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.

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 © Springer Healthcare, a part of Springer Science+Business Media; 2010.

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 <2000-3000 mm3 (~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;11:1141-1152. 2. Indridason, et al. Kidney Int. 1996;50:1663-1667. © Springer Healthcare, a part of Springer Science+Business Media; 2010.

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 © Springer Healthcare, a part of Springer Science+Business Media; 2010.

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;68:221-228. 2. Katoh, et al. Am J Kidney Dis. 2000;35:466-468 © Springer Healthcare, a part of Springer Science+Business Media; 2010.

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 © Springer Healthcare, a part of Springer Science+Business Media; 2010.

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 1994-1996 iPTH: 670-450 pg/mL ALP: 400-265 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) 1997-2003 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.

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.

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.

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 360-400 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.

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.

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

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.

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.

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.