1. Advances and Changing Trends in the Diagnosis and Treatment of Hyperparathyroidism Istanbul: June 2, 2007 Alan Dackiw MD, PhD, BSc BSc (MED) FRCSC, FACS Division of Endocrine and Oncologic Surgery Johns Hopkins University School of Medicine Baltimore, Maryland, USA

2. Primary Hyperparathyroidism Inappropriately high PTH levels in the setting of a normal or high ionized calcium Incidence of 50-100 per 100,000 50,000 new cases each year in USA Male to Female ratio 1:3 Increases after menopause (~2 per 1000 in women over 60 )

3. PTH Anatomy and Physiology

4. Parathyroid Embryology

5. Hyperparathyroidism Epidemiology/Diagnosis Localization Modern Operative Techniques Some Historical Vignettes

6. Hypersecretion of PTH by parathyroid tissue Etiology unclear; association with 11q13 mutations (MEN1), Cyclin D1 Associated with neck irradiation Primary Hyperparathyroidism

7. Etiologies: CRF and osteomalacia Long-term secondary hyperparathyroidism may result in autonomous parathyroid hyperfunction (tertiary hyperparathyroidism ) Secondary and tertiary hyperparathyroidism

8. 1:1000 –from population-based prevalence studies –includes both hyperparathyroidism and FHH Prevalence of hypercalcemia

9. Adenoma (80%) Hyperplasia (20%) –No single set of conclusive criteria differentiates adenoma from hyperplasia Carcinoma (1%) –Ca >14; high PTH –local invasion; LN mets; lung, liver, bone mets Etiology of parathyroid hormone hypersecretion

10. Often asymptomatic Systemic symptoms: weakness, fatigability, headache, weight loss, depression Renal: renal colic, nephrolithiasis, nephrocalcinosis, metabolic acidosis (ca oxalate>ca phosphate stones) Skeletal: bone pain, pathologic fractures, bone cysts, localized swellings (“brown tumors”), osteitis fibrosa cystica, gout/pseudogout, arthralgias Clinical manifestations of hyperparathyroidism I: Stones, bones, abdominal groans, psychic and fatigue overtones

11. Gastrointestinal: PUD, pancreatitis, constiptation Neurological: emotional lability, slow mentation, poor memory, depression, fatigability Neuromuscular: tongue fasciculations, proximal muscle weakness, hyperactive reflexes, muscular atrophy General: polyuria, polydipsia, constipation, shortened QT, pruritis, band keratopathy, ectopic calcification, anemia, elevated ESR, hypertension Clinical manifestations of hyperparathyroidism II

12. Most Common Clinical Manifestation in 2007 !! Elevated Calcium on blood test Calcium added to routine electrolytes measured by autoanalyzer

13. Hypercalcemia –Almost always present –Exceptions: vitamin D deficiency, hypoalbuminemia, acidosis, secondary hyperparathyroidism –Actions of PTH resorption of Ca from bone reabsorption of Ca from kidney 1,25(OH) 2 D intestinal Ca absorption Laboratory evaluation I

14. Hypophosphatemia –less reliable (50% with 1° hyperparathyroidism) phosphate clearance from kidney PTH determination –intact PTH (two-site assay) Metabolic acidosis kidney bicarbonate reabsorption Urinary Ca (differentiate FHH) Urinary cAMP increased Laboratory evaluation II

15. 1° hyperparathyroidism 2°/3° hyperparathyroidism Ectopic hyperparathyroidism –PTH-producing non-parathyroid tumor (rare) –PTH-related protein (PTHRP) producing non- parathyroid tumor Familial Hypocalciuric Hypercalcemia (FHH) –Normal PTH –Low urinary Ca Differential diagnosis of hyperparathyroidism

16. Compensatory PTH hypersecretion CRF, osteomalacia/rickets, intestinal malabsorption, Fanconi syndrome, renal tubular acidosis Etiology in CRF is multifactorial – hypocalcemia – hyperphosphatemia – decreased 1,25(OH) 2 D – decreased GI Ca absorption – decreased peripheral PTH sensitivity Secondary hyperparathyroidism

17. Oral calcium carbonate Oral or intravenous calcitriol Increase Ca concentration in the dialysate Renal transplantation Parathyroidectomy for refractory cases, 3° hyperparathyroidism, and pre-transplant Subtotal parathyroidectomy preferred over total with autotransplantation Management of 2° hyperparathyroidism in CRF

18. Primary localization procedure: “localize an experienced parathyroid surgeon” ? Controversial: routine use of preoperative localization studies (sestamibi scan), ultrasound, introperative gamma probe, and/or intraoperative rapid PTH assays Not controversial: preoperative localization in cases of –Persistent hyperparathyroidism –Recurrent hyperparathyroidism –Prior failed surgery –Redo neck Parathyroid Localization/Preoperative Localization

19. CT MRI Sestamibi Ultrasound ± FNA for PTH assay Selective venous sampling with assay for PTH General goal in reoperative setting: 2 studies which agree Preoperative Localization Methods

20. How Should Patients with Hyperparathyroidism be Selected for Surgical Treatment? Symptomatic Patient : Surgery What about the “asymptomatic” patient ?

21. 1990: NIH Consensus Development Conference on the Management of Asymptomatic Hyperparathyroidism –Sponsored by OMAR and NIDDK –Recommendations published in 1991 2002: NIH Workshop: Asymptomatic Primary Hyperparathyroidsm: A Perspective for the 21st Century –Sponsored by NIDDK, and a variety of co-sponsors –Evaluation of 1990 recommendations in light of newer data –Subgroup wrote a manuscript interpreting the results of the conference following the meeting Consensus Opinions

22. NIH Consensus Indications for Parathyroidectomy in Asymptomatic Patients Measurement1990 Guidelines2002 Guidelines Serum calcium (above ULN) 1-1.6 mg/dl1.0 mg/dl 24-hour urinary calcium>400 mgNot recommended Creatinine clearanceReduced by 30%Not recommended Serum creatinineNot recommendedIf abnormal Bone mineral densityZ-score < -2.0 (forearm) T-score < -2.5 at any site Age<50

23. Intraoperative Quick PTH assay GL Irvin et al: Am J Surg, 168:466, 1994.

24. Often asymptomatic Systemic symptoms: weakness, fatigability, headache, weight loss, depression, difficulty concentrating Clinical manifestations of hyperparathyroidism I: Stones, bones, abdominal groans, psychic and fatigue overtones

25. Surgical Benefits Biochemical normalization Sustained increase in bone density 27% of untreated, asymptomatic patients will develop worsening hypercalcemia and hypercalciuria NEJM 1999;341(17):1249-1255

26. ?? Neurospsychiatric Symptoms Both high and low calcium groups showed marked and virtually identical impairment of functional health status. Both groups showed marked improvement in health status at 2 months and additional improvement at 6 months, returning to normal or near normal in 6 of 8 SF-36 domains. Surgery 1999 Jun;125(6):608-14.

27. Fifty-three patients (42 female, 11 male) with asymptomatic, mild (serum calcium level, 10.1- 11.5 mg/dL) asymptomatic primary hyperparathyroidism were randomized into either a surgical group or an observation group. The mean calcium level was 10.31 mg/dL. Only demographic difference between groups was age, with the operative group being older (66.7 vs 62.6years; P <.03). (Surgery 2000;128:1013-21.)

28. Surgeons for the most part ignore the NIH guidelines The scores on 2 of the 9 domains of the SF-36 were significantly different (P <.007 and<.012, respectively); both favored the operative group. Surgery 2000:128: 1013-21

29. Conclusions Improved function is seen after parathyroidectomy when compared with patients who did not undergo operation. This study supports surgical management of mild primary hyperparathyroidism at the time of diagnosis because many patients have reversible non classic symptoms of the disease.

30. Primary hyperparathyroidism (pHPT) has been associated with premature death in cardiovascular diseases. Short-term results for normalization of cardiovascular derangements have been described after parathyroidectomy. Thirty consecutive patients with pHPT were reexamined 1 and 5 years after parathyroidectomy,together with 30 matched controls, with echocardiography and a bicycle exercise test. (Surgery 2005;137:632-8.)

31. The maximal blood pressure during exercise was higher before parathyroidectomy (median 223 [range, 200-268] mm Hgvs 202 [165-277] mm Hg, P<.05) but not 5 years after (230 [155-270] mm Hg vs 219 [165-252] mmHg. The ST-segment depression diminished from 1.4 (8.3-0) to 0.8 (3.3-0) mm 1 year afterparathyroidectomy and further to 0.1 (3.3-0.0) mm after 5 years but was unchanged in the control group. The number of ventricular extrasystolic beats at exercise testing in the pHPT group before parathyroidectomy was higher than in the control group (1 [0-340] vs 0 [0-3]). The isovolemicrelaxation time at rest was prolonged before parathyroidectomy (mean 100 ± 17 ms [SD] vs 89 ± 14 ms, P<.05).

32. Cardiovascular Effects ! Conclusion. Parathyroidectomy can induce long-lasting improvement in regulation of blood pressure, left ventricular diastolic function, cardiac irritability (ventricular extrasystolic beats), and other signs of myocardial ischemia, with potential implications for the postoperative life expectancy of patients withpHPT who have undergone parathyroidectomy.

33. Relative Contributions of Sestamibi Scanning, Intraoperative Gamma Probe Detection and the Rapid PTH Assay to the Surgical Management of Hyperparathyroidism Dackiw et al. Arch Surg. ;135:550-557.

34. Study Design Retrospective data base analysis to determine the specific contribution of these technologies Coordinated application of techniques studied in patients with HPTH

35. Patients and Methods 32 patients with hyperparathyroidism All patients had a sestamibi scan Intraoperative gamma probe detection –Successful = focal gamma activity in a parathyroid –Facilitated the operation = directed dissection or ex vivo identification allowed termination of operation Rapid intraoperative PTH assay –4 samples –50% drop indicative of clinical cure

36. Procedures Procedure –initial cervical exploration: 19 –reoperative procedure: 13 Directed operation: 24 –Unilateral neck: 22 –Sternotomy: 2 –9 patients done under local anesthesia Bilateral operation: 8

37. Dackiw, A. P. B. et al. Arch Surg 2000;135:550-557. Surgical treatment of 32 patients with hyperparathyroidism

38. Dackiw, A. P. B. et al. Arch Surg 2000;135:550-557. Results of technetium Tc 99m sestamibi scan and surgical procedure performed in 32 patients with hyperparathyroidism

39. Negative Sestamibi Scan

40. Ex-Vivo Gamma Probe Examination of Thymus

41. Retrospective Review of Pre- Op Sestamibi Scan

42. Rapid Parathyroid Hormone Assay Performed in 22/32 patients Performed in 15/15 patients with directed operations Successful in 15/15 patients 4/22 had an initial fall of rPTH <50% 3/4 had additional abnormal parathyroid tissue 1/4 had intraoperative rupture of parathyroid cyst Mean fall at 10 minutes: 78% (56-89.8%)

43. Rapid Parathyroid Hormone Assay: Case Report 1 MEN 1 s/p 2 cervical parathyroidectomies + autograft Sestamibi: uptake in neck and forearm Left neck parathyroid removed: rPTH 114  26 (77%) No debulking of autograft Normal iPTH, Ca, phos off supplementation at 3 months

44. Rapid Parathyroid Hormone Assay: Case Report 2 MEN 1 s/p 4-gland cervical parathyroidectomy, forearm and pectoralis autografts rPTH guided debulking of autografts Pectoralis autograft excised Forearm autograft debulked twice until rPTH 163  26 (84%) Asymptomatic, low dose Ca and vitamin D Normal iPTH, low-normal Ca, normal phos at 1 month

45. Rapid Parathyroid Hormone Assay: Case Report 3 Prior 3.5 gland resection; persistent hyperparathyroidism Localized to mediastinum; sternal split rPTH 125  88%) Forearm autograft and cryopreservation Brief period of postoperative hypoparathyroidism Normal iPTH, Ca, phos off supplements at 6 months

46. Summary When localizing, sestamibi scan was consistently helpful Combine with rPTH in performing anatomically directed operations Consider intraoperative gamma probe localization in selected patients even after a non-localizing sestamibi scan

47. Summary: rPTH assay Predicts clinical cure in minimally invasive surgery Indicates the need for bilateral exploration Predicts clinical cure in reoperative surgery Indicates the need for additional surgery in patients with parathyroid hyperplasia, including MEN 1 patients Can suggest the need for autografting and cryopreservation Gamma probe the least essential of the modalities evaluated

48. Dackiw, A. P. B. et al. Arch Surg 2000;135:550-557. Potential contributions of intraoperative gamma probe localization and the rapid parathyroid hormone (rPTH) assay to a reduction in the rate of failed parathyroid explorations