indications for surgery in primary hyperparathyroidism for...indications for surgery for...

Indications for surgery for asymptomatic primary

hyperparathyroidism Johanna Basa M.D.

Richmond University Medical Center SUNY Downstate affiliate

April 24, 2014

www.downstatesurgery.org

Goals Describe pathophysiology of primary

hyperparathyroidism (PHPT) Describe the symptoms of PHPT If a patient has asymptomatic PHPT when should they

be referred to surgery? Role of localization studies for focused parathyroid

surgery Should intraoperative parathyroid hormone assay

measurement be routinely used in parathyroidectomy?


Case 66 year old male with PMH of HTN, DM,

developmental delay (lives in nursing home), BPH and severe osteopenia had presented with elevated Ca and PTH.

No PSH PE Non verbal thin, frail, elderly gentleman with poor

dentition Pectus Carinatum Otherwise normal physical exam


Case Ca 10.9 PTH 123 Normal Vitamin D level (not provided in medical chart) CT scan showed 1 cm mediastinal mass Sestimibi showed 9mm foci in anterior mediastinum.


Case He underwent left VATs resection of anterior mediastinal

mass

Preoperative PTH 129, no access to intraoperative PTH level testing

Frozen section showed parathyroid tissue

Final pathology: parathyroid gland 1.2cm

POD#2 sent home, PTH 17



Presenter

Presentation Notes

Arise from endoderm in cranial portions of third and fourth pharyngeal pouches. Pouches are bilateral, yielding four parathyroids Cranial third pouches form inferior parathyroids and cranial fourth pouches forms superior parathyroids. Because of complex migration, position and even number of (especially inferior) parathyroid glands can be highly variable. During embryological development, the third pouch migrates downwards, dragging the inferior glands with it. The superior pair are not dragged downwards by the fourth pouch to the same degree. Consequently, the inferior glands develop in a position above the superior glands, but their positions are ultimately reversed. The glands are named after their final, not embryological, positions


Presenter

Presentation Notes

). Inferior glands are typically within 1 cm of the inferior pole of the thyroid. Other important locations for inferior glands include the cervical thymus (22%) and intimate with the thyroid capsule (17%). By contrast, superior glands arise from the fourth pharyngeal pouch and remain close to the posterior mid thyroid in a plane posterior to the RLN. With this more limited migration, there is less variability in the location of the superior compared with the inferior parathyroid glands. The majority of superior parathyroid glands (85%) are within a 2-cm diameter area centered 1 cm above the intersection of the inferior thyroid artery and RLN. Superior glands may extend posterior and caudal to the inferior thyroid artery deep in the tracheoesophageal groove. It is important to carry the surgical dissection back to the prevertebral fascia to identify superior glands that can be posteriorly situated in the paraesophageal and retroesophageal position. Approximately 3% of ectopic superior parathyroid glands are at or above the superior pole of the thyroid. The incidence of supernumerary parathyroid glands is 10–15%. The most common location for a supernumerary gland is the thymus. Additional, more rare sites of ectopic parathyroid glands include the carotid sheath and inside the thyroid gland.


Presenter

Presentation Notes

Parathyroid hormone is secreted by chief cells. Low circulating calcium concentrations stimulate the parathyroid glands to secrete parathyroid hormone which mobilizes calcium from bones by osteoclastic stimulation. PTH then stimulates the kidneys to reabsorb calcium and to convert 25-hydroxivitamin D3 (produced in the liver) to the active form, 1,25 dihydroxyvitamin D3 which stimulates gastrointestinal calcium absorption. High serum calcium concentrations have a negative feedback effect on PTH secretion.

Etiology Primary (Increased PTH, Increased Ca, Decreased

phos) Secondary (Increased PTH in response to low Ca) Renal Failure Vitamin D deficiency

Tertiary (continued excess PTH secretion to chronic secondary hyperparathyroidism)


Primary Hyperparathyroidism Classification Solitary adenoma 80-85%

Double Adenoma 5-10%

Four-gland Hyperplasia 5-10%

Parathyroid carcinoma 1%


Who Has Hyperparathyroidism? Serum Calcium Normal 8.5-10.4

Serum PTH Normal 10 to 65

Parathyroid disease?

Needs an operation?

1 11.4 121 Y Y

2 10.5 97 Y Y

3 11.1 55 Y Y

4 10.3 100 Y Y

5 11.8 158 Y Y

6 12.1 50 Y Y

7 10.9 40 Y Y

8 11.4 30 Y Y

9 10.2-11.6 85 Y if over 25 Y

10 9.8-10.2 100 Possibly Possibly

11 9.5-10.2 40 N N


Presenter

Presentation Notes

Patients 1 through 6 are very routine patients with hyperparathyroidism. The diagnosis of hyperparathyroidism should be made by most/all doctors. It's simple, these people have a parathyroid tumor that is making too much parathyroid hormone which makes the calcium go too high in the blood. These patients do not need any more testing. They don't need to measure calcium in the urine, and they don't need any x-rays or scans. They need to find an expert surgeon and have their parathyroid tumor removed. Patients 7 and 8 also have hyperparathyroidism and they also have a parathyroid tumor making too much hormone. These patients are more difficult for the average doctor to diagnose, because the doctor will say "it can't be hyperparathyroidism because your PTH level is normal". This is a very serious mistake. If the parathyroid glands were NORMAL (no tumor present) then the high calcium would make the normal parathyroid glands go to sleep and the PTH levels would be between very low (say, between 5 and 8). At least 20% of ALL patients with hyperparathyroidism are NOT DIAGNOSED appropriately because their doctor does not understand this.

Symptomatic PHPT www.downstatesurgery.org

Asymptomatic PHPT Hypertension Left ventricular hypertrophy, valvular or myocardial

calcification Peptic ulcer disease Pancreatitis, gout, pseudogout Normocytic normochromic anemia Weakness, easy fatigabillity. Anxiety Cognitive difficulties Somatic complaints and clinical depression


Comparison of New and Old Guidelines for Surgery Measurement 1990 2002 2008

Serum Ca greater than upper limit of normal

1-1.6mg/dl (0.25-0.4 mmol/Liter)

1.0mg/dl (0.25mmol/liter

1.0 mg/dl (0.25 mmol/liter)

24 hr urine for calcium

>400 mg/d (>10mmol/d)

>400 mg/d (>10mmol/d)

Not indicated

Creatinine clearance

Reduced by 30% Reduced by 30% Reduced by 30%

BMD Z score < -2.0 in forearm

T-score < -2.5 at any site

T-score < -2.5 at any site and or previous fracture fragility

Age <50 <50 <50

Bilezikian et al J Clin Endocrin Metab 2009


If a patient has asymptomatic PHPT when should they be referred to surgery??? Age <50 No ability for appropriate follow up Serum Ca >1mg/dl above normal Urine Ca >400mg/ 24 hr or above high normal lab limit 30% decrease in renal function Complications of PTHP, nephrocalcinosis, osteoporosis, or

severe psychoneurologic disorder

Udelsman et al J Clin Endocrin Metab 2009


Benefits to Parathyroidectomy Resolution of neuropsychiatric symptoms Improved quality of life Prolongs survival Reduced cardiovascular incidents Improved renal and bone density Cost of parathyroidectomy at 5 years is less than

the cost of surveillance


Sestimibi Scan -Two approaches dual radionuclide with subtraction imaging (I-123 or Tc-99m pertechnetate) -Single radiotracer with early and delayed imaging (dual phase) -Limitations of thyroid pathology or other metabolically active tissue can be overcome with double tracer subtraction technique


Presenter

Presentation Notes

Parathyroid scintigraphy is performed by IV administration of 20mCI of Tc sestamibi. The equipment setup requires a gamma camera capable of single positron emision computed tomography. Ten min after injection of the Tc sestamibi 10 min anterior image of the neck and upper mediastinum is begun while the patient is lying supine. After the immediate planar image the SPECT image is aquired. Two hours after the initial injection the SPECT images of the anterior neck and mediastinum are repeated. The intial uptake of the Tc sestamibi in parathyroid tissue is attributable to the high blood flow to these organs. The clearance of the tracer from thyroid tissue occurs more rapidly than from parathyroid tissue.

Ultrasound

-Abnormal parathyroid tissue exhibits hypoechogenic pattern -Operator dependant


4D CT

-Relies on the vascularity Of the parathyroid glands and Their relative enhancement with Contrast compared to the Surrounding structures -4D is shows changes in perfusion of contrast over time to the 3D anatomic CT images


Selective Venous Sampling and Areteriography

Selective arteriography in

conjunction with venous sampling for PTH

•Requires catheterization of multiple veins in the neck and mediastinum, from which blood samples are obtained with rapid PTH measurement in angio suite

•Parathyroid adenomas have increased vascularity, demonstrating a characteristic blush on arteriography

•Indicated for patients requiring re-exploration with negative or discordant imaging studies


Intraoperative Radioguidance

The procedure involves giving a small injection of Tc-99m sestamibi (the same agent used for the sestamibi scan, just a smaller dose) the morning of surgery. A gamma intraoperatively to guide incision placement as well as to direct the dissection, allowing the surgeon to focus in on the location of the abnormal parathyroid tissue.


Presenter

Presentation Notes

Radioguided parathyroidectomy involves giving a small injection of Tc-99m sestamibi (the same agent used for the sestamibi scan, just a smaller dose) the morning of surgery. This radioactivity concentrates in the parathyroid glands allowing you to use a gamma probe to identify them during surgery. A gamma probe can be used intraoperatively to guide incision placement as well as to direct the dissection, allowing the surgeon to focus in on the location of the abnormal parathyroid tissue. The gamma probe is also used to confirm that the tissue resected is indeed parathyroid tissue. Radioactivity > 20 % of the background is considered diagnostic for parathyroid tissue (5). No. In the years 1999-2001, a flurry of reports emerged proclaiming the benefits of radio-guided parathyroid surgery (9-12). This was followed by a similar number of reports stating that radio-guidance was unnecessary (13-16). Most experts now agree that the gamma probe does not offer any significant advantages, and it has largely been abandoned (17, 18).

http://www.uwhealth.org/endocrine-surgery/preparing-for-parathyroid-surgery/25434

Pre operative Imaging Imaging Sensitivity Specificity Cost Safety

Noninvasive

Sestamibi Moderate Moderate Moderate Safe

Sestamibi SPECT

High High Moderate Safe

Ultrasoiund Moderate Moderate Low Safe

4D-CT High High High Radiation

MRI Low Moderate Moderate Safe

Invasive

Angiography Moderate Moderate Very High Hematoma, CVA,nephropathy

Venous Localization

High High Very High Hematoma, nephropathy

US guided Biopsy

High High Moderate Hematoma, Infection


???Should intraoperative PTH measurment be routinely used in all cases of parathyroidectomy???

Gawande, A. et al ArchSurg 2006


Presenter

Presentation Notes

This table shows the relationship of pre op imaging and outcome of parathyroidectomy. Among patients with discordant imaging the location of hyperfunctioning parathyroid tissue was correctly identified in 62% of patients confirmed by appropriate drop in IOPTH levels. The failure rate of surgery with concordant localizing studies was 1% with IOPTH and 2% without IOPTH, without a significant difference. 3% had persistant hypercalcemia after parathyroidectomy. The results of this study showed that patients with 1 of 2 tests localizing disease have a 1/3rd chance of needing complete neck exploration because of incorrect lateralization. If MIP/focuse parathyroidectomy is attempted then IOPTH is essential. Second the results indicate that IOPTH provides some marginal benefit tin patients with concordant studies.

Hwang et al. Annals of Surg 2010


Presenter

Presentation Notes

There is no role for IOPTH monitoring in sestimbi positive patients. It will guide the surgeon in sestimibi negative positive sonogram. In these cases inadequate decrease in PTH levels had a highly predictive of multiglandular disease. In MIBI negative cohort of 38 patients, 27 patients had an appropriate fall of IOPTH, in the remaining 11 patients 10 were found to have additional hypercellular parathyroid tissue in the neck, the removal which led to temporally associated stepwise decrements in IOPTH.

Hwang et al. Annals of Surg 2010


Presenter

Presentation Notes

The overall sensitivity and accuracy of IOPTH according to the Miami criterion were 99.6% and 92.9% respectively. The MIBI positive cohort consisted of 242 patients with scans revealing a single focus of disease. IOPTH fell in 91.3% of patients (221). In the remaining 21 patients IOPTH did not fall >50% at 10 minutes, though 3 remained hypercellular the majority were cured.

Question A 45 year old perimenopausal woman is referred for

possible parathyrpooidectomy. Her serum calcium has ranged from 9-9.5mg/dl for the last 12 months. Additional lab values include chloride=100, PO4 3.4, PTH= 90. Bone density confirms osteopenia of the femoral neck. Sestamibi does not localize. Which of the following would you recommend?


Question A. parathyroidectomy

B. Hormone replacement therapy

C. Cinacalcet

D. Bisphosphonates

E. Measure vitamin D levels


Presenter

Presentation Notes

There is not a clear biochemical diagnosis of primary hyperparathyroidism (PHPT) in this patient. Additional biochemical workup in this patient should include ionized calcium, creatinine, albumin, and 25-OH Vitamin D levels. A chloride:phosphate (Cl:PO4) ratio greater than 33 lends further support to the diagnosis. Vitamin D deficiency is common in the setting of PHPT and warrants replacement, because increased parathyroid hormone (PTH) results in increased clearance and degradation of Vitamin D. A 24-hour urine collection for calcium and creatinine may also be indicated to exclude a renal calcium leak causing a secondary rise in PTH. Once the biochemical diagnosis of PHPT is confirmed, parathyroidectomy is recommended for symptomatic patients. PHPT is characterized by hypercalcemia in the face of a nonsuppressed PTH level. This common, often asymptomatic, endocrine disorder affects approximately 0.3% of the general population but up to 3% of postmenopausal women. Although the disease spectrum is wide, general guidelines for surgery in an otherwise asymptomatic patient require a total corrected serum calcium greater than 1.0 mg/dL above the upper limit of normal for the local laboratory, creatinine clearance less than 60 mL/min, and evidence of abnormal bone density T-score –2.5 or less. A 24-hour urine fractional excretion of calcium is also indicated for this patient to rule out familial hypocalciuric hypercalcemia as a cause of her mild hypercalcemia with an elevated PTH. Many medical therapies may also influence PHPT and its clinical manifestations. Several small studies suggest that bisphosphonates and estrogen may be as effective as surgery in increasing bone density in patients with mild PHPT. Cinacalcet is a calcimimetic agent that binds to calcium-sensing receptors on parathyroid cells and causes these receptors to become more sensitive to serum calcium, suppressing PTH release through negative feedback. The drug is approved by the US Food and Drug Administration only for use in treating secondary hyperparathyroidism associated with chronic renal disease or parathyroid cancer, as well as in complicated nonoperative candidates.

Question During neck exploration for symptomatic primary

hyperparathyroidism in a 68 yr old woman, normal bilateral superior and inferior parathyroid glands are identified. They are confirmed by frozen section to be parathyroid tissue. The left inferior parathyroid cannot be identified, despite careful examination of the lower pole of the thyroid and surrounding tissue. Which of the following is the most likely location for the missing inferior parathyroid?


Question A. Carotid

B. Posterior to the inferior thyroid artery

C. Intrathyroidal

D. Thymus


Presenter

Presentation Notes

A thorough understanding of parathyroid anatomy is paramount to successful surgical treatment of hyperparathyroidism. The inferior parathyroid glands arise from the third pharyngeal pouch and migrate with the thymus in a plane anterior to the recurrent laryngeal nerve (RLN). Inferior glands are typically within 1 cm of the inferior pole of the thyroid. Other important locations for inferior glands include the cervical thymus (22%) and intimate with the thyroid capsule (17%). By contrast, superior glands arise from the fourth pharyngeal pouch and remain close to the posterior mid thyroid in a plane posterior to the RLN. With this more limited migration, there is less variability in the location of the superior compared with the inferior parathyroid glands. The majority of superior parathyroid glands (85%) are within a 2-cm diameter area centered 1 cm above the intersection of the inferior thyroid artery and RLN. Superior glands may extend posterior and caudal to the inferior thyroid artery deep in the tracheoesophageal groove. It is important to carry the surgical dissection back to the prevertebral fascia to identify superior glands that can be posteriorly situated in the paraesophageal and retroesophageal position. Approximately 3% of ectopic superior parathyroid glands are at or above the superior pole of the thyroid. The incidence of supernumerary parathyroid glands is 10–15%. The most common location for a supernumerary gland is the thymus. Additional, more rare sites of ectopic parathyroid glands include the carotid sheath and inside the thyroid gland.

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