1. Assessment and management of parathyroid hyperplasia in secondary hyperparathyroidism
Mario Meola, MD, PhD
University of Pisa, Hospital of Cisanello, Pisa, Italy
© Springer Healthcare, a part of Springer Science+Business Media; 2010.

2. Background
Secondary hyperparathyroidism (sHPT) is one of the most common and serious complications of CKD and long-term dialysis
Severe sHPT occurs when:
Serum calcium (Ca), phosphorus (P), Ca–P product , and iPTH levels are no longer adequately controlled by conventional therapies
Clinical symptoms are associated with a significantly increased risk of cardiovascular morbidity and mortality1
Following international guidelines, parathyroidectomy becomes mandatory when:
One or more parathyroid glands are enlarged (>500 mm3)
iPTH values are >700 pg/mL
Response to conventional therapy is poor2
CKD, chronic kidney disease; iPTH, intact parathyroid hormone; sHPT, secondary hyperparathyroidism
de Francisco ALM. Clin Ther. 2004;26:1976–1993.  2. NKF-K/DOQI. Am J Kidney Dis. 2003;85:S111–S114
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3. Long-term biological and morphological changes of the parathyroid glands in CKD
Biochemical abnormalities in CKD cause persistent overstimulation of parathyroid glands, changing parathyroid cell biology
Cell hypertrophy/hyperplasia
Selection of cell clones with reduced CaR and VDR density1
Diffuse polyclonal hyperplasia followed by monoclonal nodular hyperplasia
Parathyroid glandular volume associated with secretion of PTH and severity of sHPT
Linear correlation with PTH when total volume < mm (~2-3 g)2
Biggest glands tend to disengage from receptor control mechanisms (up-regulation of CaR and VDR) and grow independently, releasing PTH at levels unrelated to total glandular volume
CaR, calcium receptor; CKD, chronic kidney disease; PTH, parathyroid hormone; sHPT, secondary hyperparathyroidism; VDR, vitamin D receptor
1. Drueke TB. J Am Soc Nephrol. 2000;11: Indridason, et al. Kidney Int. 1996;50:
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4. Multiple choice question 1
High-resolution ultrasonography with colour Doppler imaging is the only technique that accurately measures volumetric variations of the parathyroid glands and simultaneously provides information on glandular perfusion.
True
False
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5. Ultrasound imaging in the management of secondary hyperparathyroidism
PTX is traditionally the ultimate treatment for sHPT that is resistant to medical therapy, but advances in ultrasonographic techniques have increased management options
US/CD imaging can be used to localise hyperplastic parathyroid glands
Glands become well distinguished from the thyroid parenchyma due to increased cellularity and reduction of adipose cells
Serial determination of glandular volume and perfusion pattern can help in monitoring the progression of sHPT and biochemical response to therapy1,2
PTX, parathyroidectomy; sHPT, secondary hyperparathyroidism; US/CD, ultrasonography with colour Doppler imaging.
1. Fukagawa, et al. Nephron. 1994;68: Katoh, et al. Am J Kidney Dis. 2000;35:
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6. Case study A 51 year old female patient receiving MHD since 1981
Medical history
Congenital bladder exstrophy with corrective surgeries
Recurrent UTIs and compromised GFR since age 12
Bilateral vesicoureteral reflux with grade IV hydronephrosis
Multiple renal scars and corticalisation of calices
Initiated MHD and continuous oral therapy with CaCO3 (4 g/day) at age 22
CaCO3: calcium carbonate; GFR, glomerular filtration rate; MHD, maintenance haemodialysis; UTI, urinary tract infection
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7. Treatment history Year Laboratory findings US/CD findings
Treatment decision
1990
Ca: 11 mg/dL
P: 4.9 mg/dL
Ca x P: 49 mg2/dL2
iPTH: 611 pg/mL
ALP: 580 IU/L
Nodular hyperplasia of the right inferior parathyroid gland; volume: 2323 mm3
Chemical ablation of parathyroid hyperplasia with percutaneous ethanol injection
iPTH: 795 pg/mL
ALP : 952 IU/L
Right inferior gland: 3312 mm3
1993
Right inferior gland: 4260 mm3 Left hypoechoic gland: 31 mm3
Vitamin D (4 µg/week); CaCO3 reduced to 2-3 g/day
iPTH: pg/mL ALP: IU/L
Right inferior gland: 4556 mm3
Left gland: 81 mm3
Radiotracer hyperaccumulation near right inferior pole of the thyroid
Oral calcitriol replaced by iv calcitriol 1.5 μg 3 times/wk; CaCO3 stopped; Al(OH)3 added (3 tbs twice/wk)
Ca: 12.3 mg/dL
P: 5.6 mg/dL Ca x P: 68.8 mg2/dL2 ALP: 326 U/L
iPTH: 1350 pg/mL
Right inferior gland: 5299 mm3 Left gland: 210 mm3 Gland at the inferior pole of the left thyroid lobe: 65 mm3
Calcitriol interrupted due to episodes of hypercalcaemia and hyperphosphataemia; Parathyroidectomy indicated but not performed due to patient refusal
Al(OH)3: aluminium hydroxide; ALP, alkaline phosphatase; Ca, calcium; CaCO3: calcium carbonate; iPTH, intact parathyroid hormone; Ca x P, calcium/phosphate product; P, phosphate; tbs: tablets US/CD, high-resolution ultrasound colour Doppler
© Springer Healthcare, a part of Springer Science+Business Media; 2010.

8. Progression of sHPT and parathyroid hyperplasia despite conventional therapy
In 2005, calcitriol switched to paricalcitol 5 µg/week, sevelamer 4800 mg/day, and CaCO3 2 g/day
Biochemical parameters after 6 months:
Ca: 10.5 mg/dL
P: 5 mg/dL
Ca x P: 52.5 mg2/dL2
ALP 1243 U/L
iPTH 1600 pg/mL
US/CD showed 4 hyperplastic, hypoechoic and hypervascularised glands
Figures reprinted with permission from Prof. Meola
ALP, alkaline phosphatase; Ca, calcium; iPTH, intact parathyroid hormone; Ca x P, calcium/phosphate product; CaCO3: calcium carbonate; P, phosphate; US/CD, high-resolution ultrasound colour Doppler
© Springer Healthcare, a part of Springer Science+Business Media; 2010.

9. Multiple choice question 2
Long-term treatment with calcimimetics have which of the following effects in patients with CKD and severe sHPT?
Inhibition of PTH secretion via modulation of calcium-sensing receptors in the parathyroid
Stabilisation of calcium-phosphorus metabolism parameters
Reduction parathyroid hyperplasia
All of the above
CKD, chronic kidney disease; PTH, parathyroid hormone; sHPT, secondary hyperparathyroidism.
© Springer Healthcare, a part of Springer Science+Business Media; 2010.

10. Addition of cinacalcet to standard therapy improved biological markers of sHPT
First level
Second level
Third level
January 2010 Ca
8.6 mg/dL P
5 mg/dL
Ca x P
43 mg/dL2
ALP
316 IU/L
iPTH
pg/mL
Figure reprinted with permission from Prof. Meola
ALP, alkaline phosphatase; Ca, calcium; iPTH, intact parathyroid hormone; Ca x P, calcium/phosphate product; P, phosphate
© Springer Healthcare, a part of Springer Science+Business Media; 2010.

11. Multiple choice question 3
Which of the following is NOT a proposed effect of calcimimetics on parathyroid gland volume and morphology in patients with sHPT?
Direct stimulation of the calcium receptor
Indirect improvement of vitamin D receptor sensitivity and expression
Synergy with vitamin D and phosphate binders
Reduction in parathyroid cell apoptosis
sHPT, secondary hyperparathyroidism
© Springer Healthcare, a part of Springer Science+Business Media; 2010.

12. Reduction in parathyroid glandular volume
Figure reprinted with permission from Prof. Meola
© Springer Healthcare, a part of Springer Science+Business Media; 2010.

13. Volumetric variations of parathyroid glands after cinacalcet treatment
Figure reprinted with permission from Prof. Meola
© Springer Healthcare, a part of Springer Science+Business Media; 2010.

14. Key learning points
Progression of sHPT is a slow and continuous process that often occurs despite conventional therapy
US/CD imaging can be used to monitor the morphological changes of hyperplastic parathyroids in response to therapy
Provides important information for clinical/pharmacological and surgical treatment decision-making
Availability of calcimimetics has changed the natural history of clinical sHPT
May change the therapeutic utility of parathyroidectomy
sHPT, secondary hyperparathyroidism; US/CD, high-resolution ultrasound colour Doppler
© Springer Healthcare, a part of Springer Science+Business Media; 2010.

15. Conclusions
This 51-year-old patient developed severe sHPT marked by parathyroid hyperplasia and a total glandular volume of approximately 6000 mm3 (~ 6 g)
Progression of sHPT was stopped only when cinacalcet was added to conventional therapy
Treatment with cinacalcet reduced PTH serum levels and stabilised mineral metabolism, allowing the patient to avoid parathyroidectomy
sHPT, secondary hyperparathyroidism
© Springer Healthcare, a part of Springer Science+Business Media; 2010.