Calcium Conundrums California Chapter AACE September 2015 Michael W. Yeh, MD Chief, Section of Endocrine Surgery Associate Professor of Surgery and Medicine David Geffen School of Medicine at UCLA www.endocrinesurgery.ucla.edu
Case #1: Familial Hypercalcemia 50 y/o female Known history of Familial Hypocalciuric Hypercalcemia (FHH) 1-year history of increasing serum calcium and PTH levels
Legend Legend Male Male Female Female Deceased Deceased Proband Proband Affected Affected Fig. 1. Family pedigree demonstrating the pattern of inheritance (black markers) and relationship to the proband (arrow).
10.3 9.9-11.3 Legend Male Female Deceased Proband Affected 10.4-11.8 10.3-10.7
Lab History 2/10 3/10 8/10 9/10 12/10 Calcium: (Ionized) 11.1 (6.2) 10.5 (6.9) 11.2 (6.2) 10.7 11.6 PTH: (pg/ml) -- 46 144 130 62 Urine Ca: (mg/24 hr) -- 105 263 84 Vitamin D: (pg/ml) 25 78 41 -- 38
Is further workup indicated?
Lab History 2/10 3/10 8/10 9/10 12/10 Calcium: (Ionized) 11.1 (6.2) 10.5 (6.9) 11.2 (6.2) 10.7 11.6 PTH: (pg/ml) -- 46 144 130 62 Urine Ca: (mg/24 hr) -- 105 263 84 385 Vitamin D: (pg/ml) 25 78 41 -- 38
Further Imaging?
Neck Ultrasound 0.75 cm Fig. Axial (A) and sagittal (B) views of left lower lobe parathyroid adenoma on focused ultrasound.
Sestamibi Scan
Would YOU operate?
Furthermore What operation would you do? Focused? Unilateral? Bilateral? Measure of success? Interpretation of postoperative surveillance?
607 mg inferior parathyroid adenoma Superior gland normal Surgical Findings Appropriate decrease in IOPTH PTH (pg/ml) 80 70 60 50 40 30 20 10 0
Postoperative Surveillance Serum Calcium: 10.7 mg/dl Serum PTH: 32 pg/ml 24-hour urine calcium: 105 mg/24 hours Vitamin D: 38 pg/ml
Diagnosis?
Primary Hyperparathyroidism AND Familial Hypocalciuric Hypercalcemia
Case #2: A Pregnant Dilemma 21 year old G1P0 woman at 14 weeks gestation initially referred to UCLA in April 2012 for hypercalcemia Significant hyperemesis Seen in ER for dehydration Calcium markedly elevated at 12.3
Past Medical History Primary hyperparathyroidism Diagnosed at age 13 3.5 gland parathyroidectomy at Children s Hospital of Los Angeles in 2003 Hypercalcemia resolved postoperatively
Maternal Consequences of Hypercalcemia 67% will experience complications Nephrolithiasis 24-36% Pancreatitis 7-13% Hyperemesis gravidarum Preeclampsia Hypercalcemic crisis (esp. after delivery) Miscarriage: 6-fold higher rate of 2 nd trimester loss
Fetal/Neonatal Consequences of Hypercalcemia Perinatal death/stillbirth 5% Previously approximately 25% Neonatal tetany 46% Neonatal hypocalcemia 50% Suppressed parathyroid development Low birth weight Premature birth
Next step?
Localization Ultrasound: Negative Mibi: No Limited CT parathyroids:
Dynamic Parathyroid CT
Next step?
Repeat Ultrasound
May 22, 2012: FNA Biopsy
FNA Biopsy: PTH Stain Aspirate PTH level >3000
Next step?
Re-do Parathyroidectomy Index mass removed
Intra-op PTH 120 100 PTH (pg/ml) 80 60 40 20 0 PreOp PreDissect T=5 min T=10 min
Next step?
Additional masses removed from strap muscle area T=30 min T=15 min T=10 min T=5 min T=10 min T=5 min PreDissect PreOp 120 100 80 60 40 20 0 PTH (pg/ml)
Surgical Pathology
Parathyromatosis Multiple nodules of benign hyperfunctioning parathyroid tissue scattered throughout the neck and mediastinum Caused by spillage and seeding of parathyroid tissue within the operative field No reports of parathyromatosis and pregnancy in the literature
Clinical Course July 16, 2012 (28 weeks) Abdominal pain, nausea and vomiting significantly improved Calcium 10.9, ionized calcium 1.44 PTH 47 August 20, 2012 (33 weeks) Calcium 11.9 Ionized calcium 1.68
Calcimimetics: Cinacalcet (Sensipar ) FDA approved March 8, 2004 for treatment of renal hyperparathyroidism and parathyroid carcinoma Type II calcimimetic increases the sensitivity of CaSR to extracellular Ca Half-life 30-40 hrs Steddon SJ, Lancet 2005 Nemeth, PNAS 1998
Case Reports: Cinacalcet & Calcitonin Cinacalcet for hyperparathyroidism in pregnancy and puerperium Horjus et al, J Pediatr Endocrinol Metab. 2009 Aug;22(8):741-9 31 weeks gestation, calcium 12.9 Cinacalcet used immediately post-delivery 32 weeks gestation, calcium 15.8 Combination of cinacalcet and calcitonin improved calcium to 12
Clinical Course September 4, 2012 (35 weeks) Calcium 9.2 Ionized calcium 1.35 September 10, 2012 (36 weeks) Calcium 9.9 Ionized calcium 1.35 PTH 57
Clinical Course September 17, 2012 (37 weeks) Calcium 10.9 Ionized calcium 1.66 September 24, 2012 (38 weeks) Calcium 10.7, Ionized calcium 1.55 Admitted for induction of labor at term
Clinical Course During induction, developed severe flank pain unrelieved by epidural UA +RBCs presumed diagnosis of kidney stone Did not want to expose baby to additional narcotics, so converted to elective C- section
Clinical Course Baby transferred to NICU prophylactically Initial ionized calcium 1.59, phosphorus 4.2 PTH 4 Repeat ionized calcium 1.16 Patient s post-operative labs Ionized calcium levels ranged from 1.13 1.18 Discharged on POD 3 on Sensipar 30mg po QHS
Clinical Course Outpatient follow-up in Endocrine Surgery clinic 6 weeks after delivery Patient is asymptomatic after being off Sensipar for 1 week PTH 42, Calcium 10.2, Ionized calcium 1.35 Baby is doing well No problems with feeding or growth
Case #3: Persistent Hypercalcemia 67 yo man in good general health Develops polyuria, confusion, and unsteady gait Serum calcium 16.3 mg/dl (nl 8.6-10.2)
Treatment? IV fluids Calcitonin Pamidronate PTH = 58 pg/ml (nl 11-51) 25-OH Vit D = 22 pg/ml
Referred to UCLA (9/18/2012)
Imaging? Ultrasound: no definitive lesion Sestamibi: negative
Surgery? Left superior: normal Left inferior: normal Right superior: normal Right inferior: 1.5 cm adenoma within thymus 60 50 40 PTH (pg/ml) 30 20 10 0 PreOp PreDissect T=5 min T=10 min T=30 min T=24 hr
Check the pathology!
Persistent hypercalcemia Calcium 12.5 on 10/18/2012 Additional treatment? Additional workup?
More data PTH-related peptide 32 pg/ml (nl 14-27)
Stumped! Evaluated by UCLA endocrinology 5x3 cm mass over coccyx Suggested imaging of lower skull, back lesion, and chest to examine for small/miliary lung lesions or small lytic bone lesions
Treatment? Splenectomy Atypical large lymphoid cells c/w B cell lymphoma H&E CD20
Lab Total Calcium (mg/dl) On first presentation After parathyroidectomy Post-op day #1 After parathyroidectomy Post-op day #10 After splenectomy 16.3 11.1 12.9 10.6 8.9 ~ One year after splenectomy PTH (pg/ml) 58 5 4 5 78 Creatinine (mg/dl) 4.9 0.9 1.8 1.3 1.29 25D (pg/ml) 22 19 19 18.5 37 1.25 D (pg/ml) >220 133.6 62 PTHrP (pmol/l) < 2
IHC for 1-alpha hydroxylase Positive control Lymphoma
Final Diagnosis Multifactorial hypercalcemia Primary hyperparathyroidism AND Calcitriol-secreting B cell lymphoma
Stewart AF, N Engl J Med 352:373, 2005
Case #4: PTH excess 36 year-old woman with functioning renal allograft after transplantation for polycystic kidney disease PTH 3,374 pg/ml and calcium 9.5 mg/dl Symptoms: difficulty concentrating, bone pain, fatigue, memory loss, forgetfulness, depression, difficulty sleeping
Additional Medical History 1. Renal osteodystrophy 2. Living related renal transplant 85 3. Cadaveric renal transplant 88 4. Cadaveric renal transplant 12/98 5. Parathyroidectomy 1/92 6. Parathyroidectomy 8/98
History Medications: Prograf 2 mg q. AM and 3 mg q. PM Prednisone 5 mg q. day Sensipar 60 mg q. day Labs: PTH 3,374 pg/ml Calcium 9.5 mg/dl ical 1.20 mmol/l Creatinine 0.6 mg/dl Phosphate 2.5 mg/dl
Imaging
How to manage?
Operation Redo parathyroidectomy Findings: Bilateral superior neck tissue consistent with hypercellular parathyroid; bilateral thymus glands without parathyroid tissue
Pathology
Operation Redo parathyroidectomy Findings: Bilateral superior neck tissue consistent with hypercellular parathyroid; bilateral thymus glands without parathyroid tissue IOPTH: >1,700 pg/ml
Post-operative Course Within 3.5 hours: Perioral numbness Inability to talk secondary to clenched jaw Difficulty moving legs due to spasm Crushing chest pain
What happened?
Laboratory Data Calcium 7.5 mg/dl ical 0.90 mmol/l Alk phos 67 U/L
Laboratory Data Calcium 7.5 mg/dl ical 0.90 mmol/l Alk phos 67 U/L Symptoms resolved after IV calcium repletion to ical 1.15 mmol/l
Laboratory Data Calcium 7.5 mg/dl ical 0.90 mmol/l Alk phos 67 U/L N telopeptide 24 hr urine: normal Bone specific alkaline phosphatase: normal Symptoms resolved after IV calcium repletion to ical 1.15 mmol/l
What happened?
PTH Assay Elecsys PTH system (Roche) = murine Ab PTH 3,061 pg/ml Scantibodies HBR (heterophilic blocking reagent) PTH 5 pg/ml Future Diagnostics intraoppth = goat Ab PTH 5 pg/ml
True Positive PTH ANALYTE CAPTURE ANTIBODY LABEL ANTIBODY
False Positive PTH ANALYTE CAPTURE ANTIBODY LABEL ANTIBODY HETEROPHILIC ANTIBODY
Final Diagnosis False elevation in PTH caused by heterophilic antibodies from prior administration of OKT3 leading to incorrect diagnosis of tertiary hyperparathyroidism. Levin and Yeh, Falsely elevated plasma parathyroid hormone level mimicking tertiary hyperparathyroidism. Endocr Pract 2011
Bonus Case: Severe Hypercalcemia Michael W. Yeh, MD Program Director, Endocrine Surgery Assistant Professor of Surgery and Medicine David Geffen School of Medicine at UCLA www.endocrinesurgery.ucla.edu
Clinical presentation 8 yo M with incidentally discovered hypercalcemia Total Ca 17.2 mg/dl (2.15 mmol/l) Generally healthy Minor behavioral issues Possibly some decreased energy Family history unknown (adopted)
Biochemical workup
Next step?
Imaging Pt unable to comply with sestamibi Family agrees to ultrasound
The story so far Young patient Severe biochemical abnormalities Unknown family history No known risk factors, exposures Possible ectopic parathyroid adenoma
Next step?
Toby
Follow up
Pathology Parathyroid adenoma Normal thyroid tissue
Canine hyperparathyroidism Uncommon: ~300 cases reported Mean age of onset 11.2 years No gender predilection Keeshond > mixed breeding > Labrador Retriever > German shepherd = Golden Retriever > Poodle = Shih Tzu = Springer Spaniel Feldman, Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004). J Am Vet Med Assoc, 2005
Canine hyperparathyroidism Incidental laboratory finding (geriatric screening) 50% urinary symptoms (stones or infection) 40% nephrolithiasis 90% adenoma Feldman, Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004). J Am Vet Med Assoc, 2005
Canine hyperparathyroidism Feldman, Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004). J Am Vet Med Assoc, 2005
Canine hyperparathyroidism Rasor, Retrospective evaluation of three treatment methods for primary hyperparathyroidism in dogs. J Am Anim Hosp Assoc, 2007
Canine hyperparathyroidism Rasor, Retrospective evaluation of three treatment methods for primary hyperparathyroidism in dogs. J Am Anim Hosp Assoc, 2007