This morning we discussed an interesting case of an 84 year old male who presented with falls and change in mental status. Dr Nadjafi took us through an approach to delirium (see blog from July 5th for approach to delirium). After thorough investigations it was discovered that the patient's Calcium was 3.98mmol/L! Here is a quick approach to hypercalcemia:

1) Diagnosis:
- Serum Calcium: 40-50% of calcium in serum is bound to protein (mainly albumin). It is the ionized (or "free") calcium that is physiologically important. Therefore, hypo- or hyper-albuminemia can affect the serum ionized calcium. The following calculation helps you determine ionized calcium from measured calcium.

Ionized Calcium = measured Ca + 0.2(40-measured albumin)

- Degree of hypercalcemia: Mild hypercalcemia (<2.75mmol/L) usually seen in hyperparathyroidism. Severe hypercalcemia (>3.25mmol/L) usually indicates malignancy associated hypercalcemia.

2) Symptoms:
 

Neuropsychiatric	Anxiety, depression, cognitive dysfunction In severe cases lethargy and confusion
Gastrointestinal	Abdominal pain, nausea, anorexia and constipation
Renal	- Diabetes insipidis: Inability to concentrate urine, polyuria/polydipsia - Nephrolithiasis: RTA type I: Rare - Nephrocalcinosis from long standing hyperCa: Necrosis of tubular cells and interstitial fibrosis
MSK	- Bony pain (from primary cause ie. Cancer or hyperparathyroidism

"Moans, groans, stones, and psychic overtones"

3) Etiology:

a) PTH Mediated:

• Primary: Sporadic
• Secondary: Renal disease and decreased production of 1,25-dihydroxyvitamin D. Adynamic bone disease results in reduced bone turnover. The reduced uptake of calcium into bones after a calcium load leads to hypercalcemia.
• Tertiary: Prolonged hyperphosphatemia and hypocalcemia leads to hypertrophy of the parathyroid glands and unregulated release of PTH. Occurs in patients post renal transplant.
• Familial: MENI and IIa, familial hypercalciuric hypercalcemia

b) Non-PTH mediated

• Malignancy:
• Osteolytic: Bone mets resulting in induction of local osteolysis by tumor cells and release of osteoclast activating factors in multiple myeloma
• PTHrp: some tumors produce PTH related peptide that mimics PTH. These include squamous cell carcinomas (lung and H+N), breast, bladder, ovarian
• Ectopic PTH secreting tumor
• Granulomatous disease
•  Activation of extra-renal 1-aOH leading in macrophages and/or lymphocytes. Leading to PTH-independent production of 1,25-dihydroxy Vitamin D
• Drugs:
• Lithium
• Thiazides
• Increased Vitamin D intake
• Miscellaneous:
• Immobility
• Hyperthyroidism
• Pheochromocytoma
• Adrenal insufficiency
• Milk alkali syndrome: excessive ingestion of Calcium supplements
• Paget's disease

4) Treatment:

• The cornerstone of treatment is: FLUIDS, FLUIDS, FLUIDS
• Patients are often quitet hypovolemic secondary to their inability to concentrate urine and nephrogenic diabetes insipidus
• The kidneys should be able to excrete the majority of excess calcium
• Also consider:
• Calcitonin: 4u/kg IM/SC rapid reduction in serum Ca by 1-2mmol/L. Works in 4-6 hrs.
• Bisphosphonates: Pamidronate 30mg, 60mg, 90mg IV. More sustained reduction in Ca, takes 1-2 days to start working.
• Steroids: Prednisone 20-40mg/day. Decreases conversion of 25 hydroxyvitamin D to 1,25-dihydroxyvitamin D
• Lasix: Caution as this can cause worsening hypercalcemia. Only used of pt is showing signs of volume overload from fluid resuscitation. see article from Annals of Internal Medicine: Furosemide fro Hypercalcemia: An unproven yet common practice