assessment and management of parathyroid hyperplasia in secondary hyperparathyroidism mario meola,...

Assessment and management of parathyroid hyperplasia in secondary hyperparathyroidismMario 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

1. de Francisco ALM. Clin Ther. 2004;26:1976–1993. 2. NKF-K/DOQI. Am J Kidney Dis. 2003;85:S111–S114


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.


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.

A. True

B. False


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


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


Treatment history

Year Laboratory findings US/CD findings Treatment decision

1990 Ca: 11 mg/dLP: 4.9 mg/dLCa 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

1990 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/mLALP: 400-265 IU/L


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/dLP: 5.6 mg/dLCa x P: 68.8 mg2/dL2

ALP: 326 U/LiPTH: 1350 pg/mL


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: tabletsUS/CD, high-resolution ultrasound colour Doppler


Progression of sHPT and parathyroid hyperplasia despite conventional therapy

• In 2005, calcitriol switched to paricalcitol5 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

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

Figures reprinted with permission from Prof. Meola



Long-term treatment with calcimimetics have which of the following effects in patients with CKD and severe sHPT?

A. Inhibition of PTH secretion via modulation of calcium-sensing receptors in the parathyroid

B. Stabilisation of calcium-phosphorus metabolism parameters

C. Reduction parathyroid hyperplasia

D. All of the above

CKD, chronic kidney disease; PTH, parathyroid hormone; sHPT, secondary hyperparathyroidism.


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

ALP, alkaline phosphatase; Ca, calcium; iPTH, intact parathyroid hormone; Ca x P, calcium/phosphate product; P, phosphate

Figure reprinted with permission from Prof. Meola



Which of the following is NOT a proposed effect of calcimimetics on parathyroid gland volume and morphology in patients with sHPT?

A. Direct stimulation of the calcium receptor

B. Indirect improvement of vitamin D receptor sensitivity and expression

C. Synergy with vitamin D and phosphate binders

D. 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


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


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


assessment and management of parathyroid hyperplasia in secondary hyperparathyroidism mario meola,...

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