Normocalcemic Primary Hyperparathyroidism Tabitha Galloway, MD Robert P. Zitsch III, MD 17 July 2013
• Parathyroid glands are “relatively” new discovery in modern medicine • Discovered in second half of 19th century • “glandulae parathyroideae”
• Osteitis fibrosa cystica
• Animal studies advanced understanding of parathyroid disease
History Lesson Pellitteri PK, Sofferman RA, Randolph GW. Management of parathyroid disorders in Cummings Otolaryngology- Head and Neck Surgery. Elselvier, 2010.
• Albert Gahne • Tram conductor in Vienna, Austria, 1924 • Muscle fatigue, bone pain, femur fracture after fall • Dr. Felix Mandl • Surgeon who recognized these as signs of parathyroid disease
• Administered fresh parathyroid extract • Transplanted fresh parathyroid glands from victim of street accident to Gahne • Neck exploration and removal of parathyroid tumor • Immediate relief, free of pain and ambulating 4 years later
Notable Early Patients Pellitteri PK, Sofferman RA, Randolph GW. Management of parathyroid disorders in Cummings Otolaryngology- Head and Neck Surgery. Elselvier, 2010.
• Charles Martell • Sea captain, 1927 • Hypercalcemia and generalized demineralization of skeleton • 6 unsuccessful neck explorations • 7th surgery elicited mediastinal 3 cm parathyroid surgery • Developed post operative tetany • Treated successfully with Ca • Impacted ureteral stone, requiring surgery • Expired from laryngospasm after surgery
Notable Early Patients Oertlli D, Udelsman R. Surgery of the thyroid and parathyroid glands. Springer 2007.
The Normal Parathyroid http://www.drugs.com/health-guide/parathyroid-cancer.html
• Weight • 40-60 mg
• Dimensions • 5 x 3 x 1 mm
• Typical number of glands • 4 - present in 84-87% population • 3 - present in 3-6 % population • Supranumery glands- 6% population • 5-12 glands have been reported
• Color • Yellowish brown to reddish brown
The Normal Parathyroid Pellitteri PK, Sofferman RA, Randolph GW. Management of parathyroid disorders in Cummings Otolaryngology- Head and Neck Surgery. Elselvier, 2010.
http://www.endocrinesurgeon.co.uk/index.php/what-may-the-surgeon-find-when-doing-a-parathyroid-exploration
Calcium Homeostasis http://www.nbs.csudh.edu/chemistry/faculty/nsturm/CHE452/20_Calcium%20Homeostasis16.htm Pellitteri PK, Sofferman RA, Randolph GW. Management of parathyroid disorders in Cummings Otolaryngology- Head and Neck Surgery. Elselvier, 2010.
• PTH release regulated primarily by serum ionized calcium levels
• PTH • Functions to raise plasma calcium via bone and renal calcium resorption • Stimulates metabolism of Vitamin D to it’s active hormonal form 1,25-dihydroxyvitamin D3 (calcitriol)
• Major target end organs for PTH • Kidneys • Bones • Intestine
Calcium Homeostasis http://www.nbs.csudh.edu/chemistry/faculty/nsturm/CHE452/20_Calcium%20Homeostasis16.htm Pellitteri PK, Sofferman RA, Randolph GW. Management of parathyroid disorders in Cummings Otolaryngology- Head and Neck Surgery. Elselvier, 2010.
• Kidney • Increase tubular Ca resorption • Decrease tubular phosphorus resorption • Increase hydroxylation of Vitamin D to active form
• Bone • Increased Ca resorption
• Intestine • Increased absorption of Ca and Vitamin D
Calcium Homeostasis http://www.nbs.csudh.edu/chemistry/faculty/nsturm/CHE452/20_Calcium%20Homeostasis16.htm Pellitteri PK, Sofferman RA, Randolph GW. Management of parathyroid disorders in Cummings Otolaryngology- Head and Neck Surgery. Elselvier, 2010.
Calcium Homeostasis http://www.nbs.csudh.edu/chemistry/faculty/nsturm/CHE452/20_Calcium%20Homeostasis16.htm Pellitteri PK, Sofferman RA, Randolph GW. Management of parathyroid disorders in Cummings Otolaryngology- Head and Neck Surgery. Elselvier, 2010.
• PTH provides a rapid, immediate and direct mechanism of controlling calcium levels • Minor alterations can produce major change! • iCal 0.04 mmol/L can PTH by 100%
• With this rapid feedback system, if we have too much circulating hormone, can see how skews blood calcium metabolism • This alteration which is typically picked up by referring physicians
Calcium Homeostasis http://www.nbs.csudh.edu/chemistry/faculty/nsturm/CHE452/20_Calcium%20Homeostasis16.htm Pellitteri PK, Sofferman RA, Randolph GW. Management of parathyroid disorders in Cummings Otolaryngology- Head and Neck Surgery. Elselvier, 2010.
• Most start with discovery of hypercalcemia • May have complaints which warranted blood draw such as fatigue, kidney stones, constipation, bone/joint pain, decreased bone mineral density • Or may have been an incidental finding
• Typical work up on hypercalcemia proceeds • Many, many causes of non-parathyroid hormone mediated, non-malignant hypercalcemia • Includes PTH level
“Typical” parathyroid patient Pellitteri PK, Sofferman RA, Randolph GW. Management of parathyroid disorders in Cummings Otolaryngology- Head and Neck Surgery. Elselvier, 2010.
• Ca, PTH • Determine primary hyperparathyroidism • Rule out secondary or tertiary hyperparathyroidism • Rule out familial hypocalciuric hypercalcemia • There are some tumors that can secrete PTH-related protein or ectopic PTH • Patients who are on thiazide diuretics or lithium compounds may have mild hypercalcemia and increased iPTH • Determine if they are a surgical candidate…
• What about the patients who have PTH, normal Ca?
“Typical” parathyroid patient Pellitteri PK, Sofferman RA, Randolph GW. Management of parathyroid disorders in Cummings Otolaryngology- Head and Neck Surgery. Elselvier, 2010.
• Normocalcemic primary hyperparathyroidism (NCPHPT) entity first described in 1960’s • Historically PTH, iCa, normal Ca levels • Now considered that patients with NCPHPT have PTH with normal iCa and normal Ca levels
• Key component is the ability to rule out secondary causes of PTH elevation in eucalcemic patients…
NCPHPT Carneiro-Pla D and Solorzano C. A summary of the new phenomenon of normocalcemic hyperparathyroidism and appropriate management. Curr Opin Oncol 2012, 24:42-45.
• Vitamin D Deficiency • Patients with low 25-hydroxyvitamin D levels • PTH levels should normalize after replacement
• Urinary Calcium Leak • Renal tubular dysfunction • Eucalcemia, long-standing history of kidney stones and hypercalciuria • Treated with HTCZ- should normalize levels
NCPHPT- rule out Carneiro-Pla D and Solorzano C. A summary of the new phenomenon of normocalcemic hyperparathyroidism and appropriate management. Curr Opin Oncol 2012, 24:42-45.
NCPHPT Carneiro-Pla D and Solorzano C. A summary of the new phenomenon of normocalcemic hyperparathyroidism and appropriate management. Curr Opin Oncol 2012, 24:42-45.
• How are these patients identified? • Work-up for bone mineral density loss
• NCPHPT • 57% patients in one study had osteoporosis at least at one subsite • Osteoporosis more common at lumbar spine and hip than at the distal 1/3 cortical radius
• PHPT • Osteoporosis more common at cortical radius site, with fewer having osteoporosis at lumbar spine and hip
NCPHPT Carneiro-Pla D and Solorzano C. A summary of the new phenomenon of normocalcemic hyperparathyroidism and appropriate management. Curr Opin Oncol 2012, 24:42-45. Lowe H, McMahon DJ, Rubin MR, Bilezikian JP and Silverberg SJ. Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype. J Clin Endocrinol Metab 2007, 92:3001-3005.
• Does this represent a spectrum?
NCPHPT
Asymptomatic PHPT
Symptomatic PHPT
NCPHPT Carneiro-Pla D and Solorzano C. A summary of the new phenomenon of normocalcemic hyperparathyroidism and appropriate management. Curr Opin Oncol 2012, 24:42-45.
Natural history - PHPT Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, and Rubin MR. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metabol. 2009, 94 (2): 351-365.
• Most asymptomatic PHPT overall do well • DEXA may remain stable without worsening of hypercalciuria • 25% progressive disease • Worse hypercalcemia, hypercalciuria and decreased bone mass
• Age is predictive of this progression • Patients 1mg/dL above upper limit of normal • Creatinine clearance reduced more than 30% for age in the absence of another cause • Measurement of 24-hour urine calcium >400 mg/dL • Patients are less than 50 years of age • Bone mineral density at lumbar spine, hip or distal radius reduced more than 2 ½ standard deviations
Surgical Decision Making
• If the decision for surgery is made, or as part of the decision making process can utilize imaging studies • • • • •
Sestamibi studies Ultrasound studies CT studies MRI studies MIBI-CT fusion images
• Interestingly, predicative values of sestamibi and ultrasound studies are lower in patients with NCPHPT
Imaging studies
• Post-operatively what do you use as your end-point after surgery to know if it was successful? • Calcium levels • PTH levels • DEXA scores
End point
NCPHPT Carneiro-Pla D and Solorzano C. A summary of the new phenomenon of normocalcemic hyperparathyroidism and appropriate management. Curr Opin Oncol 2012, 24:42-45.
NCPHPT Carneiro-Pla D and Solorzano C. A summary of the new phenomenon of normocalcemic hyperparathyroidism and appropriate management. Curr Opin Oncol 2012, 24:42-45.
Questions?
