Challenges in the Management of Primary HPTH. Zaher Ajam, MD Ghada El-Hajj Fuleihan, MD, MPH

Transcription

1 Challenges in the Management of Primary HPTH Zaher Ajam, MD Ghada El-Hajj Fuleihan, MD, MPH

2 Case Presentation 1 This a case of a 41-year-old gentleman who is referred to Endocrinology clinic for low BMD, hx of ribs fx, and hx of kidney stones; his last extracted stone was in His PTH levels have fluctuated between 44 and 85 pg/ml; his ionized Ca has been normal; normal total Ca with highest value being 10.6mg/dl(at 13/1/2006); normal bone markers; hx of low 25(OH)vitamin D that was corrected by sterogyl; no family hx of hypercalcemia; no intake of meds that raise Ca BMD has been stable throughout the visits. Last BMD results were done at both 20/8/2009 and 20/10/2009 at AUBMC and they showed the following: AP(L1-L4) of Z-score=-2.2; Forearm (1/3 radius) of Z-score=-2.1; Total hip Z-score=-1.6; Femoral Neck Z-score=-1.5 He s s/p lithotripsy at Summer 2007; his most recent U/S shows possible tiny echogenicities bilaterally

3 Case Presentation 1 Our patient is feeling well in his last visit, except for tiredeness and reported diastolic hypertension with stress and he has been off tritace lately. He has also borderline dyslipidemia which is treated by Zocor 5mg OD; hx of premature ejaculation which was treated by Effexor Family Hx: HTN,CAD, low BMD in a cousin who had multiple fractures, hip fx in his grandmother PMH: Borderline HTN, Borderline DL, Non Diabetic, No Connective Tissue Disease Non smoker; No chronic alcohol intake; No chronic steroids intake; Estimated Ca intake is 500mg/day; Exercises 3 times weekly as walking alternating with running

4 Case Presentation 1 Medications: Zocor 5 mg OD; Ci-calD 2 tbs daily Physical Exam (last visit): Height:171cm Weight:71.5kg and it s unchanged Bld Pr: 140/80 Pulse: 88 Last labs (done in Sept. and Dec. 2009): 25(OH)vitaminD=41.20ng/ml Ca=9.5mg/dl; Phosphate=2.3mg/dl Creat. =1.0mg/dl Ionized Ca=1.32mmol/l ( ) PTH=85.80pg/ml (8-76)

5 Case Presentation 1 Bone Markers (done in June 2007) Osteocalcin=19.40ng/ml ( ) Crosslaps=263pg/ml (16-584) 24-hr urine collection and other labs (done in March 2007) 24-hr urine calcium=201.7mg/24hr (0-300) Urine volume=1540ml 24-hr urine creat.=1.53g/24hr (0.60-2) Creat.=1mg/dl Ca=9.9mg/dl Ca/Cr Cl=UCa*SCr/SCa*UCr=0.0133

6 Case Presentation 1 Patient s Mom labs (done in April 2010): 25(OH)vitaminD=14.40ng/ml Ca=9.3mg/dl; Phosphate=3.3mg/dl Ionized Ca=1.37mmol ( ) Creat.=0.8mg/dl PTH=80.20pg/ml Patient s Brother labs (done in April 2010): 25(OH)vitaminD=11.20ng/ml Ca=9.3mg/dl; Phosphate=3mg/dl Ionized Ca=1.38mmol/l Creat.=0.8mg/dl PTH=113pg/ml

7 Case Presentation 1 Patient s Sister labs (done in April 2010): Ca=9.4mg/dl; Phosphate=3.8mg/dl Ionized Ca=1.39mmol/l Creat.=0.6mg/dl PTH=62pg/ml Patient s Dad labs (done in April 2010) Ca=9.3mg/dl; Phosphate=2.6mg/dl Ionized Ca=1.32mmol/l Creat.=0.8mg/dl PTH=52.10pg/ml

8 Introduction Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting. Most persons with this condition are asymptomatic. However, recognition of primary hyperparathyroidism has increased dramatically since the introduction of multichannel autoanalyzers in the 1970s. The disorder can occur in persons of any age but is more common in persons older than 50 years. In the United States, its estimated incidence in persons older than 65 years is one case per 1,000 in men and two to three cases per 1,000 in women. Am Fam Physician 2004;69:333-9,340

9 Introduction In patients with asymptomatic primary hyperparathyroidism, the serum calcium concentration is elevated, but usually only to within 1 mg per deciliter above the upper limit of normal (10.2 mg per deciliter). The parathyroid hormone level, measured by means of immunoradiometric assay, is usually 1.5 to 2.0 times the upper limit of normal (65 pg per milliliter), although it may be inappropriately normal. Hypophosphatemia and hyperchloremia, which were common among patients with symptomatic disease, are uncommon among patients with asymptomatic disease. The 24-hour urinary calcium excretion tends to be near the upper limit of normal. N Engl J Med 2004;350:

10 Introduction Although radiography almost never shows skeletal involvement, bone densitometry typically does. As measured on dual-energy x-ray absorptiometry, the greatest reduction in bone density is at the distal third of the radius, a site composed predominantly of cortical bone that is vulnerable to the catabolic actions of parathyroid hormone. The hip and the lumbar spine, sites where bone becomes progressively more cancellous, show smaller reductions. Approximately 20 percent of patients are symptomatic, with kidney stones, overt bone disease, or proximal neuromuscular weakness. Some patients do report weakness, easy fatigability, intellectual weariness, and even depression. These symptoms are nonspecific and are hard to attribute to primary hyperparathyroidism. N Engl J Med 2004;350:

11 Introduction A less common presentation of asymptomatic primary hyperparathyroidism is characterized by a normal serum calcium level but an elevated parathyroid hormone level. This condition is typically identified during an evaluation of skeletal health. The diagnosis is made when there is no apparent cause of secondary elevations of the parathyroid hormone level and the serum 25- hydroxyvitamin D level is not below the lower limit of the physiologically normal range (i.e., is above 20 ng per milliliter). This normocalcemic variant may represent the earliest manifestation of primary hyperparathyroidism. N Engl J Med 2004;350:

12 Etiology and Pathogenesis Primary Hyperparathyroidism Primary hyperparathyroidism is caused by the inappropriate secretion of PTH, which results in hypercalcemia. The condition usually occurs sporadically, although familial forms are well recognized. In 85 percent of patients with primary hyperparathyroidism, the underlying cause is an adenoma in a single parathyroid gland. Hypertrophy of all four parathyroid glands and multiple adenomas within the parathyroid glands account for the remainder of cases. Am Fam Physician 2004;69:333-9,340

13 Etiology and Pathogenesis Fewer than 0.5 percent of cases are caused by parathyroid malignancies. Most patients with primary hyperparathyroidism are postmenopausal women. The incidence of the condition increases with age, and the average age at diagnosis is 55 years. A small percentage of patients presents years after external neck irradiation. In 10 to 20 percent of patients, primary hyperparathyroidism is caused by an inherited hyperfunction of multiple parathyroid glands.these patients tend to be diagnosed at a younger age. Am Fam Physician 2004;69:333-9,340

14 Etiology and Pathogenesis Although rare, familial disorders should be considered in patients diagnosed with primary hyperparathyroidism. With several of these familial disorders, patients should be evaluated for significant associated abnormalities. Familial forms of primary hyperparathyroidism include multiple endocrine neoplasia type I and type II, neonatal severe primary hyperparathyroidism, hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, and familial isolated hyperparathyroidism. Am Fam Physician 2004;69:333-9,340

15 Etiology and Pathogenesis MEN1 and MEN2A occur due to germline mutations of MEN1 and RET, respectively (Marx, Nature Reviews. Cancer 2005). FHH cases result mostly from a mutation of the calcium-sensing receptor gene (CASR) (Brown, Physiological Reviews 2001).

16 Etiology and Pathogenesis FIHP is estimated to have a frequency of approximately 1% among all primary hyperparathyroidism (HPT) (Simonds WF, Medicine Baltimore 2002). Studies have shown that patients with familial isolated hyperparathyroidism actually constitute a heterogenous group of disease, both clinically and genetically (J.D.Chen, Journal of Internal Medicine 2003).

17 Etiology and Pathogenesis In 1998, two FIHP families with solitary adenoma were mapped to the same region as the HPT-JT syndrome on chromosome 1q21-q32 (Teh BT, JCEM 1998). These patients were followed-up for many years but had no evidence of any other types of tumours (J.D.Chen, Journal of Internal Medicine 2003). These patients presented also with profound hypercalcaemia or hypercalcaemic crisis even though nobody developed malignancy (J.D.Chen, Journal of Internal Medicine 2003). A mutation was detected in the HPT-JT gene in one of the patients confirming that they were allelic to the HPT-JT syndrome (Carpten JD, Nature Genet 2002).

18 Etiology and Pathogenesis Hyperparathyroidism jaw tumour (HPT-JT) syndrome was first documented by Jackson in 1958 (Jackson CE, Ann Intern Med 1958). HPT-JT syndrome is an autosomal dominant disorder with incomplete penetrance and variable expression and is characterized by multiple parathyroid tumours, with a relatively high prevalence of carcinomas and atypical adenomas, ossifying fibromas of mandible and/or maxilla, and less frequently, a variety of renal lesions and uterine tumours (Carpten JD, Nat Genet 2002, Jackson CE, Surgery 1990). There is a reduced penetrance in females (Teh BT, JCEM 1996). Hyperparathyroidism occurs in about 80% of patients, and parathyroid carcinoma occurs in about 10-15% of affected individuals (Carpten JD, Nat Genet 2002).

19 Journal of Internal Medicine 2005; 257: 27 37

20 Journal of Internal Medicine 2005; 257: 27 37

21 Clinical Manifestations A National Institutes of Health (NIH) consensus panel classified primary hyperparathyroidism into two categories: symptomatic and asymptomatic. Manifestations of symptomatic primary hyperparathyroidism secondary to hypercalcemia include overt bone disease; kidney stones; and nonspecific gastrointestinal, cardiovascular, and neuromuscular dysfunction. Asymptomatic primary hyperparathyroidism accounts for 75 to 80 percent of cases. Am Fam Physician 2004;69:333-9,340

22 Clinical Manifestations Patients in this category have no signs or symptoms of hypercalcemia. Signs and symptoms that may be present but are not clearly associated with primary hyperparathyroidism include: hypertension, left ventricular hypertrophy valvular or myocardial calcification, peptic ulcer disease pancreatitis, gout or pseudogout, normocytic normochromic anemia weakness, easy fatigability, lassitude, anxiety cognitive difficulties, somatic complaints, clinical depression Am Fam Physician 2004;69:333-9,340

23 Differential Diagnosis Familial hypocalciuric hypercalcemia FHH is due to an inactivating mutation in the calcium-sensing receptor in both parathyroid glands and kidneys (El-Hajj Fuleihan, J Bone Miner Res 2002). A family history of hypercalcemia and absence of symptoms and signs of hypercalcemia are characteristic of this disorder. The major feature that distinguishes FHH from PHPT is a low urine calcium excretion and Ca/Cr clearance ratio. FHH is therefore a benign inherited condition that does not require parathyroidectomy.

24 Differential Diagnosis Drugs Thiazide diuretics reduce urinary calcium excretion and so they cause mild hypercalcemia (up to 11.5 mg/dl). If a patient taking a thiazide is found to be hypercalcemic, the drug should then be withdrawn, and Ca and PTH will then be assessed 2 to 3 months later. Lithium enhances PTH secretion by shifting the calcium-pth curve to the right and reduces urinary calcium excretion. Hypercalcemia may resolve if lithium can be stopped without exacerbating the psychiatric condition.

25 Differential Diagnosis Normocalcemic primary hyperparathyroidism It might be expected that early in the natural history of PHPT, elevated PTH levels would precede the development of overt hypercalcemia. The serum calcium concentration in these patients would be expected to rise above the upper limit of normal when followed over time.

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27 Context PHPT commonly presents as a disorder of mild, asymptomatic hypercalcemia in which biochemical indices and bone mineral density (BMD) remain stable over time in most patients. Because both hypercalcemia and the typical pattern on bone densitometry are generally present at the time the diagnosis is made, it has been hypothesized that PHPT has a biphasic disease course. During the first phase, when the PTH concentration is initially elevated in the circulation, hypercalcemia is not yet present. J Clin Endocrinol Metab 92: , 2007

28 Context The elevated PTH concentration in this early phase is postulated to cause reduced cortical bone density. The second phase of PHPT, the clinically apparent presentation, is defined by the development of hypercalcemia. The natural history of PHPT in most patients is consistent with this theoretical construct, in that progression of the disease after the diagnosis is made is seen in only a minority of patients. J Clin Endocrinol Metab 92: , 2007

29 Context Patients with elevated PTH and consistently normal serum calcium levels may represent the earliest presentation of primary hyperparathyroidism (PHPT). To note, secondary causes of hyperparathyroidism should be excluded first in this population of patients. In this report, researchers document their growing experience with normocalcemic PHPT, an experience that has led to new hypotheses about the nature and significance of this clinical finding. J Clin Endocrinol Metab 92: , 2007

30 Objective The objective of the study was to characterize patients with normocalcemic PHPT referred to a bone disease unit. J Clin Endocrinol Metab 92: , 2007

31 Design and study subjects This was a longitudinal cohort study. Ambulatory patients were referred to the metabolic bone disease unit. The study population included 37 patients [aged 58 yr, range 32 78; 95% female; serum calcium, 9.4 +/- 0.1 (SEM) mg/dl, reference range, ; PTH, 93+/-5 pg/ml] J Clin Endocrinol Metab 92: , 2007

32 Interventions and Main Outcome Measures Interventions included yearly (median 3 yr; range 1 8 yr) physical examination, biochemical indices, and bone mineral density (BMD). They measured the development of features of PHPT. J Clin Endocrinol Metab 92: , 2007

33 Results Evaluation for classical features of PHPT revealed a history of kidney stones in five (14%), fragility fractures in four (11%), and osteoporosis in 57% [spine (34%), hip (38%), and/or distal one third radius (28%)]. BMD did not show preferential bone loss at the distal one third radius (T scores: spine,-2.00+/-0.25; hip,-1.84+/-0.18; one third radius, /-0.22). J Clin Endocrinol Metab 92: , 2007

34 Results Further signs of PHPT developed in 40% (seven hypercalcemia; one kidney stone; one fracture; two marked hypercalciuria; six had>10% BMD loss at one or more site(s) including four patients developing World Health Organization criteria for osteoporosis). Seven patients (three hypercalcemic, four persistently normocalcemic) underwent successful parathyroidectomy. J Clin Endocrinol Metab 92: , 2007

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39 Discussion In this report, they describe the clinical course of 37 patients with normocalcemic PHPT who were followed for up to 8 yr (median 3.0). Their diagnostic criteria excluded those with elevated serum or urinary calcium levels (the latter because they could lead to a secondary rise in PTH concentration). They did not find these patients to have the clinical phenotype typical of mild asymptomatic PHPT. Confirming their preliminary observations, they also did not find evidence of preferential cortical bone loss by BMD. J Clin Endocrinol Metab 92: , 2007

40 Discussion Indeed, the only finding suggestive of typical mild PHPT was an elevated 1,25-dihydroxyvitamin D concentration in 24% of patients. Instead the majority of patients had clinical features of classical PHPT: nephrolithiasis (14%), osteoporosis (57%), and/or fragility fracture (11%). Although many were initially discovered as part of an evaluation for low bone density, some did develop further features of PHPT during the course of follow-up (hypercalcemia in 19%, marked hypercalciuria in 5%, or progressive cortical bone loss in 29%). Progressive bone loss in these patients was not confined to the more highly cortical distal radius, instead occurring at all sites. J Clin Endocrinol Metab 92: , 2007

41 Conclusion Patients seen in a referral center with normocalcemic hyperparathyroidism have more substantial skeletal involvement than is typical in PHPT. They also develop more features and complications over time. These patients may represent the earliest form of symptomatic, rather than asymptomatic, PHPT. J Clin Endocrinol Metab 92: , 2007

42 Case Presentation 2 This is a case of a 62-year-old lady who visited the Endocrinology clinic few years ago for further assessment concerning her persistent hyperparathyroidism. She s also known to have DCIS s/p surgery at 2007 and s/p XRT 21 sessions and is currently on Tamoxifen daily; she s hypertensive and dyslipedemic and both are controlled by treatment; she has nodular thyroid; she has also superficial varices She underwent parathyroidectomy at USA in 2001 after she was diagnosed biochemically to be hyperparathyroid and after the sestamibi scan revealed a left parathyroid adenoma. Her PTH has been persistently inappropriately elevated between 70 and 100 pg/ ml for a Ca level of 10mg/dl to 10.2mg/dl and a normal 24-hr urinary Ca. Her U/ S in 2006 showed no kidney stones and her ionized Ca had been borderline elevated. She s currently on Actonel 1 tb PO per week, on Caltrate 1 tb PO daily, and on Vitamin D 5000IU/tb/day.

43 Case Presentation 2 She was FU at Johns Hopkins for Breast Ca and was advised to do parathyroidectomey because she did labs at AUBMC at Jan.2010 that revealed a Ca of 10.4mg/dl and Ionized Ca of 1.41mmol/l; BMD (done in Dec.2009) showed at the femoral neck a T-score=-3.1, so there is about -11.1% BMD change with previous one In her last visit, her Ca was 10mg/dl and her PTH was 66pg/ml; 24-hr urine calcium was not elevated; 25(OH)vitaminD was 21 ng/ml; Ionized Ca=1.41mmol/l Bone markers (done at AUBMC in Jan.2009):Alkaline Phosphatase=40 IU/l; Osteocalcin=12.50 ng/ml (8-55.9); Crosslaps=123 pg/ml ( ) Re-evaluation at AUBMC in March 2010 revealed her BMD was stable and it revealed a T-score of -1.3 at the forearm, and a T-score of -3.1 at the total hip.the BMD showed a 14% increase at the total hip compared to 2001 and 12% increase compared to 2000, but BMD of her femoral neck has decreased substantially probably due to rotation changes?; BMD of her spine increased by 4 to 6% on the same machine.

44 Case Presentation 2 The patient s last U/S of her thyroid revealed a small right parathyroid adenoma and multinodular thyroid with nodules of different dimensions such as: cm, cm, cm She underwent FNA under U/S guidance for left inferior nodule that turned to be pathologically an adenomatoid nodule with cystic degeneration. She underwent also FNA under U/S guidance for right middle nodule that turned to be pathologically an adenomatoid nodule. In her last visit, she was feeling well with no major complaints and she has come for re-assessment of her persistent hyperparathyroidism.

45 Case Presentation 2 Family History: Patient s Mom has hx of multiple fractures; positive family history of HTN; strong family history of nodular thyroid disease PMH: Primary Hyperparathyroidism; HTN; DL; DCIS at 2007 s/p Breast surgery and s/p XRT 21 sessions; Endometrial hyperplasia; Nodular thyroid PSH: Left parathyroid adenoma resection; Breast surgery Medications: Amlor 5mg PO Bid; Capoten 25mg PO Bid; Actonel 1 tb PO weekly; Caltrate 1 tb PO daily; Lipitor 10mg PO daily; Vitamin D 5000IU/ tb/day; Tamoxifen daily

46 Case Presentation 2 Physical Exam: Height=162cm and is unchanged Weight=65.5kg and is up by 1.5kg Bld.Pr=135/80 Pulse=92 Thyroid=presence of scar but no palpable nodules are felt Breast=normal

47 Elevated PTH after Parathyroidectomy In the surgical literature, a significant number of patients are reported to exhibit a normal calcium concentration but a PTH concentration elevated above the reference range as long as 15 years after parathyroidectomy. However, the clinical significance of an elevated postoperative PTH concentration in the setting of a normal calcium level is unclear. Endocr Pract. 2010;16:

48 Elevated PTH after Parathyroidectomy Prevalence of postoperative normocalcemic PTH elevation. Surgeons who use intraoperative PTH measurements look for a greater than 50% decrease in the PTH concentration from the baseline preoperative level. So, a decrease in the PTH level into the defined reference range is the evidence of successful parathyroidectomy. Despite an intraoperative PTH concentration meeting these parameters, 9% to 62% of patients later exhibit normocalcemic PTH elevation anywhere from 1 week to 5 years after surgery. Endocr Pract. 2010;16:

49 Elevated PTH after Parathyroidectomy Most investigators who followed up the patients during the late postoperative period (beyond 6 months) reported that the percentage of patients with PTH elevation later decreased as the time from surgery increased. Interestingly, patients who exhibited elevated PTH in the early postoperative period were not necessarily the same as those who had PTH elevation much later after surgery. Endocr Pract. 2010;16:

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51 Elevated PTH after Parathyroidectomy Predictors of postoperative normocalcemic PTH elevation All of the studies demonstrated a higher preoperative PTH concentration in patients with postoperative PTH elevation. In accordance with this finding, Bergenfelz et al showed that the preoperative PTH level correlated with the postoperative PTH level at 1 year (r = 0.36; P<.01). Endocr Pract. 2010;16:

52 Elevated PTH after Parathyroidectomy Other studies also demonstrated higher preoperative calcium concentrations and larger adenomas in patients with postoperative PTH elevation. Some studies showed evidence of more severe bone disease in patients with postoperative PTH elevation. This was demonstrated by lower preoperative 25- hydroxyvitamin D and higher alkaline phosphatase, osteocalcin, and propeptide of type 1 collagen. A strong correlation was seen between the preoperative osteocalcin level and the postoperative PTH concentration measured at 1 year (r = 0.53; P<.001) in the study by Bergenfelz et al. Endocr Pract. 2010;16:

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54 Elevated PTH after Parathyroidectomy Potential mechanism for postoperative PTH elevation Several authors have demonstrated impaired renal responsiveness to PTH. Yamashita et al showed impaired urinary cyclic adenosine monophosphate production before surgery in patients with higher preoperative PTH and lower 25-hydroxyvitamin D levels. What he revealed implies that these patients go into surgery with an underlying resistance to PTH action. Endocr Pract. 2010;16:

55 Elevated PTH after Parathyroidectomy Lower 1,25-dihydroxyvitamin D levels were seen in patients with elevated PTH 6 weeks after surgery than in those with normal PTH despite similar 25- hydroxyvitamin D levels. In addition, the 1,25-dihydroxyvitamin D to PTH ratio was significantly lower in those with elevated PTH than in those with normal PTH. These findings are the opposite of the expected increased production of 1,25-dihydroxyvitamin D in the setting of increased PTH. Endocr Pract. 2010;16:

56 Elevated PTH after Parathyroidectomy In contrast, Westerdahl reported no difference in suppression of PTH in response to an oral calcium load in patients with or without elevated postoperative PTH, suggesting normal parathyroid gland responsiveness to calcium feedback. So, these study findings suggest impaired responsiveness to PTH possibly due to PTH receptor down-regulation in patients with higher preoperative PTH concentrations. When the PTH levels decrease immediately after parathyroidectomy, decreased responsiveness to the lower circulating PTH leads to development of secondary hyperparathyroidism several weeks after surgical resection. Endocr Pract. 2010;16:

57 Elevated PTH after Parathyroidectomy Another potential mechanism for postoperative normocalcemic PTH elevation is vitamin D deficiency and metabolic bone disease. Beyer et al prospectively studied the impact of vitamin D deficiency on postoperative PTH levels in patients undergoing parathyroidectomy. Patients with 25-hydroxyvitamin D levels less than 20 ng/ml had more severe disease as demonstrated by: significantly higher preoperative serum calcium concentrations (11.3 mg/dl vs 10.8 mg/ dl) higher PTH concentrations (204 pg/ml vs 156 pg/ml) larger adenomas than in those with 25-hydroxyvitamin D levels greater than 20 ng/ml. Patients with vitamin D deficiency had also higher preoperative alkaline phosphatase levels and were more likely to exhibit postoperative normocalcemic PTH elevation. Endocr Pract. 2010;16:

58 Elevated PTH after Parathyroidectomy Mandel and Udelsman prospectively followed the clinical course of patients undergoing parathyroidectomy. Twelve percent of the patients had normocalcemic PTH elevation 1 week after surgery. The patients with elevated PTH demonstrated a decrease in serum calcium from postoperative day 1 to day 7. Whereas, patients with normal postoperative PTH had stable calcium levels. The authors proposed that these findings were evidence of bone hunger causing increased PTH secretion. This is a reasonable hypothesis because patients with postoperative normocalcemic PTH elevation have evidence of more severe bone disease. Endocr Pract. 2010;16:

59 Elevated PTH after Parathyroidectomy Long-term implications of postoperative PTH elevation Normocalcemic PTH elevation after parathyroidectomy commonly occurs. However, whether the postoperative PTH level predicts future recurrence of primary hyperparathyroidism is not clear. Yen et al evaluated the positive predictive value of a normal PTH level at 1 week, 3 months, and 6 months to predict operative cure (defined as normocalcemia) and found excellent correlation of 97.1%, 97.3%, and 96.5%, respectively. Endocr Pract. 2010;16:

60 Elevated PTH after Parathyroidectomy This suggests that a normal PTH concentration at any of these time points is highly predictive of cure. These investigators also explored whether the converse was true whether an elevated PTH concentration at these time points predicts operative failure. They reported negative predictive values of 13.7%, 14.3%, and 14% at 1 week, 3 months, and 6 months after surgery, suggesting that an elevated postoperative PTH concentration does not predict surgical failure as measured by recurrent hypercalcemia. Endocr Pract. 2010;16:

61 Elevated PTH after Parathyroidectomy Prevention or treatment of postoperative PTH elevation Several studies have identified a low preoperative 25-hydroxyvitamin D concentration as a risk factor for postoperative PTH elevation. In light of these findings, Beyer et al evaluated whether postoperative vitamin D supplementation would prevent postoperative PTH elevation. They evaluated the postoperative course in patients undergoing parathyroidectomy at 2 different institutions with different postoperative management. After surgery, one institution routinely treated patients with calcium carbonate, 2 to 3 g daily, and calcitriol, 0.25 mcg daily. At the other institution, patients received oral calcium carbonate at the discretion of the surgeon, but were never treated with calcitriol. Endocr Pract. 2010;16:

62 Elevated PTH after Parathyroidectomy At the first follow-up visit less than 30 days after surgery, the number of patients with PTH elevation was similar in both groups. However by the 4- to 6-month follow-up visit, a significantly greater number of patients treated only with calcium exhibited PTH elevation than those receiving both calcium and vitamin D treatment (43% vs 13%). In another study, Carty et al prospectively followed the clinical course of 380 patients after parathyroidectomy. Endocr Pract. 2010;16:

63 Elevated PTH after Parathyroidectomy Patients with PTH elevation at 5 months were instructed to take calcium supplements (calcium carbonate, 1 g twice daily). They reported an increased time to normalization of PTH in patients who: never took postoperative calcium supplementation than in those who started calcium supplementation 5 months or more after surgery began calcium supplementation immediately after surgery (781 days, 484 days, and 347 days, respectively) Endocr Pract. 2010;16:

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65 Elevated PTH after Parathyroidectomy Conclusion PTH elevation in the setting of a normal serum calcium concentration commonly occurs after parathyroidectomy to treat primary hyperparathyroidism. Risk factors include vitamin D deficiency; higher concentrations of preoperative calcium, PTH, and bone markers; and larger adenomas. However, no current evidence suggests that postoperative PTH elevation is predictive of surgical failure leading to recurrent hypercalcemia. Endocr Pract. 2010;16:

66 Elevated PTH after Parathyroidectomy Some authors have suggested postoperative PTH elevation is due to impaired renal responsiveness as a result of receptor down-regulation. Still others suggest hungry bone due to more severe underlying bone disease leading to secondary hyperparathyroidism as the bone disease improves. Endocr Pract. 2010;16:

67 Elevated PTH after Parathyroidectomy Finally, 2 studies suggest that postoperative supplementation with calcium and/or vitamin D may decrease the risk for postoperative PTH elevation. However, further evaluation of the mechanism for prolonged PTH elevation after parathyroidectomy is needed to better understand this phenomenon. Possible explanations for PTH elevation that have not been studied include the presence of other PTH fragments such as PTH 7-84 that may be contributing to the postoperative PTH levels and potential calcium malabsorption in the postoperative setting. Endocr Pract. 2010;16:

68 Elevated PTH after Parathyroidectomy In addition, the effect of anesthesia on PTH levels has not been evaluated. Because postoperative PTH elevation does not predict recurrent hypercalcemia, the postoperative calcium level is the best indication of surgical success. The PTH level can be used as a measure of adequate calcium and vitamin D intake. For long-term bone health after parathyroidectomy, all patients should be instructed to maintain adequate calcium and vitamin D intake to ensure normal 25-hydroxyvitamin D levels. Endocr Pract. 2010;16:

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70 Preoperative Localization for Recurrent or Persistent HPT Five to 10 percent of patients undergoing surgery for hyperparathyroidism have persistent disease. In such cases, the diagnosis of primary hyperparathyroidism should be confirmed and indications for surgery reevaluated. This type of surgery should be done by a surgeon who has experience with previously treated patients, preferably at a referral center. Even in such centers, preoperative localization is required for those undergoing repeat surgery. The preoperative evaluation is different in patients with recurrent or persistent hyperparathyroidism because of the differences in adenoma location and in surgical morbidity due to fibrosis as compared with unoperated patients.

71 Preoperative Localization for Recurrent or Persistent HPT In several studies, the abnormal parathyroid glands were found at the second operation in the following sites: 30 to 54 percent were in the neck 16 to 34 percent were in the mediastinum 14 to 39 percent were retroesophageal 5 percent were in the aortic arch area 8 percent were in the upper cervical area A few were in the carotid sheath

72 Preoperative Localization for Recurrent or Persistent HPT The success rate of reoperative surgery without preoperative localization is only 60 percent; this can be improved to 95 percent or more with localization. Localization studies identifying a single adenoma do not exclude the existence of abnormal parathyroid glands in other locations. Almost 30 percent of patients undergoing reoperation have multiple gland hyperplasia.

73 Preoperative Localization for Recurrent or Persistent HPT Sestamibi scans detected 67 to 77 percent of the adenomas in 2 large studies with few false positives. The other noninvasive procedures detected slightly fewer adenomas in one series but 15 to 20 percent fewer in the other. Other localization tests that can be used if initial imaging tests are equivocal include fine needle aspiration (FNA) for PTH assay (guided by ultrasound or CT). It is used to confirm that the suspicious lesion is parathyroid tissue. Selective arterial or venous angiography can be considered as an option.

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76 Thank You!