This week in morning report we reviewed a case of hypercalcemia with the ultimate etiology being secondary to vitamin D toxicity. In our discussion we went over an approach to the history and physical examination based on the differential diagnosis, a discussion on the homeostasis of calcium, symptoms and general principles to management of hypercalcemia. I have included key points below and shared an article below on hypercalcemia from Vitamin D toxicity! Credit to the amazing former WCH CMR Dr. Baruch Jakubovic for some of his amazing hypercalcemia summary notes.

1. Differential diagnosis of Hypercalcemia

PTH-dependent	PTH-independent
Primary hyperparathyroidism – Hyperplasia – Adenoma – Cancer Remember regarding malignancy to think about MEN syndromes I (3Ps): pituitary, parathyroid hyperplasia, pancreatic tumours IIA: medullary thyroid cancer, pheochromocytoma, parathyroid hyperplasia IIB: neuromas, Marfanoid body habitus, medullary thyroid, pheochromocytoma	Malignancy: – PTH-related peptide squamous cell lung cancer, renal cell carcinoma, H&N – Lymphoma due to ectopic 1 alpha hydroxylase – Osteolytic: solid organ mets, multiple myeloma
Secondary Hyperparathyroidism Vitamin D deficiency, increased PTH	Elevated vitamin D: – increased intake – Conversion increased in the setting of: a) Granulomatous diseases TB, sarcoid, Wegner’s granulomatosis (GPA) b) Acromegaly
Tertiary Hyperparathyroidism Seen in the setting of end-stage renal disease	Normal vitamin D – Milk alkali syndrome (calcium intake), low excretion (thiazide diuretics), immobility – Other medications: theophylline, hypervitaminosis A, Paget’s, thyroid disease

Remember that familial hypocalcuric hypercalacemia (FHH) is an inherited disorder to keep in mind that is relevant in the setting of hypercalcemia with increased or normal PTH. The diagnostic test to help here is the 24-hour urine calcium. When the 24-hour urine calcium is increased i.e. > 200 mg (5 mmol) of urine calcium in 24 hours, this points towards primary hyperparathyroidism. When the 24-hour urine calcium is low i.e. < 100 mg (2.5 mmol) or Ca/creat < 0.01 this leads to a diagnosis of FHH.

FHH is a rare, benign, autosomal dominant condition caused by inactivating mutations in the calcium sensing receptor (CASR) gene. This leads to a hyposensitivity to calcium and compensatory hypercalcaemia and hypocalciuria. Patients with FHH are followed, but this does not require treatment.

Remember that 45-55% of circulating calcium is albumin-bound so we must take into account albumin levels when calculating the corrected calcium. Only ionized calcium is what matters/is physiologically important and this is what is regulated by PTH and Vitamin D mechanisms.

SHORTCUT calculation:
– Subtract 40-measure albumin
– Move decimal place over by 2
– Multiply by 2
– Add to serum calcium
– Gives a reasonable estimate/corrected Ca

2) Symptoms of Hypercalcemia

Calcium has many functions in the body including aiding in the process of neurotransmitter release, muscle contraction, serving as an enzyme cofactor (i.e. clotting cascade), and bone stability. Symptoms of hypercalcemia can be synthesized with the acronyms “moans, bones, groans, stones.”

• Moans: anorexia, nausea, vomiting, constipation, pancreatitis
• Bones: weakness, bone pain, fractures, osteopenia, osteoporosis, and crystal arthropathy
• Groans: altered mental status, confusion, poor concentration, coma
• Stones: kidney stones, polyuria, polydipsia, acute kidney injury, chronic kidney disease
• Other Features: hypertension, shortened QT interval

3) Homeostasis of Calcium

4) Principles of Management of Hypercalcemia

Management of hypercalcemia depends on the severity, whereby:

• < 3 mmol/L is mild hypercalcemia
• 3-3.5 mmol/L moderate, and
• > 3.5 mmol/L severe

In mild hypercalcemia, fluids are the mainstay of therapy and avoiding offending medications. Fluids + biphosphonates are typically given in moderate hypercalcemia (unless contraindications to bisphosphonates and need to consider alternative agents), and then immediate management with multi-pronged approach using the armamentarium below is needed in severe hypercalcemia:

Non-pharmacologic:

• Sun protection
• Stop offending agents such as Tums, Vitamin D

Pharmacologic:

• FLUIDS FLUIDS FLUIDS
• Lasix (diuretics)
• Dialysis if very high/can’t give fluids or anuric
• Bisphosphonates such as pamidronate, zoledronic acid – usually work over 48-72 hours, and work by inhibiting osteoclast-mediated bone resorption.
  • Side effects include flu-like symptoms, ocular inflammation, hypocalcemia, hypophosphatemia, impaired renal function, nephrotic syndrome
  • Rare side effects include osteonecrosis of the jaw and atypical femur fractures (in patients who require long-term therapy)
• Calcitonin
  • Tachyphylaxis can occur which is means decreasing response to successive doses of a drug, making it less effective
  • Dosing is 4 IU/kg IM/SC q 12 hours; doses can be increased up to 6-8 IU /kg every six hours
• Steroids –> which block 1-alpha hydroxylase pathway
  • Helpful in cases of over-ingestion of vitamin D, or endogenous overproduction of calcitriol (1,25-dihydroxyvitamin D) in patients with chronic granulomatous diseases (eg, sarcoidosis) and in patients with lymphoma
• Cinacalcet reduces PTH production; approved for use in secondary hyperparathyroidism and refractory parathyroid carcinoma (https://ascopubs.org/doi/full/10.1200/jop.2016.011155)
• Surgical parathyroidiectomy (see below)

5) Indications for Surgery in Primary Hyperparathyroidism

We reviewed the surgical indications for primary hyperparathyroidism when diagnosed. After FHH is ruled out, these are the clinical situations in which if any one of these is present alongside primary hyperparathyroidism, surgery is indicated:

a) Symptomatic primary hyperparathyroidism
b) Serum calcium is > 0.25 mmol/L above normal
c) Evidence of renal involvement include nephrolithiasis, nephrocalcinosis, hypercalcuria (24-hour urine calcium > 400 mg/day or > 10 mmol/day) with increased stone risk, or impaired renal function (EGFR < 60 mL/min)
d) Primary hyperparathyroidism and osteoporosis (T-score < – 2.5 at L-spine, total hip, femoral neck or distal 1/3 of radius)
e) Primary hyperparathyroidism and vertebral fracture by x-ray, CT, MRI, or VFA 
e) Primary hyperparathyroidism diagnosed at age 50 or younger

If you have any questions please do not hesitate to email me at cmr@wchospital.ca. Questions and comments are always welcome! I hope this review was helpful!

6) References:

1. CMAJ Primary Hyperparathyroidism – https://www.cmaj.ca/content/cmaj/183/10/E685.full.pdf
2. Management of Primary Hyperparathyroidism – https://jamanetwork.com/journals/jamasurgery/fullarticle/2542667
3. Hypercalcemia secondary to vitamin D toxicity CMAJ article – https://www.cmaj.ca/content/191/14/E390?ijkey=09c5265a7e697b6c47d95090856709dc5db54630&keytype2=tf_ipsecsha
4. FHH – https://journals.lww.com/co-endocrinology/Abstract/2011/12000/Familial_hypocalciuric_hypercalcaemia__a_review.5.aspx