvitamin D to its most active form, 1,25-dihydroxyvitamin D. This compound then acts directly on the small intestine, stimulating calcium absorption, and on the parathyroid glands, where it inhibits PTH gene expression. As loss of functional renal parenchyma progresses in CRF, vitamin D activation capacity is proportionally compromised, which results in both hypocalcemia and direct activation of PTH synthesis. Hyperphosphatemia, which is common in patients with renal failure, also contributes to hypocalcemia by titrating ionized calcium from the serum as calcium phosphate and by directly inhibiting renal activation (hydroxylation) of 25-hydroxyvitamin D.

BOX 1:╇ Factors that contribute to secondary hyperparathyroidism 1. Hyperphosphatemia 2. Hypocalcemia 3. Impaired vitamin D activation 4. Parathyroid resistance to fibroblast growth factor 23

A recent discovery was the elucidation of FGF23 function in phosphate metabolism. FGF23 acts on the kidney, stimulating phosphate excretion, and on the parathyroid gland, inhibiting PTH synthesis and secretion. As progressive hyperphosphatemia develops during chronic renal failure, serum FGF23 levels correspondingly increase. Despite this increase, however, FGF23 receptor concentrations in the parathyroid gland decline as renal failure progresses. Thus, the abnormal parathyroid tissue characteristic of 2°HPT becomes progressively resistant to FGF23, and hyperparathyroidism results. 3°HPT is diagnosed when the inciting cause for 2°HPT is corrected, and, nonetheless, the parathyroid glands continue to overproduce PTH. This typically manifests biochemically as elevated serum calcium and PTH levels. The inability of the parathyroid glands to revert to their normal inhibitory feedback response, as mediated by elevated serum calcium levels, may relate to the hyperplasia that originally developed during the preceding 2°HPT and CRF. CLINICAL MANIFESTATIONS OF SECONDARY AND TERTIARY HYPERPARATHYROIDISM The clinical sequelae of 2°HPT and 3°HPT can be both debilitating and life threatening. All cause and, in particular, cardiovascularrelated mortality rates are increased in 2°HPT. Periarticular calcium deposition can produce arthritis, joint space effusion, and impaired joint function. 2°HPT-associated bone disease in the context of CRF, termed renal osteodystrophy, is an additional source of significant morbidity in this patient population. The development of nephrocalcinosis can exacerbate kidney failure and produce a vicious cycle that accelerates the progression of both renal dysfunction and 2°HPT. Finally, calcification of cutaneous arterioles, with associated subcutaneous tissue inflammation, is the hallmark of calciphylaxis, a rare but highly morbid condition associated with CRF-mediated 2°HPT. This condition is characterized by progressive cutaneous ischemia that presents as painful erythematous skin lesions, usually on the distal extremities or trunk, which progress to frank gangrene and subsequent sepsis. Mortality rates in affected patients can reach 80%. MEDICAL MANAGEMENT Curative management in patients with CRF-related 2°HPT requires renal transplantation, which, when successful, results in normalization or near normalization of serum calcium, phosphorous, and PTH levels in up to 95% of patients. Demand for donor renal grafts, however, far exceeds supply, and the vast majority of patients with 2°HPT are therefore managed medically. Curative medical therapy remains to be developed, so current medical treatment strategies thus focus on control of serum PTH, calcium, and phosphorous levels. Consensus treatment guidelines for the management of CRF, including associated 2°HPT, have been published by the National Kidney Foundation (Kidney Disease Outcomes Quality Initiative [KDOQI]) and by the Kidney Disease: Improving Global Outcomes (KDIGO) foundation. These treatment algorithms are designed to minimize cardiovascular (KDOQI) and bone/extraskeletal calcification (KDIGO)–related mortality in CRF-associated 2°HPT. Most experts use one or both algorithms in the management of these patients. Management of Hyperphosphatemia Treatment of hyperphosphatemia should be initiated when serum phosphate levels exceed 5.5╯mg/dL in stage 3, stage 4, or stage 5 CRF (glomerular filtration rate [GFR], 30-59, 15-29, and <15╯mL/ min/1.73╯mol/L2, respectively). The treatment goal in these cases is stabilization of serum phosphate levels between 3.5 and 5.5╯mg/dL. Management should begin with restriction of daily dietary phosphate intake to less than 900╯mg and, when end-stage renal disease is present, dialysis. Phosphate-binding medications should be added when dietary restriction and, if applicable, dialysis fail to consistently produce serum phosphate levels below 5.5╯mg/dL. Management of Serum Parathyroid Hormone Levels and Hypocalcemia Optimal overall outcomes among patients with CRF requiring dialysis have been associated with serum PTH maintenance between 150 and 300╯pg/mL. Treatment in these patients therefore focuses on stabilization of serum PTH levels within this range. Activated vitamin D analogs can lower serum PTH levels, and use of these agents is indicated when serum PTH levels rise above 300╯pg/mL in end-stage renal disease or exceed the upper limit of normal in nondialysis CRF cases. Because vitamin D may exacerbate hyperphosphatemia, however, and may produce hypercalcemia, activated vitamin D treatment is contraindicated when serum phosphate levels exceed 5.5╯mg/ dL or the corrected serum calcium concentration is greater than 9.5╯mg/dL. In addition, vitamin D therapy should be discontinued if corrected serum calcium levels exceed 10.2╯mg/dL or if serum phosphate levels rise above 5.5╯mg/dL. Finally, vitamin D supplementation should be stopped if serum PTH levels fall below 150╯pg/mL in patients with dialysis-dependent 2°HPT. The calcimimetics are a relatively new medication class and function to increase the sensitivity of the calcium-sensing receptor (CaSR) protein to calcium, thus acting to inhibit secretion of parathyroid hormone. Use of cinacalcet, the prototype agent, in the management of patients on dialysis with 2°HPT is associated with improved serum phosphate, calcium, and PTH control. Moreover, cinacalcet appears to attenuate fracture risk, rates of parathyroidectomy, and hospitalization rates in these patients. Cinacalcet therapy should be considered for patients on dialysis in whom phosphate binders provide inadequate serum PTH suppression. Hypocalcemia contraindicates calcimimetic therapy, and treatment should be discontinued if corrected serum calcium levels fall below 8.4╯mg/dL. In addition, cinacalcet has not been approved for use in patients with CRF before dialysis; and although cinacalcet is associated with improvements in serum PTH in such patients, its efficacy and safety in this population remain to be established. The medical management of 2°HPT in patients with CRF is challenging, and the combination and dosage of phosphate binders, vitamin D analogs, calcium supplements, and calcimimetics chosen is patient specific. Treatment assessment and medication dosage titration therefore require careful monitoring of serum calcium, phosphate, and PTH levels. Serum total calcium, phosphate, and PTH should be measured weekly until stable levels are achieved with a given medication regimen, and then every 1 to 3 months. Serum 25-hydroxyvitamin D levels tend to change slowly and should be evaluated every 3 to 6 months in this patient group. SURGICAL MANAGEMENT Surgical resection of hyperplastic parathyroid tissue can provide durable resolution of 2°HPT in patients with CRF, with consequent symptomatic improvement, reversal of bone demineralization, and decreases in long-term mortality rates. Because 2°HPT develops when otherwise healthy parathyroid tissue responds inappropriately to pathologic external stimuli, all parathyroid tissue is affected and four-gland hyperplasia results. Thus, the aim of parathyroid surgery in 2°HPT is to remove enough hyperplastic parathyroid tissue to improve calcium homeostasis and treat otherwise unremitting symptoms, without producing hypoparathyroidism. Indications Parathyroid surgery for CRF-associated 2°HPT is indicated when: (1) medical therapy fails to control serum PTH levels, hypercalcemia, or hyperphosphatemia; (2) 2°HPT-related symptoms become refractory to medical therapy; (3) intractable rapid turnover bone disease develops; or (4) calciphylaxis is present (Box 2). Patients in whom serum PTH levels exceed 800╯pg/mL and in whom serum calcium levels are greater than 10╯mg/dL or in whom serum phosphate levels are above 5.5╯mg/dL, despite maximal medical therapy, should be offered surgery. Similarly, intractable symptoms in a background of medically refractory 2°HPT merit surgical intervention. These include refractory pruritus, bone pain, muscle pain, anemia, abdominal pain, and weakness. Rapid turnover bone disease that does not respond to medical management should also prompt surgical intervention, especially when associated with pathologic fracture. Finally, biopsy-confirmed calciphylaxis is an absolute indication for emergent parathyroidectomy, which may arrest disease progression and improve wound healing. Tertiary Hyperparathyroidism Instances in which PTH levels remain elevated after renal transplantation represent 3°HPT; posttransplantation parathyroid surgery remains the primary management strategy in these cases. Recent studies, however, question this approach. Multiple contemporary series show a significant risk of transplant dysfunction and rejection when parathyroid surgery is performed after renal transplantation. The underlying mechanisms to explain these findings remain unknown, and graft dysfunction does not occur in all postparathyroidectomy transplant cases. Nonetheless, some experts now advocate parathyroid surgery before renal transplantation to potentially avoid postparathyroidectomy renal graft dysfunction. This strategy remains controversial because those patients with CRF in whom 3°HPT does not develop and who therefore do not need parathyroidectomy cannot be identified before transplantation and thus are subjected to unnecessary parathyroid surgery. In addition, renal graft function among patients undergoing pretransplant parathyroid surgery, relative patients receiving parathyroid surgery after renal transplantation, remains to be objectively defined.

BOX 2:╇ Indications for parathyroidectomy in patients with chronic renal failure 1. Persistent hyperphosphatemia, hypercalcemia, or elevated parathyroid hormone, despite maximal medical therapy 2. Refractory hypercalcemic symptoms 3. Intractable renal osteodystrophy 4. Calciphylaxis

Medical therapy for 3°HPT continues to improve. Cinacalcet, for example, has shown efficacy in lowering both serum calcium and PTH levels in 3°HPT cases. Nonetheless, small studies that compare medical therapy with parathyroid surgery for 3°HPT suggest that parathyroidectomy affords superior serum PTH, calcium, and phosphate control. Until long-term outcome data comparing these interventions become available, parathyroid surgery remains the preferred intervention for 3°HPT. Medial therapy should be reserved for patients who are not surgical candidates or for stabilization in anticipation of parathyroidectomy. Preoperative Assessment In addition to verification of both the diagnosis of 2°HPT and the presence of associated surgical indications before surgery, the operative candidacy of all patients with CRF-associated 2°HPT should be formally assessed with preoperative risk stratification. Patients in whom severe preexisting comorbidities contraindicate surgery should be managed medically. In addition, imminent renal transplantation is a relative contraindication to parathyroidectomy, at least among those experts who do not ascribe to routine pretransplantation parathyroidectomy (see Tertiary Hyperparathyroidism). Formal preoperative imaging for purposes of localizing abnormal parathyroid glands is unnecessary in both 2°HPT and 3°HPT, as pathologic involvement of all four glands is expected and four-gland exploration is therefore indicated. Localization imaging should be limited to rare cases in which supernumerary or ectopic parathyroid glands are suspected. All patients with 2°HPT and 3°HPT should, however, receive a formal preoperative thyroid ultrasound scan, both for identification of any potentially malignant coincident thyroid nodules that may be present and for assessment of parathyroid anatomy. Discovery of suspicious thyroid nodules should prompt an appropriate preoperative malignancy workup, and failure to identify all four parathyroid glands is a reasonable indication for additional localization imaging. Preoperative sestamibi or four-dimensional computed tomographic (CT) scanning can be used to localize ectopic parathyroid glands that are not visualized with ultrasound scan. Operative Technique Adequate surgical management of 2°HPT and 3°HPT requires either subtotal parathyroidectomy, in which 3.5 parathyroid glands are resected, or total parathyroidectomy with autotransplantation. Despite ongoing debate, the balance of reported data does not demonstrate relative superiority for either procedure, and surgeon preference thus dictates technique selection. The procedure begins with semi-Fowler patient positioning. The cervical spine is placed in extension, and after application of sterilizing skin preparation, a 4-cm to 6-cm symmetric Kocher’s incision is made approximately 2 fingerbreadths above the sternal notch. The relatively prominent anatomic location of this incision should always prompt careful consideration of cosmesis, and whenever possible, postoperative scarring should be minimized by placing the incision within a preexisting skin crease. Dissection is carried through the platysma muscle and subplatysmal flaps are elevated, exposing the underlying strap musculature. The median raphe defining the plane of symmetry between the strap musculature on either side of the neck is then incised, and the sternohyoid muscle is dissected free from the underlying thyroid gland. The thyroid is then carefully mobilized to avoid injury to associated branches of the inferior thyroid artery, which supply both the thyroid and the parathyroid glands. Systematic examination of all four parathyroid glands is then performed. If subtotal parathyroidectomy is planned, all four parathyroid glands should be visualized before resection. This allows selection of the least abnormal-appearing parathyroid tissue for remnant creation. An approximately 40-mg parathyroid remnant, marked with a nonabsorbable suture or a titanium clip, is left attached to its associated vascular pedicle. The identity of this tissue should be verified with frozen section analysis of its resected component, and the remnant should be carefully observed for signs of inviability. Cases in which the remnant appears inviable should prompt either autotransplantation of remaining parathyroid tissue or creation of a new remnant from a separate parathyroid gland. The most fragile structure associated with the ipsilateral parathyroid glands, and thus at risk for iatrogenic injury during parathyroid exploration, is the recurrent laryngeal nerve (RLN). Identification and preservation of both RLNs, which supply motor function to the vocal cords, is thus a critical component parathyroid surgery. Although parathyroid gland anatomy can be highly variable, the inferior parathyroid gland is generally situated just anterior to the course of the ipsilateral RLN, and the superior parathyroid gland tends to localize posteriorly relative to this nerve. Cases in which total parathyroidectomy is performed should generally prompt intraoperative parathyroid reimplantation. Although omission of autotransplantation decreases the probability of disease recurrence, most experts prefer to accept an increased recurrence risk in exchange for minimization of permanent postoperative hypocalcemia risk. For autotransplantation, the most normal-appearing parathyroid gland is selected; this tissue is sharply minced into 1-mm fragments. The identity of this tissue should be verified with frozen section analysis before autotransplantation. Appropriate autotransplant acceptor sites include the sternocleidomastoid muscle, the brachioradialis muscle of the nondominant forearm, and the subcutaneous soft tissue of the chest wall. Site selection depends on surgeon preference, although autotransplantation distant from the neck allows either biochemical or imaging-based differentiation between cervical and implant-associated disease in cases of recurrence. Three or 4 pockets adequately sized to accept 5 to 10 parathyroid tissue fragments are then created with blunt dissection at the donor site, and approximately 10╯mg of minced parathyroid tissue is placed into each pocket. The aperture of each implantation site is closed with nonabsorbable suture or with titanium clips. Cases in which recurrent disease develops from progressive hyperplasia of autotransplanted tissue may be managed with resection of one or more of the implantation pockets with local anesthesia. Special Considerations and Intraoperative Adjuncts Gland ectopy is a relatively common finding in parathyroid surgery. Ectopic inferior glands are most frequently found within the ipsilateral thymus, and ectopic superior parathyroids are often paraesophageal. Other ectopic localization sites include the carotid sheath, the anterior mediastinum, adjacent to the cervical vertebral bodies, and within the ipsilateral thyroid lobe parenchyma. Failure to localize any of the four parathyroid glands in their typical anatomic positions should prompt careful exploration of potential ectopic sites. Cases in which an ectopic parathyroid gland localizes to the anterior mediastinum may require partial sternotomy. A number of adjunctive intraoperative strategies have been proposed for improving the success of parathyroid surgery. These include ultrasound scan and gamma probe-assisted intraoperative gland localization and titration of parathyroid tissue resection on the basis of serial intact PTH measurements. Although data that support the value of these techniques have been reported, the adoption of these data remains controversial, and the use of intraoperative adjuncts during surgery for 2°HPT remains surgeon specific. The presence of supernumerary glands, although rare, may confound the adequacy of subtotal parathyroidectomy or total thyroidectomy with autotransplantation for 2°HPT and 3°HPT. This potential pitfall may be avoided through intraoperative PTH monitoring, as associated persistent serum PTH elevation prompts further surgical exploration and gland resection. In addition, some experts include routine intraoperative cervical thymectomy in the operative management of 2°HPT and 3°HPT because supernumerary parathyroid gland localization is often thymic. POSTOPERATIVE MANAGEMENT 2°HPT exists in the context of severe hypocalcemia; thus, rapid decreases in serum PTH levels that occur after successful parathyroid surgery can result in the rapid and profound bony absorption of serum calcium. The sequelae of this process, termed hungry bone syndrome, can produce significant symptoms, including tetany, seizures, and heart failure. Patients after 2°HPT surgery must therefore be carefully monitored for signs and symptoms of hypocalcemia. Although the hypocalcemia may have been corrected in 3°HPT, the bone loss is often present and these patients are also at risk for hungry bone syndrome. Routine postoperative oral supplementation with 4 to 6╯g of calcium, divided into 3 or 4 daily doses, should be initiated immediately after surgery, and serum calcium levels should be serially monitored. Patients with persistent hypocalcemia, despite these interventions, need intravenous (IV) calcium gluconate administration. Postoperative hypocalcemia in patients who previously needed dialysis may also be controlled by increasing dialysate bath calcium concentration. Postoperative supplementation with activated vitamin D (e.g., calcitriol) should be started if preoperative vitamin D deficiency is present, if hypocalcemia persists despite aggressive oral calcium supplementation, or if intravenous calcium infusion is necessary. Finally, hypomagnesia can accompany hypocalcemia and interfere with normalization of low serum calcium concentrations. Serum magnesium levels should thus be monitored after surgery, and hypomagnesia should be corrected with oral or intravenous magnesium sulfate. The hypocalcemic nadir after parathyroidectomy for 2°HPT generally occurs 2 to 4 days after surgery, with most patients showing improving serum calcium levels thereafter. A small number of these patients have persistent hypocalcemia, however, presumably as a result of parathyroid remnant or autotransplant failure. These patients need ongoing calcium and vitamin D supplementation. Finally, all patients after 2°HPT and 3°HPT surgery must be followed for the development of recurrent or persistent disease. Serum calcium and PTH concentrations should be measured 1 week after surgery, 6 months later, and then annually. Rising serum calcium and PTH concentrations are suggestive of recurrent or persistent disease and should prompt evaluation for additional medical or surgical therapy. S u g g e s t e d R e a d i n g s Goldfarb M, Gondek SS, Lim SM, et al: Postoperative hungry bone syndrome in patients with secondary hyperparathyroidism of renal origin, World J Surg 36(6):1314–1319, 2012. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group: KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), Kidney Int Suppl (113):S1–S130, 2009. Pitt SC, Panneerselvan R, Chen H, et al: Secondary and tertiary hyperparathyroidism: the utility of ioPTH monitoring, World J Surg 34(6):1343– 1349, 2010. Shen WT, Kebebew E, Suh I, et al: Two hundred and two consecutive operations for secondary hyperparathyroidism: has medical management changed the profiles of patients requiring parathyroidectomy? Surgery 146(2):296–299, 2009; Epub 2009

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