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13 Workup andManagement ofPrimary Hyperparathyroidism
22. Rajaei MH, Oltmann SC, Schneider DF, Sippel RS, Chen H.Outcomes after subtotal parathyroidectomy for primary hyperparathyroidism due to hyperplasia: signicance of whole
vs. partial gland remnant. Ann Surg Oncol. 2015;22(3):966–71. https://doi.org/10.1245/
s10434- 014- 4022- x.
23. Cheng D, Jacob LA, Scoutt L.Parathyroid Imaging. In: Oertli D, Udelsman R, editors. Surgery
of the thyroid and parathyroid glands. Berlin, Heidelberg: Springer Berlin Heidelberg; 2007.
p.245–59.
121
Chapter 14
Secondary andTertiary
Hyperparathyroidism
JaclynGellings andSophieDream
Pathogenesis
– Secondary hyperparathyroidism (SHPT) is characterized by an increase in PTH
secretion in response to an underlying cause, most commonly due to vitamin D
deciency, but also can be seen in other clinical settings, including kidney disease and gastrointestinal malabsorption (Table14.1).
Secondary hyperparathyroidism occurs in ~40% of individuals with chronic
kidney disease (CKD) 3, 82% of patients with CKD IV, and virtually all
patients with CKD V [1, 2].
Hyperparathyroidism in CKD begins as a physiologic adaption to renal disease but becomes pathologic with time [2].
– Secondary hyperparathyroidism is characterized by low to normal serum cal-
cium with elevated PTH that is often markedly high especially in cases of renal
hyperparathyroidism.
Normal Physiology
– Calcium (Ca) and phosphate (PO4) are maintained via three hormones: PTH,
1,25-dihydroxyvitamin D (calcitriol), and broblast growth factor 23 (FGF23).
In normal physiology, PTH maintains Ca homeostasis via several mechanisms:
J. Gellings · S. Dream (*)
Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin,
Milwaukee, WI, USA
e-mail: jgellings@mcw.edu; sdream@mcw.edu
Switzerland AG 2024
R. M. Gartland, J. A. Lee (eds.), Endocrine Surgery Clerkship, Contemporary
Surgical Clerkships, https://doi.org/10.1007/978-3-031-62091-1_14
123© The Author(s), under exclusive license to Springer Nature
124
Table 14.1 Etiologies of secondary hyperparathyroidism
Vitamin D deciency
• Lack of sunlight
• Dietary intake
• Malabsorption secondary to liver biliary disease
• Altered vitamin D metabolism due to medication
Renal impairment
Gastric malabsorption of calcium
• Gastric bypass
• Celiac disease
• Inammatory bowel disease (e.g., Crohn’s disease)
• Cystic brosis
• Pancreatic insufciency
Bisphosphonate treatment
Hungry bone syndrome
Increasing bone mineral dissolution to release Ca and PO4.
Increasing kidney reabsorption of Ca and excretion of PO4.
Increasing conversion of inactive vitamin D to calcitriol.
Synthesis of calcitriol to increase the gastrointestinal absorption of Ca
and PO4.
J. Gellings and S. Dream
Secondary Hyperparathyroidism
– In CKD, the kidney has diminished ability to maintain normal Ca and PO4 levels,
and the conversion of vitamin D to calcitriol also decreases.
– Decreased kidney excretion of phosphorus stimulates production of FGF23. This
leads to a decreased kidney production of calcitriol causing decreased Ca levels
(Fig.14.1).
High phosphorus and low calcitriol also stimulate production of PTH, resulting in increased production of FGF23 [3].
This results in continued stimulation and proliferation of parathyroid cells,
causing hypertrophy of the parathyroid gland.
As CKD progresses, most patients develop multigland enlargement and
formation of parathyroid nodules [4–6].
– Nodular PTH glands in the setting of uremia show reduced expression of inhibi-
tory Ca, calcitriol, and FGF23 receptors, making the parathyroid less sensitive to
these inhibitory compounds (Fig.14.2).
This can progress to refractory or tertiary hyperparathyroidism (THPT), in
which PTH levels are inappropriately increased despite hypercalcemia. This
is most often seen in patients on long-term dialysis or following kidney
transplant.
14 Secondary andTertiary Hyperparathyroidism
Chronic Kidney
Disease
125
Phosphorus
Retention
Bone Resistance
to PTH
Increased PTH
Secretion
Increased FGF23
Secondary
Hyperparathyroidism
Downregulation
of parathyroid
receptors
Calcitriol
deficiency
Hypocalcemia
Fig. 14.1 Physiology of hyperparathyroidism due to renal disease. Kidney disease results in
decreased reabsorption of phosphorus, thus increasing broblast growth factor 23 which decreases
creation of calcitriol. This decreases calcium and stimulates production of PTH
Low calcium
High phosphorus
Low 1,25(OH)
D
2
VDR
CaSR
VDR
CaSR
polyclonal proliferation
Normal
gland
Diffuse
hyperplasia
Early
nodularity
Monoclonal proliferation
Nodular
hyperplasia
Single
nodular gland
Fig. 14.2 Progression of parathyroid hyperplasia with progressive CKD.From Lau etal. [7].
Continued stimulation of parathyroid glands results in parathyroid hyperplasia and eventual nodule formation
126
J. Gellings and S. Dream
Tertiary Hyperparathyroidism
– As described above, HPT is common among renal transplant patients due to the
development of secondary hyperparathyroidism (SHPT) and hypertrophic, nodular parathyroid glands during the late-stage CKD and end-stage renal disease period.
– Tertiary hyperparathyroidism (THPT) is characterized by autonomous hyperse-
cretion of PTH.It is often diagnosed after the cause of SHPT has been corrected,
such as following kidney transplant.
Post-kidney transplant, improvement in kidney function results in increased
production of calcitriol. Vitamin D analogs and calcium-containing phosphate
binders are stopped, resulting in:
Gradual decrease in PTH concentrations in the 3–6 months
post-transplant.
Shortly after the initial decrease in PTH, calcium and PTH concentrations
gradually increase due to enhanced calcium reabsorption in the functioning allograft, calcitriol causing gastrointestinal uptake of calcium, and
PTH causing calcium efux from the bone.
– THPT is characterized by hypercalcemia or normocalcemia, hypophosphatemia,
and persistently elevated PTH.
Decreased vitamin D occurs in the majority of cases (81%).
Evaluation
Laboratory Tests
– Secondary Hyperparathyroidism.
Hypocalcemia, Hyperphosphatemia, low calcitriol in the setting of elevated
PTH (2–9 times the upper limit of normal) (Table14.2).
– Tertiary Hyperparathyroidism.
Table 14.2 Lab values in
secondary and tertiary
hyperparathyroidism
SHPT
THPT
Calcium Phosphorus PTH
14 Secondary andTertiary Hyperparathyroidism
Hypercalcemia, hypophosphatemia, and persistently elevated PTH
(Table14.2).
Imaging
– In primary hyperparathyroidism, imaging can be useful inlocalizing parathyroid
adenomas; however, it is less benecial in the setting of secondary and tertiary
hyperparathyroidism as multigland parathyroid disease (hyperplasia) is suspected in the majority of cases.
– Imaging (sestamibi or CT scan) may be useful inlocalizing ectopic parathyroid
glands. Ultrasound is useful for identifying concomitant thyroid nodules that
may need further work-up or treatment.
Treatment
Medical Management
– Medical management is the rst-line treatment for secondary hyperparathyroid-
ism and should address the underlying cause (e.g., SHPT due to vitamin D deciency should focus on vitamin D supplementation).
– Focused on suppression of PTH, reducing PO4 levels, increasing calcium levels,
and increasing calcitriol levels.
127
Vitamin D—Patients with SHPT should attempt vitamin D repletion prior to
parathyroidectomy.
Usually using analogs of calcitriol including paricalcitol, doxercalciferol,
and alphacalcidol to maximize PTH suppression and minimize Ca and PO4
absorption in the intestine.
Calcium—Most patients should follow national guidelines for calcium intake.
Cinacalcet—A calcimimetic that mimics the hypercalcemia effect on calciumsensing receptors to decrease PTH levels.
– Goals of treatment are improvement of bone histology and reduced cardiovascu-
lar morbidity and mortality.
128
J. Gellings and S. Dream
Parathyroidectomy
– Resection of hyperfunctioning parathyroid tissue reduces production of PTH,
thus lowering Ca and PO4. This leads to a reduction of PTH toxicity including
cardiovascular morbidity, renal osteodystrophy, and all-cause mortality [2].
– All parathyroidectomies for kidney disease require bilateral exploration.
All four glands should be identied and assessed prior to surgical resection.
Limited resection can be indicated only if 1 or 2 glands are abnormally
enlarged.
– Indications for parathyroidectomy in SHPT include PTH 9 times the upper limit
of normal in patients who are refractory to medical therapy or have complications and adverse outcomes related to HPT (Table14.3).
SHPT refractory to medical therapy refers to SHPT with:
PTH 9 times the upper limit of normal.
Despite medical treatments (including calcimimetics), OR.
Medical treatments are ineffective or not tolerated.
Perioperative Management
– Patients undergoing parathyroidectomy for SHPT and THPT are most at risk for
perioperative complications secondary to patient comorbidities and postoperative severe hypocalcemia related to hungry bone syndrome. Perioperative management is targeted at minimizing these risks.
– Patients should be started on calcitriol as tolerated in the preoperative period to
reduce their risk of hungry bone syndrome.
– Preoperative evaluation should include evaluation of cardiovascular risk, coagu-
lopathy, hypertension, immunosuppression, and timing of dialysis if needed [2].
Table 14.3 Indications for parathyroidectomy in patients with refractory secondary HPT
– Hypercalcemia of hyperphosphatemia (ca x PO4 product >55)
– Renal osteodystrophy
– Calciphylaxis of severe extraskeletal calcication
– Intractable symptoms including:
• Fatigue
• Pruritis
• Persistent anemia
• Bone pain
• Muscle pain
• Weakness
• Abdominal pain
– Kidney transplant anticipated within 6months with hypercalcemia
14 Secondary andTertiary Hyperparathyroidism
Dialysis: Electrolytes checked as close to surgery as possible, and dialysis
routines should be maintained.
Hypertension: Antihypertensive regimen should be continued to maintain a
blood pressure goal of <180/110, ideally <140/90.
Patients with voice changes or prior surgical history placing the recurrent
laryngeal or vagus nerve at risk should have preoperative vocal cord
assessment.
Operative Techniques
Subtotal Parathyroidectomy
– Resection of three full parathyroid glands and a portion of the fourth, leaving a
parathyroid remnant with its blood supply intact. All glands should be identied
and inspected, and the most normal appearing is chosen to remain partially
intact. The remnant is usually marked with a permanent suture or metal clip to
aid future identication, all other glands are completely excised.
Total Parathyroidectomy Without Autotransplantation
129
– Removes all identied parathyroid glands without leaving a remnant behind,
thus eliminating the risk of persistent or remnant disease.
This procedure should not be performed on patients who may undergo a kidney transplant.
This procedure has the highest risk of permanent hypoparathyroidism.
Total Parathyroidectomy withAutotransplantation
– Removes all parathyroid tissue with reimplantation of a parathyroid autograft
into a well-vascularized muscle bed. This may be the nondominant brachioradialis or the sternocleidomastoid.
130
J. Gellings and S. Dream
Transcervical Thymectomy
– May be performed in kidney-related hyperparathyroidism in conjunction with
subtotal parathyroidectomy or total parathyroidectomy with autotransplantation
due to the high prevalence of parathyroid tissue residing in the thymus. Typically,
thymectomy is not performed with total parathyroidectomy without autotransplantation as these patients rely on intrathymic parathyroid tissue for parathyroid
function.
Intraoperative PTH Monitoring
– Due to the impaired renal and hepatic clearance of PTH in kidney failure, PTH
half-life is less predictable than in primary hyperparathyroidism. Additionally,
bilateral exploration is required in SHPT and THPT, thus intraoperative PTH
levels may not change intraoperative decision-making. However, some studies
have found that the rate of recurrent and persistent disease are lower when intraoperative PTH monitoring is used [2].
– Patients who have undergone kidney transplant theoretically have predictable
decline in intraoperative PTH postresection. However, some patients may have
delayed clearance thus extension of the expected 50% decline in 10min to 15 to
25min may be more accurate.
Postoperative Outcomes forSecondary
andTertiary Hyperparathyroidism
Postoperative hypocalcemia—Extremely common postoperatively due to metabolic derangements from ESRD and hungry bone syndrome.
– Hungry bone syndrome—State of unopposed osteoblast uptake of calcium after
a decrease in PTH, resulting in severe and prolonged hypocalcemia. This is
dened by a decrease in serum calcium less than 8.4mg/dL or hypocalcemia for
more than 4days postoperatively [2]. Patients may also have hypophosphatemia,
hypomagnesemia, and hyperkalemia.
Patients may experience typical symptoms for hypocalcemia including perioral numbness, digital paresthesia, and muscle cramps.
Treatment of postoperative hypocalcemia should be treated with oral and IV
calcium as needed in addition to calcitriol.
Hypophosphatemia and hypomagnesemia may result in refractory hypocalcemia. Patients should receive phosphate and magnesium as indicated to reverse
these derangements.
14 Secondary andTertiary Hyperparathyroidism
131
Recurrent andPersistent Hyperparathyroidism
– Persistent disease typically indicates one or more unresected gland.
– Recurrent disease following subtotal parathyroidectomy or a total parathyroidec-
tomy with autotransplantation may be due to regrowth of the remnant gland,
stimulation of a parathyroid rest, or stimulation of the autotransplant.
Reoperation has higher complication rates and higher rates of operative failure compared to the initial operation. Preoperative localization is crucial prior
to reoperation.
References
1. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, etal. Prevalence of abnor-
mal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease:
results of the study to evaluate early kidney disease. Kidney Int. 2007;71(1):31–8.
2. Dream S, Kuo LE, Kuo JH, Sprague SM, Nwariaku FE, Wolf M, et al. The American
Association of Endocrine Surgeons Guidelines for the denitive surgical management of secondary and tertiary renal hyperparathyroidism. Ann Surg. 2022;276(3):e141–e76.
3. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, etal. Fibroblast growth factor-
23 mitigates hyperphosphatemia but accentuates calcitriol deciency in chronic kidney disease. J Am Soc Nephrol. 2005;16(7):2205–15.
4. Matsuoka S, Tominaga Y, Sato T, Uno N, Hiramitu T, Goto N, etal. Relationship between the
dimension of parathyroid glands estimated by ultrasonography and the hyperplastic pattern in
patients with renal hyperparathyroidism. Ther Apher Dial. 2008;12(5):391–5.
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ogy, histopathology, and medical and surgical management. Surg Today. 1997;27(9):787–92.
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Histopathology. 1998;33(1):46–51.
7. Lau WL, Cobi Y, Kalantar-Zadeh K. Parathyroidectomy in the management of secondary
hyperparathyroidism. Clin J Am Soc Nephrol. 2018;13:952–61.