diagnosis and management of parathyroid disease

1. Diagnosis and Management of Parathyroid Disease Nino Zaya, MD December 1, 2005

3. CALCIUM HOMEOSTASIS AND PARATHYROID HORMONE SECRETION AND REGULATION Parathyroid hormone (PTH) contains 84 amino acids Degradation into amino(N) and carboxyl(C)-terminal fragments. The N-terminal fragment biologically active and rapidly cleared C-terminal fragment is biologically inert and cleared by the kidney

4. Continued�. PTH release governed by serum ionized calcium levels. PTH secreted in response to decrease in serum-ionized calcium and inhibited by an increase serum-ionized calcium. Target end organs: kidneys, skeletal system, and intestine. PTH binding to receptor sites results in cAMP 2nd messenger system activation. Half-life PTH few minutes.

5. Continued�.

6. Etiology and Pathogenesis of Hyperparathyroidism Parathyroid adenomas (PA) considered monoclonal or oligoclonal neoplasms. Propagation through clonal expansion of cells with altered sensitivity to calcium. PRAD1 implicated in only some PA. Another mechanism involves alternation in tumor suppressor gene expression.

7. Continued�.

8. Continued�.

9. Parathyroid Anatomy and Histopathology: The Normal Parathyroid Gland Supernumerary fifth parathyroid found between 0.7%-5.8% patients 5th glands found in the mediastinum (thymus or related to the aortic arch), thyrothymic tract

10. Parathyroid Gland Location 80% of superior parathyroid glands found at the cricothyroid junction ~1 cm cranial to juxtaposition of RLN & ITA. Inferior parathyroid glands (IPG) variable in location. 61% of (IPG) near the lower pole of the thyroid gland and 26% in thyrothymic ligament. Incidence of intrathyroidal parathyroid glands ~0.5% to 3%.

11. Embryology

12. Morphologic Characteristics of Parathyroid Glands Shape-oval, bean, or teardrop appearance or flat shape when juxtaposed to thyroid gland. Color-yellowish brown to reddish brown in normal parathyroid glands and lighter gray tone in pathological states.

13. Vascular Anatomy of the Parathyroid Glands Normal parathyroid glands most commonly are supplied by a single dominant artery (80%). The length of the dominant artery supplying glands vary from 1 to 40 mm. ITA is dominant blood supply to both superior & inferior parathyroid glands most of the time.

14. Histopathology of the Parathyroid Glands Parathyroid gland composed of chief cells, oxyphilic cells and intermediate cells Solitary parathyroid adenoma ~80%-85% of patients with primary hyperparathyroidism Variations in parathyroid adenoma includes other subtypes (oncocytic adenoma, lipoadenoma, large clear cell adenoma, water-clear cell adenoma, and atypical adenoma).

15. Continued�. Primary parathyroid hyperplasia-proliferation of parenchymal cells with increase in weight in multiple glands with absence of stimulus for parathyroid hormone secretion. Two types of parathyroid hyperplasia are seen: the common chief cell hyperplasia and the rare water cell or clear cell hyperplasia.

16. Continued�. Parathyroid carcinoma (PC) ~0.1% to 5.0% cases of primary hyperparathyroidism. PC tend to be large tumors, (30% to 50% palpable presentation). May measure up to 6 cm in diameter, mean ~3 cm. Lesion adheres to surrounding tissues including soft tissues of the neck (thyroid gland, strap muscles, trachea & recurrent laryngeal nerve). Regional metastasis rare. Pulmonary metastasis most common distant metastasis site.

17. Continued�. PC tends to be an indolent tumor. Multiple recurrences after resection common and may occur over a 15- to 20-year period. Death results from from effects of excessive PTH secretion and uncontrolled hypercalcemia rather than growth of the tumor mass.

18. Clinical features Primary Hyperparathyroidism (PH) Incidence 27 cases annually per 100,000 Prevalence PH general population 0.1%-0.3% Prevalence women >60 years more than 1%

19. CALCIUM HOMEOSTASIS AND PARATHYROID HORMONE SECRETION AND REGULATION

20. Continued�. Osteitis fibrosis cystica Nephrolithiasis Hypercalcemic crisis Osteitis fibrosis occurs ~1% of patients Renal stones ~10%-20% of patients have renal stones. Nonspecific symptoms: malaise, fatigue, depression, sleep disturbance, weight loss, abdominal pains, constipation, vague musculoskeletal pains in the extremities, and muscular weakness

21. Continued�. Kidney/Urinary Tract: 4% with nephrolithiasis and nephrocalcinosis (stone composition, calcium oxylate or calcium phosphate). Sx of urolithiasis: renal colic, hematuria, pyuria. Skeletal System: Osteitis fibrosis cystica (rare) Subperiosteal erosion of the distal phalanges Bone wasting and softening Chondrocalcinosis as a result of bone demineralization Bone pain Pathologic fracture Cystic bone changes Bone loss: cortical bone sites sparing trabecular bone

22. Continued�. Neuromuscular: Muscle weakness, (proximal extremity muscle groups with fatigue and malaise) Neuromuscular syndrome improves in 80%-90% of patients. Neurologic: Depression, nervousness, and cognitive dysfunction Deafness, dysphagia, and dysosmia Many psychiatric symptoms improve after parathyroidectomy. Fifty percent of patients with depression or anxiety, or both will improve after surgery.

23. Continued�. Cardiovascular Hypertension (50% of patients) Parathyroidectomy results in a reduction in BP in minority of patients. Hypercalcemic syndrome polydipsia and polyuria, anorexia, vomiting, constipation, muscle weakness and fatigue, mental status changes. Metastatic calcifications at the corneal/scleral junction, so-called band keratopathy Shortened Q-T interval on electrocardiogram, ectopic calcium deposits, and pruritus.

24. Continued�. Band Keratopathy

25. Continued�. Diagnosis: Elevated serum Ca Elevated PTH (suppressed in PTH-rp induced hypercalcemia) Other: Albumin Phosphorous BUN/Cr 24-hour urine Ca (r/o FHH) Bone Mineral Density

26. Localization Studies Noninvasive preoperative methods�� Ultrasonography� Radioiodine or technetium thyroid scan�� Thallium-technetium scintigraphy�� Technetium-99m sestamibi scintigraphy�� Computed tomography scan�� Magnetic resonance imaging Invasive preoperative methods�� Fine-needle aspiration�� Selective arteriography or digital subtraction angiography�� Selective venous sampling for parathyroid hormone assay� Arterial injection of selenium-ethionine Intraoperative Methods Intraoperative ultrasonography�� Toluidine blue or methylene blue�� Urinary adenosine monophosphate�� Quick parathyroid hormone intraoperative

27. Sestamibi-Technetium 99m Scintography Sestamibi taken up mitochondria of parathyroid cells greater than surrounding parenchyma. Inject 20 to 25 millicuries of technetium-99m sestamibi. Images obtained at 10-15 minutes then 2-3 hours after the injection. Late phase preferable for detecting parathyroid adenomas, as thyroid nodules clear uptake faster than do parathyroid neoplasms. Sensitivity (solitary adenoma) ~100%, Specificity ~90%. False-positive: Solid thyroid nodules (adenomas) Hurthle cell carcinoma Malignant thyroid lymph node metastases No false-positive with cystic lesions of the thyroid gland

28. Continued�. False-negatives Smaller parathyroid adenoma size. Suboptimal dosing of technetium-99m sestamibi.

29. Continued�. Four gland hyperplasia

30. Continued�. Double adenoma

31. Medical Management Intravascular volume expansion + loop diuretics (avoid thiazide diuretics) Bisphosphonates Calcitonin Plicamycin Estrogens therapy Oral phosphate salts Calcimimetic agents (investigational drug R-568)

32. Case 1 65 y.o. male with history of a left thyroid mass underwent, FNA atypical follicular lesion. Patient underwent L. thyroid lobectomy with final diagnosis of follicular adenoma. Patient had been noted in past to have asymptomatic hypercalcemia. PTH 126, 24-hour urine calcium 380mg, Ionized Ca 1.4

33. Continued�. Tc-99m Sestamibi suggested parathyroid adenoma in R inferior pole of thyroid gland.

34. Continued�. Patient taken to OR for MIRP using a Neoprobe.

35. Continued�. 664 mg right superior parathyroid gland identified PTH decreased from 126 to 15

36. Surgical Management Clinical indicators for surgery* Serum calcium is >1.0 mg/dL above the upper limit of normal. Creatinine clearance is reduced >30% for age in the absence of another cause. Twenty-four hour urinary calcium is >400 mg/dL. Patients are younger than 50 years of age. Bone mineral density measurement at the lumbar spine, hip, or distal radius is reduced >2.5 standard deviations (by T score). Patients request surgery, or patients are unsuitable for long-term surveillance.

37. Continued�. Adenoma Directed unilateral cervical exploration. Curative in >95% of patients Preoperative localization with technetium-99m sestamibi + IOPTH

38. Continued�. MEN 1 Subtotal vs. total with autotransplantation. Men 2a- 100% cure rate with no recurrences whether total parathyroidectomy, subtotal parathyroidectomy, or excision of enlarged glands performed. R/O pheochromocytoma prior to OR trip (hypertensive crisis).

39. Continued�. Non-MEN familial hyperparathyroidism (NMFH). Subtotal or total (autotransplant) with bilateral cervical thymectomy. Familial neonatal hyperparathyroidism. Total (autotransplant) + bilateral transcervical thymectomy

40. Continued�. Renal failure-induced hyperparathyroidism. Subtotal vs. total parathyroidectomy (autotransplant) with or without cryopreservation. Parathyroid Carcinoma en bloc resection of the tumor and areas of potential local invasion and/or regional metastasis (ipsilateral central neck contents including the thyroid lobe and tracheoesophageal soft tissues, lymphatics, and resection of soft tissues within the superior anterior mediastinum) RLN, esophageal wall, or strap muscles may require sacrifice if the tumor adheres to them. Not enough data to recommend for or against chemotherapy or RT.

41. Continued�. MIRP Preoperative administration of technetium 99m sestamibi before operation + intraoperative hand-held gamma probe. Advantages: Improved patient comfort postoperatively. Performance of ambulatory procedures. Reduced cost. Avoidance of general anesthetic. Disadvantages: Potential for conversion to bilateral dissection in event of failed exploration. Patient anxiety when conversion needed (general anesthesia).

42. Conclusion No substitute for strong foundation surgical embryology, anatomy, and technique for approaching parathyroid disease.

43. Bibliography Cummings Otolaryngology Head and Neck Surgery. 2005. Rosen F., Pou A., Parathyroid Disease. March 2002. UTMB site http://www.mrcophth.com/corneacommoncases/bk.html (Image-Band Keratopathy)