Hypocalcemia

Endocrine University 2018-Bone Module

Rochester, Minnesota
March 7, 2018
Bart L. Clarke, M.D.
Metabolic Bone Disease Core Group
Division of Endocrinology, Diabetes,
Metabolism, and Nutrition
Professor of Medicine
Mayo Clinic College of Medicine
Rochester, Minnesota, USA
 Faculty Disclosures
3/7/18

• Relevant Financial Relationships:

− Research Grant Support from NPS
Pharmaceuticals, Inc./Shire
− Data Monitoring Committees for Amgen
Denosumab Oncology and Glucocorticoid-
Induced Osteoporosis

• Off-Label Usage: None

 Objectives

• 1) To appreciate recent advances in the

epidemiology of hypoparathyroidism

• 2) To be able to describe the biochemical findings

and signs and symptoms of hypoparathyroidism

• 3) To be aware of recent and coming advances in

management of hypoparathyroidism
 Mechanism of Hypocalcemia
in Hypoparathyroidism
Normal

+
Surgery Other Causes

↓PTH –
–

↓1,25 D

↓Ca ↓Ca
↓Ca

↓ECF Ca
Biochemical Diagnosis of Hypoparathyroidism
Bilezikian JP et al. JBMR 2011;26:2317-2337.

• Biochemical Parameters:
– Low-normal to decreased serum calcium
– High-normal to increased serum phosphate
– Inappropriately low-normal or decreased intact parathyroid
hormone
– Low-normal to decreased total alkaline phosphatase
– Low-normal to decreased markers of bone turnover
• Serum bone specific alkaline phosphatase
• Serum beta-CTx-telopeptide
– Low-normal to decreased urinary calcium and calcium to
creatinine clearance ratio (<0.01)
– Low-normal to decreased serum 1,25-dihydroxyvitamin D
– Decreased serum chloride and bicarbonate
– Normal serum magnesium
 Differential Diagnosis of Hypoparathyroidism

• Post-surgical hypoparathyroidism
• Autoimmune hypoparathyroidism
• Iron overload due to thalassemia or
hemochromatosis
• Copper overload due to Wilson’s Disease
• Metastatic disease to parathyroid glands
• Radioactive iodine therapy
• Magnesium deficiency or excess
• Genetic causes
 Post-Surgical Hypoparathyroidism
Shoback D. New Engl J Med 2008;359:391-403.

• Anterior neck surgery is most common acquired

cause of acute or chronic hypoparathyroidism
– Post-surgical hypoparathyroidism usually due to
inadvertent removal of, or damage to,
parathyroid glands or their blood supply
– May occur with surgery on thyroid or parathyroid
glands, or during neck dissection surgery
– Permanent hypoparathyroidism present for
longer than 6 months after surgery
 Post-Surgical Hypoparathyroidism
Thomusch O et al. Surgery 2003;133:180-195.
Asari R et al. Arch Surg 2008;143:132-137.

• Post-surgical hypoparathyroidism:
– Estimates of post-thyroid surgical permanent
hypoparathyroidism range from 0.5-6.6%, with
centers doing endocrine surgery reporting 0.9-
1.6%
– Estimates of post-thyroid surgical transient
hypoparathyroidism range from 6.9-46%
– Higher risk of hypoparathyroidism if reoperation,
more extensive thyroid resection, substernal
goiter, cancer, or Graves’ disease
 Postoperative Day 2 PTH and Calcium Levels
Predict Hypoparathyroidism
Asari R et al. Arch Surg 2008;143:132-137.

50
45
40
35 No HypoP
30
PTH, pg/mL

Transient HypoP
25
Perm HypoP1
20
15 Perm HypoP 2
10
5
0
1 day 4 days 28 days 6 months
 Reoperative Parathyroidectomy in 228 Patients
Before and After Intraoperative PTH Monitoring
Richards ML et al. Am J Surg 2008;196:937-943.

100
90
80
70
Percentage, %

60
1989-1997
50
1998-2005
40
30
20
10
0
Cure HypoP RLN Injury
 Non-Surgical Causes
of Acquired Hypoparathyroidism
• Acquired Disorders:
– Autoimmune hypoparathyroidism
• Autoimmune polyglandular syndrome type I
• Isolated
– Accumulation of iron (thalassemia or hemochromatosis):
19% of 44 cases of hemochromatosis
– Accumulation of copper (Wilson’s disease): 1:50,000 to
1:100,000
– Very rarely may occur after I-131 therapy for thyroid
disease
– Rarely occurs with metastatic infiltration of glands
– Magnesium deficiency (e.g., PPI therapy) or excess
(e.g., tocolytic therapy during pregnancy)
Clinical Manifestations of Hypoparathyroidism

Large spectrum of symptoms: mild – debilitating

• Most symptoms and signs due to hypocalcemia
• Large inter-individual difference in threshold of calcium
• Highly variable descriptions of symptoms
Neuromuscular irritability:
• Tingling of fingers and toes, perioral numbness
• Muscle cramps, laryngospasm, seizure
Neurocognitive and neuropsychiatric manifestations:
• “Brain fog” (mental lethargy)
• Inability to focus/concentrate
• Increased anxiety
 Chvostek’s Sign
Jesus JE, Landry A. N Engl J Med. 2012;367:e15.

Tapping facial nerve in front of

ear results in twitching of the
upper lip on the same side
Trousseau’s Sign
 Cardiac Manifestations: Long QT
Mannstadt M, Mitchell DM. Follow-up in Chronic Hypoparathyroidism.
In: Hypoparathyroidism. Springer; 2015.

Calcium 7.3 mg/dL

QT 518 msec
QTc 543 msec

Calcium 9.2 mg/dL

QT 466 msec
QTc 457 msec
 Abnormal Microarchitecture in
Hypoparathyroidism
Rubin MR et al. Bone. 2010;46:190-195.

Hypoparathyroid Control
 Bone Turnover Decreased
BMD Increased
Bone Turnover Markers Bone Density (DXA)

Ebeling PR et al. J Bone Miner Res. 1992;7:1243-1250.

Minisola S et al. Osteoporos Int. 2002;13:171-175.
Rubin MR et al. J Bone Miner Res. 2008;23:2018-2024.
 Other Manifestations of Hypoparathyroidism

Dental enamel hypoplasia Cataract

Short, blunted roots (premolars)
Delay/absence of eruption
Hypoplastic  prone to caries

Basal ganglia calcifications

 Risk of Complications of Hypoparathyroidism
Clarke BL et al. J Clin Endocrinol Metab 2016;101:2284-2299.

Risk of hospitalization for Postsurgical Nonsurgical

Complications
Renal Insufficiency
Renal stones
Ischemic CV disease
Neuropsychiatric Disease
Seizures
Cataracts
Upper Extremity Fractures
Intracranial Calcifications
Hypoparathyroidism Hypoparathyroidism
HR 3.10; 95% CI, 1.73-5.55 HR 6.01; 95% CI, 2.45-14.75
HR 4.02; 95% CI, 1.64-9.90 -
HR 1.09; 95% CI, 0.83-1.45 HR 2.01; 95% CI, 1.31-3.09
HR 1.26; 95% CI, 1.01-1.56 HR 2.45; 95% CI, 1.78-3.35
HR 3.82; 95% CI, 2.15-6.79 HR 10.05; 95% CI, 5.39-
18.72
HR 1.17; 95% CI, 0.66-2.09 HR 4.21; 95% CI, 2.13-8.34
HR 0.69; 95% CI, 0.49-0.97 HR 1.93; 95% CI, 1.31-2.85
56% 69-74%
 Treatment of
Acute Symptomatic Hypoparathyroidism
Bilezikian JP et al. JBMR 2011;26:2317-2337.

• Dilute 10 mL of 10% calcium gluconate solution in 100 mL

D5W and infuse over 5-10 minutes to give 90 mg elemental
calcium immediately
• Longer infusion of 10 ampules of calcium gluconate (900
mg) diluted in 1 L D5W at 50 mL/hour to give 15 mg
elemental calcium/kg
• Infusion will raise serum calcium by 2 mg/dL over 8 hours
• Avoid calcium chloride due to venous irritation
• Magnesium supplementation if deficient
• Begin oral calcium and vitamin D supplementation as
appropriate
 Conventional Management of
Chronic Hypoparathyroidism
Brandi ML et al. J Clin Endocrinol Metab 2016;101:2273-2283.

• Guidelines published by:

− European Society of Endocrinology
− First International Conference on the Management of
Hypoparathyroidism
− AACE/ACE Disease State Clinical Review on
Postoperative Hypoparathyroidism
• Treatment targets:
− Low-normal serum calcium
− High-normal serum phosphorus
− 24-hr urine calcium <300 mg (<7.5 mmol)
− Calcium-phosphate product <55 mg2/dL2
 Conventional Management of
Chronic Hypoparathyroidism
Brandi ML et al. J Clin Endocrinol Metab 2016;101:2273-2283.

• Calcium citrate or carbonate, 1-9 g/day in divided

doses
• Calcitriol 0.25-2.00 mcg/day, often in divided
doses
• Vitamin D2 or D3 800-2,000 IU/day
• Thiazide diuretics and low-salt diet when
necessary to manage hypercalciuria
• Phosphate binders and low phosphate diet if
necessary to control hyperphosphatemia
 Indications for Considering Use of
rhPTH(1-84) in Hypoparathyroidism
Brandi ML et al. J Clin Endocrinol Metab 2016;101:2273-2283.

• Inadequate control of serum calcium

• Oral calcium/vitamin D medications required to control
serum calcium or symptoms that exceed 2.5 g calcium
or >1.5 μg active vitamin D
• Hypercalciuria, renal stones, nephrocalcinosis, stone
risk, or reduced creatinine clearance or eGFR (< 60
ml/min)
• Hyperphosphatemia and/or calcium x phosphate
product that exceeds 55 mg2dl2 (4.4 mmol2L2)
• GI tract disorder associated with malabsorption
• Reduced Quality of Life
 Advantages of Considering Use of
rhPTH(1-84) in Hypoparathyroidism
Brandi ML et al. J Clin Endocrinol Metab 2016;101:2273-2283.

• 1) Stabilize blood calcium level while reducing

amount of calcium and calcitriol tablets required
each day
• 2) Decrease risk of low blood calcium
• 3) Normalize serum phosphorus
• 4) Reduce calcium x phosphorus product
• 5) Feel better and improve quality of life
• 6) Restore more normal skeletal physiology
• 7) Prevent long-term complications such as kidney
stones, kidney dysfunction, cataracts, etc.
 Summary and Conclusions

• Hypoparathyroidism is a rare disorder with multiple

symptoms and complications
• Caused by surgery in 75% of cases, but other
acquired causes are due to autoimmunity, iron or
copper overload, metastatic disease, radioactive
iodine therapy, magnesium deficiency or excess, or
genetic causes
• Standard of care includes calcium and calcitriol
supplementation, magnesium and thiazide-type
diuretic as needed, and rhPTH 1-84 treatment when
appropriate