1. Calcium Disorders Dima L. Diab, MD, FACE, FACP, CCD
Associate Professor of Medicine
Division of Endocrinology, Diabetes and Metabolism
University of Cincinnati College of Medicine
Bone Health and Osteoporosis Center
Metabolic Bone Diseases and Mineral Disorders 1

2. Regulation of Serum Ca Liver Kidney
Vitamin D 25(OH)Vit D 1,25(OH)Vit D
PTH
Increased distal Parathyroid gland Increased
tubular Ca bone resorption
reabsorption
Serum Ca
Increased intestinal
Ca absorption

3. PTH Action 3

4. Serum PTH concentrations in hypercalcemia and hypocalcemia
There is a steep inverse sigmoidal relationship between the serum calcium and PTH concentrations in normal subjects.
Data from Haden, ST, Brown, EM, Hurwitz, S, et al. The effects of age and gender on parathyroid hormone dynamics. Clin Endocrinol 2000; 52:329. 4

5. Hypercalcemia There are two categories of hypercalcemia:
1. PTH-mediated (primary dysfunction of parathyroid glands)
2. Non-PTH-mediated (appropriate parathyroid suppression )

6. Primary hyperparathyroidism
Definition
A primary abnormality of the parathyroid tissue leading to inappropriate secretion of PTH
In turn, this sustains excessive renal Ca reabsorption, phosphaturia, and 1,25 D synthesis as well as increased bone resorption
Williams Textbook of Endocrinology, 10th ed.

7. Diagnostic Studies
Diagnosis: inappropriately normal or elevated PTH concentration given the patient's hypercalcemia.
Measure 24-hr urinary calcium after repleting vitamin D to rule out familial hypocalciuric hypercalcemia or FHH (rare).

8. Preventive Measures
Avoid factors that aggravate hypercalcemia (HCTZ, Li, volume depletion, prolonged bed rest)
Encourage physical activity and adequate hydration (at least 6-8 glasses of water/d)
Maintain good Ca and vit D intake to avoid aggravating bone disease

9. Medical Therapy Bisphosphonates (for low BMD)
Cinacalcet (for symptomatic hypercalcemia)

10. Guidelines for Asymptomatic Disease
Surgery vs. medical therapy
JCEM 2014;99:

11. Guidelines for parathyroid surgery in asymptomatic PHPT
Guidelines for patients with asymptomatic PHPT who do not undergo parathyroid surgery
Measurement
2013
Serum calcium (>upper limit of normal)
1.0 mg/dL
(0.25 mmol/liter)
24-h urine for calcium
>400 mg/d (>10 mmol/d) and increased stone risk by urine biochemistry or presence of stones by imaging
Creatinine clearance (calculated)
Reduced to <60 ml/min
BMD
T-score <-2.5 at any site and/or fragility fracture (clinical or by imaging)
Age (yr)
<50
Measurement
2013
Serum calcium
Annually
24-h urinary calcium
If renal stones suspected, along with stone panel
Creatinine clearance (24-h urine collections)
Not needed
Serum creatinine
Annually with eGFR
Bone density
Every 1–2 yrs (3 sites), x-ray or VFA if clinically indicated
Abdominal imaging
If renal stones suspected

12. Examples of other causes of hypercalcemia
Hypercalcemia of malignancy
Vitamin D intoxication
Chronic granulomatous disorders (eg. sarcoidosis, tuberculosis): activation of extrarenal 1 alpha-hydroxylase
Medications: thiazide diuretics, lithium (PTH not suppressed), teriparatide
Miscellaneous: thyrotoxicosis, immobilization, milk alkali syndrome, FHH (PTH not suppressed)

13. Causes of Hypocalcemia
Deficient vitamin D supply or activation
Vitamin D resistance
Chelation of calcium by bone or plasma chelators
Deficient synthesis or secretion of PTH
PTH resistance

14. Causes of Hypoparathyroidism
Destruction of parathyroid glands (including postsurgical, radiation, infiltrative diseases, and autoimmune)
Impaired PTH secretion (including Magnesium disorders)
Agenesis or dysgenesis of parathyroid glands (e.g. DiGeorge Syndrome)

15. Hypoparathyroidism Treatment
In patients with permanent hypoparathyroidism, the goals of therapy are:
to relieve symptoms
to raise and maintain the serum calcium concentration in the low-normal range ( mg/dL)
to avoid hypercalciuria (24-hour urinary calcium <300 mg)
Shoback D: Clinical practice: hypoparathyroidism. N Engl J Med 359: , 2008.

16. Case 1
A 55-year-old male with HTN, on lisinopril 40 mg and HCTZ 25 mg daily, presents for evaluation of hypercalcemia found incidentally on routine blood work.
He has no history of fractures or kidney stones.
There is no family history of calcium disorders.
Physical examination findings, including his vital signs, are essentially unremarkable. There are no masses palpable in the neck.

17. Case 1 (cont’d) His laboratory evaluation reveals the following:
Ca 11.0 mg/dL (normal, )
Phosphorus 2.6 mg/dL (normal, )
Albumin 4.1 g/dL (normal, )
PTH 65 pg/mL (normal, )
Creatinine 0.9 mg/dL (normal, )

18. Question #1 What is the cause of his hypercalcemia?
HCTZ use
Primary hyperparathyroidism
Occult malignancy
Familial hypocalciuric hypercalcemia (FHH)
Unable to determine at this time

19. Answer #1 What is the cause of his hypercalcemia? A. HCTZ use
B. Primary hyperparathyroidism
C. Occult malignancy
D. Familial hypocalciuric hypercalcemia (FHH)
E. Unable to determine at this time
While primary hyperparathyroidism (answer B) is the most common cause of hypercalcemia in the outpatient setting, thiazide diuretics (answer A) may cause mild hypercalcemia which is generally thought to be due to decreased renal calcium clearance. The hypercalcemia usually resolves with discontinuation of the drug unless it is coexistent with primary hyperparathyroidism.

20. What is the cause of his hypercalcemia? A. HCTZ use
B. Primary hyperparathyroidism
C. Occult malignancy
Occult malignancy (answer C) is incorrect since it is one of the causes of non-PTH mediated hypercalcemia and this patient’s PTH is not suppressed.
D. Familial hypocalciuric hypercalcemia (FHH)
E. Unable to determine at this time

21. What is the cause of his hypercalcemia?
A. HCTZ use
B. Primary hyperparathyroidism
C. Occult malignancy
D. Familial hypocalciuric hypercalcemia (FHH)
FHH is an autosomal dominant disorder characterized by longstanding, mild hypercalcemia and low urinary calcium excretion. In most cases, it is due to an inactivating mutation in the calcium-sensing receptor in the parathyroid glands and the kidneys.
The diagnosis of FHH (answer D) cannot be made without evaluation of the urinary Ca excretion. Furthermore, there is no family history of hypercalcemia that is noted in this case.
E. Unable to determine at this time
American Family Physician (2003) 67:
JAMA December 24; 312(24): 2680–2681. doi: /jama

22. Case 1 (cont’d)
His HCTZ is held for 3 months, and repeat laboratory evaluation reveals the following:
Ca 10.7 mg/dL (normal, )
Phosphorus 2.5 mg/dL (normal, )
Albumin 4.2 g/dL (normal, )
PTH 70 pg/mL (normal, )
Creatinine 0.8 mg/dL (normal, )
24-hr urine Ca 100 mg/day (normal, )

23. Question #2 What is the best next step?
Check 25-hydroxy vitamin D level
Check 1, 25-dihydroxy vitamin D level
Check PTH-related peptide (PTHrP) level
Check serum calcitonin level

24. Answer #2 What is the best next step?
A. Check 25-hydroxy vitamin D level
Measurement of this patient’s 25-hydroxy vitamin D level is the most appropriate next step.
Since there is a high prevalence of concurrent vitamin D deficiency which can stimulate parathyroid hormone secretion, repletion should be provided if this is identified.
Furthermore, vitamin D deficiency may lower the urinary calcium concentration, making it more difficult to differentiate primary hyperparathyroidism from FHH.

25. What is the best next step?
A. Check 25-hydroxy vitamin D level
B. Check 1, 25-dihydroxy vitamin D level
C. Check PTH-related peptide (PTHrP) level
Checking 1,25-dihydroxy vitamin D (answer B) or PTHrP (answer C) levels would not be indicated in the setting of PTH-mediated hypercalcemia.
PTHrP is the principal mediator of hypercalcemia associated with solid tumors. It is homologous with PTH at the amino terminus, the region that comprises the receptor-binding domain. PTHrP mimics the biologic effects of PTH on bones and the kidneys.
D. Check serum calcitonin level

26. What is the best next step?
A. Check 25-hydroxy vitamin D level
B. Check 1, 25-dihydroxy vitamin D level
C. Check PTH-related peptide (PTHrP) level
D. Check serum calcitonin level
Serum calcitonin is produced by the thyroid parafollicular C-cells and is used as a tumor marker in patients with medullary thyroid cancer. Checking serum calcitonin (answer D) is not relevant in the setting of hypercalcemia.
J Clin Endocrinol Metab Apr;90(4):
Clin Endocrinol (Oxf) Jun;80(6): doi: /cen

27. Case 1 (cont’d) His 25-hydroxyvitamin D level is low at 14 ng/mL.
He was treated with vitamin D, and repeat laboratory studies 3 months later were as follows:
25-(OH) D 34 ng/mL (normal, )
Ca 10.8 mg/dL (normal, )
Albumin 4.2 g/dL (normal, )
PTH 60 pg/mL (normal, )
Creatinine 0.9 mg/dL (normal, )
Urinary calcium 250 mg/day (normal, )
Urinary creatinine 1 gr/day (adequate sample)

28. Case 1 (cont’d)
Dual energy x-ray absorptiometry (DXA) revealed a T-score of -2.5 in the left femoral neck.
A sestamibi scan of the parathyroid glands showed a right superior parathyroid adenoma.

29. Question #3 What is the best next step?
Start cinacalcet
Start calcitonin
Refer for parathyroidectomy
Monitor with annual serum calcium and creatinine levels

30. Answer #3 What is the best next step? A. Start cinacalcet
B. Start calcitonin
C. Refer for parathyroidectomy
This patient has primary hyperparathyroidism (elevated calcium level, inappropriately normal PTH level, and elevated Ca/Cr clearance ratio).
Even though he is asymptomatic from his mild hypercalcemia, he meets one of the criteria for parathyroid surgery based on the newest guidelines (namely, osteoporosis).
D. Monitor with annual serum calcium and creatinine levels

31. What is the best next step?
A. Start cinacalcet
There is no indication to treat with cinacalcet (answer A), which is a calcimimetic, since he has mild hypercalcemia and is asymptomatic.
B. Start calcitonin
Calcitonin (answer B) may be used in the inpatient setting as part of the initial management of severe hypercalcemia but has no role in this clinical scenario.
C. Refer for parathyroidectomy
D. Monitor with annual serum calcium and creatinine levels
Monitoring only (answer D) would be inappropriate since he meets the threshold for parathyroid surgery.

32. Case 2
A 65-year-old female with multiple myeloma presents to the emergency room with increasing fatigue and confusion for the past week. She appears chronically ill.
Laboratory tests reveal serum calcium of 12.6 mg/dL (normal, ), albumin 2.6 g/dL (normal, ), creatinine 1.4 mg/dL (normal, ), and PTH 4 pg/mL (normal, ).

33. Question #1 What is the best next step in the management of her hypercalcemia?
Furosemide
Prednisone
Intravenous zoledronic acid
Intravenous normal saline

34. Answer #1
What is the best next step in the management of her hypercalcemia?
A. Furosemide
B. Prednisone
C. Intravenous zoledronic acid
D. Intravenous normal saline
Aggressive rehydration with normal saline is the best next step in this patient’s management.

35. What is the best next step in the management of her hypercalcemia?
A. Furosemide
Loop diuretics (answer A) may be used cautiously to promote calciuria only AFTER volume repletion is achieved.
B. Prednisone
Glucocorticoids (answer B) are useful in treatment of hypercalcemia that is mediated by active vitamin D (such as granulomatous diseases), which is not the case in this patient.
C. Intravenous zoledronic acid
D. Intravenous normal saline

36. What is the best next step in the management of her hypercalcemia?
A. Furosemide
B. Prednisone
C. Intravenous zoledronic acid
Bisphosphonates such as zoledronic acid (answer C) inhibit bone resorption in areas of high turnover such as sites of malignancy and may be used in conjunction with saline infusions (and calcitonin) to treat moderate-to-severe hypercalcemia.
However, hydration remains the best next step in the management of this patient’s hypercalcemia.
D. Intravenous normal saline
Approach to Hypercalcemia. Goltzman D.
SourceEndotext [Internet]. South Dartmouth (MA): MDText.com, Inc; 2016 Aug 8.

37. Case 2 (cont’d)
She receives intravenous hydration and also an infusion of zoledronic acid.
Laboratory tests 2 weeks later show calcium 7.0 mg/dL (normal, ), albumin 2.6 g/dL (normal, ), and phosphorus 2.4 mg/dL (normal, ).

38. Question #2 What is the most likely underlying problem?
Hypoparathyroidism
Vitamin D deficiency
Magnesium deficiency
There is no problem; this patient’s corrected calcium is normal.

39. Answer #2 What is the most likely underlying problem?
A. Hypoparathyroidism
B. Vitamin D deficiency
This patient had underlying undiagnosed vitamin D deficiency (25-D level of 12 ng/mL), and bisphosphonate treatment inhibited osteoclastic bone resorption resulting in hypocalcemia.
C. Magnesium deficiency
D. There is no problem; this patient’s corrected calcium is normal.

40. What is the most likely underlying problem?
A. Hypoparathyroidism
B. Vitamin D deficiency
C. Magnesium deficiency
D. There is no problem; this patient’s corrected calcium is normal.
This patient is truly hypocalcemic (answer D is incorrect). The total serum calcium concentration falls ~0.8 mg/dL for every 1 g/dL reduction in the serum albumin concentration, so her calculated corrected calcium is still below 8.5 mg/dL.
Hypocalcemia: Diagnosis and Treatment. Schafer AL, Shoback DM.
SourceEndotext [Internet]. South Dartmouth (MA): MDText.com, Inc; 2016 Jan 3.

41. What is the most likely underlying problem?
A. Hypoparathyroidism
There is no clinical reason to suspect hypoparathyroidism (answer A) in this patient. The most common cause of hypoparathyroidism is removal or damage to the glands during neck surgery, which this patient has not had.
She also has a mildly low phos level, which would be inconsistent with a hypoparathyroid state.
Note that her initial PTH level was appropriately suppressed in the setting of severe hypercalcemia.
B. Vitamin D deficiency
C. Magnesium deficiency
D. There is no problem; this patient’s corrected calcium is normal.
Hypocalcemia: Diagnosis and Treatment. Schafer AL, Shoback DM.
SourceEndotext [Internet]. South Dartmouth (MA): MDText.com, Inc; 2016 Jan 3.

42. What is the most likely underlying problem?
A. Hypoparathyroidism
B. Vitamin D deficiency
C. Magnesium deficiency
Finally, while magnesium deficiency (answer C) could be a cause of hypocalcemia, there is no reason to clinically suspect this as the cause of hypocalcemia in this patient either. This is commonly seen in patients with malnutrition (such as alcohol abuse), malabsorption (such as chronic diarrhea), or diuretic / PPI use.
Low magnesium levels may impair PTH secretion and action. Hypomagnesemia has to be corrected if present in order to fix the hypocalcemia.
D. There is no problem; this patient’s corrected calcium is normal.
Hypocalcemia: Diagnosis and Treatment. Schafer AL, Shoback DM.
SourceEndotext [Internet]. South Dartmouth (MA): MDText.com, Inc; 2016 Jan 3.

43. Case 3
A 30-year-old man is referred by his PCP for a serum Ca level of 8 mg/dL found on routine blood work.
He is asymptomatic and denies any paresthesias or muscle cramps.
He has no history of neck surgery and does not take any medications.
He is adopted.
His physical examination is essentially unremarkable.

44. Case 3 (cont’d) His laboratory evaluation reveals the following:
Ca 8.1 mg/dL (normal, )
Phosphorus 4.8 mg/dL (normal, )
Albumin 3.8 g/dL (normal, )
PTH 8 pg/mL (normal, )
Creatinine 1.0 mg/dL (normal, )
25-(OH) D 34 ng/mL (normal, )
1,25 dihydroxy D 16 (normal, )
Mg 2.0 mg/dL (normal, )
Urinary calcium 200 mg/day (normal, )

45. Question Which one of the following strategies is most appropriate?
Measure tissue transglutaminase antibodies
Start hydrochlorothiazide
Begin therapy with calcium and calcitriol
Instruct about symptoms of hypocalcemia but give no other therapy

46. Answer Which one of the following strategies is most appropriate?
A. Measure tissue transglutaminase antibodies
B. Start hydrochlorothiazide
C. Begin therapy with calcium and calcitriol
D. Instruct about symptoms of hypocalcemia but give no other therapy
This patient has mild hypocalcemia due to primary hypoparathyroidism, most likely of autoimmune etiology (other less common causes include infiltrative diseases and congenital defects such as DiGeorge syndrome).
Since he is asymptomatic, there is no need to treat him with calcium and calcitriol (answer C) at this time.

47. Which one of the following strategies is most appropriate?
A. Measure tissue transglutaminase antibodies
There is no concern for celiac since he has no evidence for malabsorption with a normal 25-D level, so checking tissue transglutaminase antibodies (answer A) is incorrect.
B. Start hydrochlorothiazide
Hydrochlorothiazide (answer B) may be useful in patients with hypercalciuria, but his 24-hr urinary calcium is normal.
C. Begin therapy with calcium and calcitriol
D. Instruct about symptoms of hypocalcemia but give no other therapy

48. Thank you for your attention!