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Advances and Changing Trends in the Diagnosis and Treatment of HyperparathyroidismIstanbul: June 2, 2007
Alan Dackiw MD, PhD, BSc BSc (MED) FRCSC, FACSDivision of Endocrine and Oncologic SurgeryJohns Hopkins University School of MedicineBaltimore, Maryland, USA
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)
PTH Anatomy and Physiology
Parathyroid Embryology
Hyperparathyroidism
• Epidemiology/Diagnosis
• Localization
• Modern Operative Techniques
• Some Historical Vignettes
•Hypersecretion of PTH by parathyroid tissue•Etiology unclear; association with 11q13 mutations (MEN1), Cyclin D1
•Associated with neck irradiation
Primary Hyperparathyroidism
•Etiologies: CRF and osteomalacia•Long-term secondary hyperparathyroidism may result in autonomous parathyroid hyperfunction (tertiary hyperparathyroidism)
Secondary and tertiary hyperparathyroidism
•1:1000–from population-based prevalence studies–includes both hyperparathyroidism and FHH
Prevalence of hypercalcemia
•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
•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
• 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
Most Common Clinical Manifestation in 2007 !!
• Elevated Calcium on blood test
• Calcium added to routine electrolytes measured by autoanalyzer
• 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)2D intestinal Ca absorption
Laboratory evaluation I
• 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
•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
•Compensatory PTH hypersecretion• CRF, osteomalacia/rickets, intestinal malabsorption, Fanconi syndrome, renal tubular acidosis
• Etiology in CRF is multifactorial–hypocalcemia–hyperphosphatemia
–decreased 1,25(OH)2D
–decreased GI Ca absorption–decreased peripheral PTH sensitivity
Secondary hyperparathyroidism
• 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
• 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
•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
How Should Patients with Hyperparathyroidism be
Selected for Surgical Treatment?
• Symptomatic Patient : Surgery
• What about the “asymptomatic” patient ?
• 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
NIH Consensus Indications for Parathyroidectomy in Asymptomatic
PatientsMeasurement 1990 Guidelines 2002 Guidelines
Serum calcium (above ULN)
1-1.6 mg/dl 1.0 mg/dl
24-hour urinary calcium >400 mg Not recommended
Creatinine clearance Reduced by 30% Not recommended
Serum creatinine Not recommended If abnormal
Bone mineral density Z-score < -2.0 (forearm)
T-score < -2.5 at any site
Age <50 <50
Intraoperative Quick PTH assay
GL Irvin et al: Am J Surg, 168:466, 1994.
•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
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
?? 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.
• 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.)
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
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.
• 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.)
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).
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.
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.
Study Design
• Retrospective data base analysis to determine the specific contribution of these technologies
• Coordinated application of techniques studied in patients with HPTH
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
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
Dackiw, A. P. B. et al. Arch Surg 2000;135:550-557.
Surgical treatment of 32 patients with hyperparathyroidism
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
Negative Sestamibi Scan
Ex-Vivo Gamma Probe Examination of Thymus
Retrospective Review of Pre-Op Sestamibi Scan
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%)
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
11426 (77%)• No debulking of autograft• Normal iPTH, Ca, phos off supplementation
at 3 months
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
16326 (84%)• Asymptomatic, low dose Ca and vitamin D• Normal iPTH, low-normal Ca, normal phos at
1 month
Rapid Parathyroid Hormone Assay: Case
Report 3• Prior 3.5 gland resection; persistent
hyperparathyroidism• Localized to mediastinum; sternal split• rPTH 125<15 (>88%)• Forearm autograft and cryopreservation• Brief period of postoperative
hypoparathyroidism• Normal iPTH, Ca, phos off supplements at 6
months
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
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
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