Current Concepts in the Evaluation and Management of Abnormal Parathyroid Hormone (PTH) Levels Shireen Fatemi, M.D. April, 2012 Disclosures I have no financial relationships with commercial interests, but I do have 4 parathyroid glands. They are all working normally to the best of my knowledge.
Cultural & Linguistic Competency Cultural and linguistic competency will be addressed in this activity. Differences in prevalence, diagnosis, treatment in a diverse population; linguistic skills; pertinent cultural data, etc. Outline Overview of parathyroid hormone secretion and action Primary hyperparathyroidism (PHPT) Secondary hyperparathyroidism Overview of vitamin D: metabolism and deficiency PTH and chronic kidney disease (CKD) Medical and surgical management of hyperparathyroidism Clinical application approach to the patient who has an elevated parathyroid hormone
Outline Overview of parathyroid hormone secretion and action Primary hyperparathyroidism (PHPT) Secondary hyperparathyroidism Overview of vitamin D: metabolism and deficiency PTH and chronic kidney disease (CKD) Medical and surgical management of hyperparathyroidism Clinical application approach to the patient who has an elevated parathyroid hormone Parathyroid hormone secretion and action PTH release, synthesis and degradation is regulated by calcium. PTH and calcitriol (1,25 D) are the two major hormones regulating calcium and phosphate homeostasis in the body. PTH 1-84 is the active hormone. It binds to PTH receptors in the bone and kidney, but is present in many other tissues (breast, skin, heart, blood vessels and pancreas). PTH has a short half-life (2 to 4 minutes). It is degraded in the liver and kidney.
Actions of PTH Principal targets are bone and kidney Bone: Mobilizes calcium from skeletal stores by activating bone resorption Kidney: Reabsorption of filtered calcium ( sca) Excretion of phosphate ( spo4) Synthesis of 1,25 vitamin D ( s1,25d) Other actions? Intestine, liver, adipose tissue, cardiovascular and neuromuscular function
Relationship between PTH and calcium PTH Calcium Calcium sensing receptors
Abnormalities in PTH secretion I Mutations in the calcium receptor Results in inappropriate PTH release (as in familial hypocalciuric hypercalcemia or autosomal dominant hypocalcemia) Primary hyperparathyroidism Parathyroid adenoma or hyperplasia causes a shift to a higher set-point for calcium Secondary hyperparathyroidism Kidney failure causes PTH hyperplasia, resulting in increased secretion of PTH as well as a reduced expression of calcium sensing receptors resulting in a higher calcium level Lithium Causes a reduced sensitivity to PTH secretion, thus resulting in a higher serum calcium level; also decreases renal calcium excretion Abnormalities in PTH secretion II Calcimimetic drugs Bind to the calcium sensing receptor and inhibit PTH secretion (cinacalcet) Nonhypercalcemic Vitamin D analogs 1,25 D analogues have been developed to inhibit PTH synthesis and secretion while minimizing intestinal calcium absorption or bone resorption (example : paricalcitol) Ectopic PTH secretion Largely due to tumor production of PTH related protein
Outline Overview of parathyroid hormone secretion and action Primary hyperparathyroidism (PHPT) Secondary hyperparathyroidism Overview of vitamin D: metabolism and deficiency PTH and chronic kidney disease (CKD) Medical and surgical management of hyperparathyroidism Clinical application approach to the patient who has an elevated parathyroid hormone Primary Hyperparathyroidism (PHPT)* *Sporadic vs. multiple endocrine neoplasia
Primary Hyperparathyroidism (PHPT) Most common clinical presentation: asymptomatic hypercalcemia. F>M, peak incidence 4 th -6 th decade Frankly elevated PTH with hypercalcemia or inappropriately normal PTH given the patient s hypercalcemia =normocalcemic primary hyperparathyroidism If uncertain of diagnosis -- 24 hour calcium excretion, 25 D or 1,25 D may help Localization studies (sestamibi scans) are not used to establish the diagnosis Use total corrected serum calcium when evaluating hypercalcemia (correction: for every 1 gm increase in albumin, decrease the calcium by 0.8) Outline Overview of parathyroid hormone secretion and action Primary hyperparathyroidism (PHPT) Secondary hyperparathyroidism Overview of vitamin D: metabolism and deficiency PTH and chronic kidney disease (CKD) Medical and surgical management of hyperparathyroidism Clinical application approach to the patient who has an elevated parathyroid hormone
Etiologies of Secondary Hyperparathyroidism* 1.Low 25 vitamin D/hypocalcemia 2. Calcium malabsorption (bariatric surgery, celiac disease, fat malabsorption) / decreased intake 3. Renal losses hypercalciuria, diuretics 4. CKD (and acute renal failure)-impaired 1,25D formation, hyperphosphatemia 5. Lithium use 6. Calciolytic agents-cause lowering of serum calcium *Paul Miller, 2012 Outline Overview of parathyroid hormone secretion and action Primary hyperparathyroidism (PHPT) Secondary hyperparathyroidism Overview of vitamin D: metabolism and deficiency PTH and chronic kidney disease (CKD) Medical and surgical management of hyperparathyroidism Clinical application approach to the patient who has an elevated parathyroid hormone
120 INFLUENCE OF 25-OH VIT D ON SERUM PTH LEVELS 100 Serum PTH pg/ml 80 60 40 20 0 0 5 10 15 20 25 30 35 40 45 50 55 25-OH Vit D ng/ml J Endo Invest Epub 5/2011 VITAMIN D METABOLISM
INDICATIONS FOR 25(OH)D SCREENING FOR VITAMIN D DEFICIENCY I Rickets Osteomalacia Osteoporosis Chronic kidney disease Hepatic failure Malabsorption syndromes (bariatric surgery, cystic fibrosis, Crohn s disease, inflammatory bowel disease, radiation enteritis). Hyperparathyroidism Medications (antiseizure, glucocorticoids,aids, antifungals, cholestyramine) INDICATIONS FOR 25(OH)D SCREENING FOR VITAMIN D DEFICIENCY II African-Americans and Hispanics Pregnant and lactating women Older adults with a history of falls and/or fractures Obese individuals (BMI over 30 kg/m 2 ) Granuloma forming disorders (sarcoidosis, TB, histoplasmosis, coccidiomycosis,berylliosis). Some lymphomas
If you want to keep sun energy all winter long drink vitamin D fortified Schlitz beer. Schlitz Sunshine Vitamin D Beer Schlitz aware of the benefits of vitamin D and in the 1930 s markets its product accordingly FDA (not amused)- prohibits vitamin D addition to the beer in 1947 THERAPY OF VITAMIN D DEFICIENCY 50,000 iu per week x 12 weeks Recheck If low, repeat If adequate, then 1000 2000 iu/day Vitamin D supplementation appears safe and may offer more benefit than bone health Should be considered in all individuals
VITAMIN D: What Should We Tell Our Patients Vitamin D effects most tissues in the body Required for normal bone metabolism and may reduce risk of osteoporosis Likely will not be of benefit in treatment of disease May help reduce the risk of certain diseases Unlikely to produce side effects, if taken in recommended dosages However, if a little is good, a lot is not better Outline Overview of parathyroid hormone secretion and action Primary hyperparathyroidism (PHPT) Secondary hyperparathyroidism Overview of vitamin D: metabolism and deficiency PTH and chronic kidney disease (CKD) Medical and surgical management of hyperparathyroidism Clinical application approach to the patient who has an elevated parathyroid hormone
Changes in mineral metabolism as a consequence of CKD* GFR Stage 1,25 D PO4 Calcium PTH 2 fold 4 fold 8 fold *Andress, Semin in Dialysis, 2005 Diagnosis of Osteoporosis in Populations with Known Reduced GFR 1. Stage 1-3 CKD (GFR <90-30 ml/min): diagnose with osteoporosis the same as patients without National Kidney Foundation (NKF) defined CKD as long as there are no other biochemical abnormalities suggesting CKD-metabolic bone disease. 2. Stage 4-5 CKD (GFR <30 ml/min): Cannot use WHO criteria and/or fragility fractures since all forms of severe renal osteodystrophy (histomorphometry defined) may have low T-scores or low trauma fractures. Need Nephrologist s input. Moe S, et al, 2009 Miller, PD Sem Dial 2008
Outline Overview of parathyroid hormone secretion and action Primary hyperparathyroidism (PHPT) Secondary hyperparathyroidism Overview of vitamin D: metabolism and deficiency PTH and chronic kidney disease (CKD) Medical and surgical management of hyperparathyroidism Clinical application approach to the patient who has an elevated parathyroid hormone Symptomatic HPT is an Indication for Parathyroid Surgery SYMPTOMS ARE: Nephrolithiasis Fractures Neuropsychiatric
Asymptomatic Patients: Indications for Parathyroid Surgery:* Serum Ca 1.0 mg/dl or more above the upper limit of normal (11.5 mg/dl or > in SCPMG lab) Creatinine clearance < 60 ml/min T-score < - 2.5 at hip, spine or forearm or a fragility fracture Age < 50 years * From the 2008 3 rd International Workshop. Excludes those who refuse or are unfit for surgery monitor annual Ca,cr and BMD. Medical Management of asymptomatic PHPT* Indicated for those with low bone mass and risk factors for fracture, or those with osteoporosis who refuse or are not candidates for surgery For medical therapy, bisphosphonates are first choice. HT (estradiol) also effective Calcimimetics may prove useful to lower PTH Ensure 25 vitamin D status is normalized *Those who refuse or are not surgical candidates
Outline Overview of parathyroid hormone secretion and action Primary hyperparathyroidism (PHPT) Secondary hyperparathyroidism Overview of vitamin D: metabolism and deficiency PTH and chronic kidney disease (CKD) Medical and surgical management of hyperparathyroidism Clinical application approach to the patient who has an elevated parathyroid hormone PTH >65: 1. calcium high/(+ 25D low)? HPTH 2. calcium normal/low and vitamin D low?give vitamin D
Bibliography 1. Potts, JT, Juppner, H. Parathyroid hormone: molecular biology and regulation. In: Bilezikian, JP, Raisz, LG, Rodan, GA (Eds), Principles of Bone Biology, Academic Press, New York 1996. p. 325 2. Goodman WG, Frazao JM, Goodkin DA, Turner SA, Liu W, Coburn JW A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int. 2000; 58(1):436. 3. Brown EM Lithium induces abnormal calcium-regulated PTH release in dispersed bovine parathyroid cells J Clin Endocrinol Metab. 1981;52(5):1046. 4. Eastell R, Arnold A, Brandi ML, Brown EM, D'Amour P, Hanley DA, Rao DS, Rubin MR, Goltzman D, Silverberg SJ, Marx SJ, Peacock M, Mosekilde L, Bouillon R, Lewiecki EM Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009;94(2):340. 5. Lowe H, McMahon DJ, Rubin MR, Bilezikian JP, Silverberg SJ Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype. J Clin Endocrinol Metab. 2007;92(8):3001. 6. Szulc P, Delmas, PD. Biochemical markers of bone turnover in osteoporosis. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 6th ed, Rosen, CJ, (Ed), American Society of Bone and Mineral Research, 2008; p.174. 7. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911. 8. Silverberg SJ, Bilezikian JP SO. Asymptomatic Primary Hyperparathyroidism. A Surgical Perspective. Surgery Clin North Am. 2004;84 (3): 787. 9. Ambrogini E, Cetani F, Cianferotti L, Vignali E, Banti C, Viccica G, Oppo A, Miccoli P, Berti P, Bilezikian JP, Pinchera A, Marcocci C SO. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab. 2007;92(8):3114. Bibliography 10. Andress, D. Vitamin D Treatment in Chronic Kidney Disease. Seminars in Dialysis. 2005; 18 (4): 315. 11. Moe S, Drueke T, Cunningham J, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 69: 1945-1953. 12. Miller PD. Is there a role for bisphosphonates in chronic kidney disease? Semin Dial 2007; 20: 186-190. 13. Eastell R, Arnold A, Brandi ML, Influence OF 25-OH VIT D On Serum PTH Levels J Endo Invest 2011 14. Eastell R, Arnold A, Brandi ML, et. al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009;94(2):340. 15. Nissen PH, Christensen SE, Heickendorff L, et.al. Molecular genetic analysis of the calcium sensing receptor gene in patients clinically suspected to have familial hypocalciuric hypercalcemia: phenotypic variation and mutation spectrum in a Danish population. J Clin Endocrinol Metab. 2007;92(11):4373. 16. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med. 1999;341(17):1249. 17. Lowe H, McMahon DJ, Rubin MR, et al. Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype. J Clin Endocrinol Metab 2007;92: 3001. 18. Sywak MS, Knowlton ST, Pasieka JL. Do the National Institutes of Health consensus guidelines for parathyroidectomy predict symptom severity and surgival outcome in patients with primary hyperparathyroidism? Surgery 2002; 132: 1013.
Bibliography 19. Bollerslev J, Jansson S, Mollerup CL, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective randomized trial. J Clin Endocrinol Metab 2007; 92: 1687. 20. Guo CY, Thomas WE, al-dehaimi AW, et al. Longitudinal changes in bone mineral density and bone turnover in postmenopausal women with mild primary hyperparathyroidism. J Clin Endocrinol Metab 1996; 81: 3487. 21. Parker CR, Blackwell PJ, Fairbalm KJ, Hosking DJ, Alendronate in the treatment of primary hyperparathyroid related osteoporosis: a 2 year study. J Clin Endocrinol Metab 2002; 87: 4482. 22. Peacock M, Bolognese MA, Borofsky M, et al. Cinacalcet treatment of primary hyperparathyroidism: biochemical and bone densitometric outcomes in a five-year study. J Clin Endocrinol Metab 2009; 94: 4860. 23. Bilezikian JP. Primary hyperparathyroidism. When to observe and when to operate. Endocrinol Metab Clin North Am 2000; 29: 465. 24. Bilezikian JP, Khan A, Potts J. Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Third International Workshop. J Clin Endocrinol Metab 2009; 94:335. Thank You! QUESTIONS??