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1 Hyperparathyroidism When to Suspect, How to Diagnose, When and How to Intervene November 6, 2013 Johanna A. Pallotta, MD, FACP, FACE Potential conflicts of interest: None Johanna A. Pallotta, MD Outline Definition of hyperparathyroidism (Primary, Secondary, Tertiary) Changing presentation of primary hyperparathyroidism Clinical manifestations of primary hyperparathyroidism Indications for surgery Localization techniques for primary hyperparathyroidism Surgical techniques for primary hyperparathyroidism Management for ongoing hyperparathyroidism 1

2 Calcium Homeostasis Calcium Vitamin D Bicarbonate + Bone CALCIUM + + Parathyroid Hormone (PTH) Gut 1 alpha Hydroxylase + Liver Skin/Gut 1,25 Dihydroxy Vitamin D Kidney 25 Hydroxy Vitamin D 25 alpha Hydroxylase Vitamin D Hyperparathyroidism When to Suspect Hypercalcemia Routine labs (asymptomatic patients) Bone density changes Nephrolithiasis Other causes of hypercalcemia: Malignancy, granulomatous disease, vitamin intoxication (A,D), medications (lithium, thiazides, calcium, theophylline), hyperthyroidism, immobilization Elevated PTH in the setting of hypercalcemia = hyperparathyroidism Hyperparathyroidism 1 0 hyperparathyroidism most common Elevated calcium in the setting of an elevated PTH Non-suppressed PTH with high/normal calcium Can be associated with MEN syndrome 2

3 Hyperparathyroidism 2 0 hyperparathyroidism Renal failure Elevated PTH response to chronic low Ca Lithium Vitamin D deficiency 3 0 hyperparathyroidism Corrected renal failure (s/p transplant) Ca normalized/elevated PTH remains unsuppressed (glands have become autonomous) 1 0 Hyperparathyroidism 80-85% caused by a single adenoma 15 20% caused by 4-gland hyperplasia or double adenomas 0.5 2% caused by parathyroid carcinoma Treatment is surgical removal of enlarged, hypercellular gland(s) 3

4 1 0 Hyperparathyroidism 1. Establish diagnosis 2. Review indications for surgery 3. Localize abnormal gland(s) 4. Operate Keep in this order! Diagnosis and Presentation 1 0 Hyperparathyroidism Presentation stones, moans, bones, and groans. Elevated calcium level Osteoporosis Kidney stones Stone analysis Hypercalcemic crisis 4

5 Captain Martell First patient diagnosed with hyperparathyroidism between 1918 and 1926 Changing Presentation of Primary HPT Silverberg et al. Am J Med 1990;89: Hyperparathyroidism Clinical Manifestations Asymptomatic Kidney stones Polyuria Depression Memory loss Fatigue Constipation Osteoporosis Calciphylaxis Hypercalcemic crisis Musculoskeletal pain Peptic ulcers Pancreatitis Brown tumors 5

6 1 0 Hyperparathyroidism Diagnosis Elevated calcium and PTH levels Note normocalcemic hyperparathyroidism Low phosphorous level 24 hour urine calcium level Normal or elevated FHH (24 hour level < 100 mg) Low Ca/Cr ratio Genetic testing available Vitamin D levels Indications for Surgery Indications for Parathyroid Surgery From Consensus Conference Serum calcium > 1 mg/dl above normal Decreased renal fxn GFR < 60 ml/min Low bone density (T score < -2.5) Age < 50 Medical surveillance not desirable or possible Symptoms: fragility fractures, kidney stones, an episode of hypercalcemic crisis Bilezikian et al JCEM 87:5353. Silverberg et al JCEM 94:351. 6

7 Indications for Parathyroid Surgery Other Things to Consider Neuropsychiatric symptoms and QOL Bone density and fracture risk Data confirms improvement s/p surgery Cardiovascular disease and survival Age and operative risk Changes in Bone Density Over Time in Patients Who Undergo Observation Versus Surgery Silverberg et al JCEM 94:351. If No Indication For Surgery How to Follow? Annual serum calcium level Annual serum creatinine level and calculated GFR Bone density every 1-2 years Not recommended 24 hour urine calcium levels Creatinine clearance Abdominal x-ray or U/S to r/o kidney stones Bilezikian et al JCEM 94:335. 7

8 Localization Parathyroid Imaging Available Tests Sestamibi scan Ultrasound 4D-CT scan MRI FNA with U/S guidance Venous Sampling Arteriography Parathyroid Imaging Available Tests First line studies Sestamibi scan Neck U/S 4D-CT scan Other localization tests MRI PET scan Invasive, second line studies (reserved for specific cases) Venous catheterization Arteriogram U/S guided FNA 8

9 Study Sensitivity% Specificity% Sestamibi U/S Endo U/S 71 CT MRI Thal-Tc PET Arter+Vein Vein only Review article Current Practice: Parathyroid localization B. Dijkstra. J.R. Coll Edin 47 August 2002 Sestamibi Scan Simple and universally available Evaluates both neck and mediastinum Not operator dependent Interpretation can be challenging when NOT classical 9

10 Easy on patient No radiation Parathyroid Ultrasound Significantly compliments sestamibi but much better anatomic delineation Simultaneous evaluation of the thyroid Requires significant operator experience Left Upper Parathyroid Adenoma Thyroid Nodule 10

11 Arici et al. Surgery patients All underwent pre-operative localization and surgery When sestamibi and U/S identified a single and corresponding lesion 101/105 patients that was the correct and only abnormal gland Sensitivity 96% Currently the most widely used studies are U/S and sestamibi Imaging with 4D-CT Multi-planar images with perfusion characteristics over time (4 th dimension) Demonstrates distinct anatomic location Adenomas show rapid contrast uptake and washout Useful for difficult to localize parathyroid cases Surgery 11

12 Parathyroidectomy Traditional Approach No pre-operative localization All 4 glands explored Abnormal/enlarged glands removed Biopsy and frozen section of normal glands Excellent success rate (3-5% failure) Low complication rate (1-2%) Nerve injuries, hypoparathyroidism, hypothyroidism Van Heerden et al. Surgical treatment of primary hyperparathyroidism: an institutional perspective. W. Journal of Surgery s Unilateral exploration proposed 1988 Intra-operative PTH assay 1990 s Sestamibi scan high resolution U/S Pre-operative localization and intraoperative PTH monitoring were the key innovations facilitating focal exploration Trends in Parathyroid Surgery From Udelsman, Annals of Surgery 2002 National trends in parathyroid surgery from 1998 to 2008: a decade of change From Greene, J Am Coll Surg

13 Parathyroidectomy Focused Approach Pre-operative localization Focused exploration Intraoperative PTH measurement Termination of procedure if abnormal gland found and adequate decrease in PTH level Parathyroidectomy Focused Approach Contraindications Inconclusive pre-operative localization Familial disease (MEN I, IIa) 2 0 or 3 0 hyperparathyroidism Need for simultaneous thyroid surgery Grant et al. Archives of Surgery 2005 Mayo Clinic patients Follow-up 25 months Compared standard exploration to MIP Equal cure rates 50% of MIP patients had local anesthesia and 50% had same day discharge 4-gland exploration versus minimally invasive approach remains an ongoing debate 13

14 Parathyroid disease is usually cured in under 20 minutes! At our Endocrine Surgery Clinic, parathyroid surgery is all we do. We invented the techniques and tools used in mini-parathyroid surgery. Most parathyroid operations take less than 18 minutes, with a cure rate of around 99%. 'Standard Old-Fashioned Parathyroid Surgery' has some very BIG problems! There are a number of reasons that MIRP mini-parathyroid surgery is not widely available mostly due to economic reasons, and lack of experience. Post-operative Management Monitor for signs and symptoms of hypocalcemia Muscle cramping, paresthesias, tetany Chvostek s and Trousseau s sign (carpopedal spasm) Ongoing Care of Hyperparathyroidism 14

15 Management of Patients with Ongoing Hyperparathyroidism Continue to follow patient closely (q 6 months) Proper hydration (8 glasses of water each day) Exercise (aerobic if possible) Diet: - Calcium (1000 to 1200 mg/day) Don t cut out all calcium from the diet. - Vitamin D - keep level >30 ng/ml ( IU/day) Management of Patients with Ongoing Hyperparathyroidism Avoid drugs that increase Ca (eg. Lithium, Thiazides) If dehydration occurs seek medical attention If severe hypercalcemia (ie corrected calcium 13 or greater), needs hospitalization for fluids and other treatment Medications to Control Ca, PTH and Preserve Bone Density Calcitonin For acute hypercalcemia Bisphosphonates Zoledronic acid and pamidronate (IV, for acute Rx) Alendronate and risedronate (oral, for long term Rx) Improve bone density Ca and PTH may drop initially, but return to baseline at 3 months 15

16 Medications to Control Ca, PTH and Preserve Bone Density Raloxifene Small series studied Lowers Ca, improves BMD No change in PTH Cinacalcet Inhibits PTH secretion and drops Ca level No effect on BMD Increases urinary calcium excretion Cinacalcet Effects on Calcium and PTH Peacock et al JCEM Jan;96(1):E9-18. Parathyroid Locations Kronenberg H. Williams Textbook of Endocrinology, 11 th Edition. 16

17 Patient E.M. 73 Year-Old Female History of head and neck irradiation Bilateral partial thyroidectomy Presented with primary HPT Ca 12.2, PTH 150 Normal Vit D levels, 24 h urine Ca 200 mg Osteoporosis on bone density Patient E.M. 73 Year-Old Female Outside U/S report noted thyroid nodule at right lower pole Sestamibi scan noted a likely right lower parathyroid adenoma 17

18 What next? 18

19 Patient E.M. 73 Year-Old Female U/S guided needle biopsy of suspected parathyroid adenoma Cytology - inconclusive PTH level - 41,410 carotid trachea parathyroid adenoma thymus 19

20 Failed Parathyroid Exploration 41 yo woman presents after failed parathyroid exploration During first pregnancy, developed intractable kidney stones and noted to be hypercalcemic (10.3) PTH 143, Ph 2.7, 25OHD 29 At 28 weeks, she underwent parathyroid exploration During surgery: 2 glands were removed, a total thyroidectomy was done along with a cervical thymectomy without obvious parathyroid adenoma Failed Parathyroid Exploration Pathology of glands removed was normal Referred to us Non-invasive studies including sestamibi and U/S were negative Vein catheterization was done 20

21 Venous Sampling Selective Venous Sampling for Patient VW 09/29/ :25 #1 RT SUPERIOR 71* #2 LOW RT SUPERIOR 82* #3 ORIGIN RIGHT VERTEBRAL 70* #4 LEFT VERTEBRAL 94* #5 LEFT SUPERIOR 83* # 6 LOW LEFT SUPERIOR 82* #7 LEFT INTERNAL MAMMARY 81* #8 THYMIC 67* #9 THYMIC >5000* #10 COMMON INFERIOR TRUNK 260* #11 LEFT SIDE LEFT INOMINATE 83* #12 MID LEFT INOMINATE 80* #13 RT SIDE LEFT INOMINATE 470* #14 RT INOMINATE 165* #15 SVC 207* Right internal mammary artery 2 3 Final images after ablation 6 1 Parathyroid adenoma Subselective catheterization Parathyroid adenoma Coils V.W. Parathyroid ablation 4 5 Persistent staining Adenoma prior to starting ablation Adenoma after contrast ablation note swelling 21

22 Selective left inferior thyroid Superselective injection Coils following ablation Mediastinal adenoma Post angiography Post injection of Hyperosmolar contrast Selective arteriography and ablation 1. 2a. 2b. 3. Arterial phase Tissue phase Arteriogram Take Home Points Parathyroid disease is a biochemical diagnosis Imaging should be reserved for when you are planning on taking the patient to surgery U/S and sestamibi are the first line imaging modalities to locate a parathyroid adenoma Only experienced parathyroid surgeons should be used 22

23 Take Home Points Patients who require only medical follow up need close observation Difficult cases require referral for more sophisticated diagnostic studies Don t rush patients to surgery if unsure of diagnosis or indications If you don t know what to do, don t do anything -Robert Loeb, MD Questions Chose the answer that includes, in all 3 listed, indications for surgery in primary HPT, as outlined in the recent consensus conference: A. Osteoporosis, hypercalcuria, calcium > 11 B. Osteoporosis, age < 50, calcium > 12 C. Osteopenia, kidney stones, musculoskeletal pain Questions The best laboratory data supporting the diagnosis of primary HPT is: A. calcium, PTH, albumin, phosphorous B. calcium, albumin, PTH, phosphorous, 24-hour urine calcium C. calcium, albumin, phosphorous, vitamin D 23

24 Question for Panel The patient has a high calcium level and hyperparathyroidism, and you suggest that they take 1000mg of calcium daily, preferably in their diet. When they question your recommendation based on their high calcium level, how do you answer them? 24