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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
1. 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.
A. True
B. 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
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
19941996
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)
19972003
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?
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.
© Springer Healthcare, a part of Springer Science+Business Media; 2010.
Addition of cinacalcet to standard
therapy improved biological markers of
sHPT
• First level
January 2010
— Second level
• Third level
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?
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
© 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.