Hypercalcemia  (Hypercalcemia) is a condition that indicates an elevated calcium (Ca2+) level in the blood. It may be presented as acute, chronic, or transitional dysfunction.

With mild hypercalcemia below 12mg/dL, many individuals stay virtually asymptomatic, although the symptoms thought to be always present in mild form, such as elevated thirst, anxiety, sleep problems and fatigue. Hypercalcemia can occur due to abnormally high skeletal calcium release mediated by parathyroid hormone release, increased intestinal calcium absorption, or decreased renal efficiency of calcium excretion.

The neuromuscular side effects of hypercalcemia are caused by a negative bathmotropic effect resulting from increased interaction of calcium with sodium channels. This raises the threshold for depolarization because calcium blocks sodium channels and inhibits depolarization of muscle and nerve fibers. This appears contributes to chronic painful syndromes development such as Myofascial pain syndrome and fibromyalgia.

Hypercalcemia increases urinary excretion of ionized calcium (iCa), ionized magnesium (iMg), sodium, phosphate, potassium, and chloride.

Causes of Hypercalcemia

When PTH is high and calcium is normal or high

Parathyroid hormone increases osteoclast activity and the osteoclasts break down bone, which increases blood levels of calcium.

  • Hyperparathyroidism – marked by high PTH levels overactivity of parathyroid glands [srs]
    • Primary hyperparathyroidism
      • Causes: Enlargement of parathyroid glands
      • Tests: Elevated PTH hormone, elevated calcium, low vitamin D
    • Secondary hyperparathyroidism
      • Causes: Deficiency of vitamin D levels either due to dietary deficiency or kidney failure
      • Tests: Elevated PTH hormone, low calcium, low vitamin D
  • Familial hypocalciuric hypercalcemia is a condition where a serum calcium level typically above 10.2 mg/dL. Mostly associated with loss of function mutations in the CASR gene, which encodes a calcium-sensing receptor, expressed in parathyroid and kidney tissue. The perceived lack of calcium levels by the parathyroid leads to high levels of parathyroid hormone, resulting in hypercalcemia.
  • Immunoreactive PTH (iPTH) secretion by histamine effect on H2 receptors [srs]
  • Multiple endocrine neoplasia (MEN) [srs]
  • Hyperthyroidism or excessive thyroid hormone intake
  • Addison’s disease
  • Paget’s disease of bone
  • Postmenopausal syndrome
  • Teriparatide intake, a recombinant form of parathyroid hormone, used in the treatment of osteoporosis
  • Nutritional
    • Magnesium deficiency – low magnesium levels inhibit parathyroid PTH release and can mimic hypoparathyroidism
    • Vitamin D with calcium supplementation dramatically increases calcium levels [srs]
    • Lysine (amino acid) supplementation
    • Calcium imbalance in addition to calcium and potassium rich diet and low magnesium
    • Potassium excess antagonizing magnesium and causing secondary magnesium deficiency
    • Lithium toxicity may increase the release of parathyroid hormone and cause hypercalcemia
    • Hypervitaminosis with A [srs] or D [srs] vitamins. Continuous supplementation with vitamin A is associated with with osteoporosis and hip fractures apparently due to vitamin a impairing the expression of proteins dependent on vitamin K to reduce the efficacy of vitamin D. Studies have linked high vitamin A doses with increased bone resorption and decreased bone formation. Vitamins A and D may also compete for the receptors that affects parathyroid hormone production that affects the levels of calcium in serum.
    • Milk-alkali syndrome [srs] (Regular milk and/or antacids consumption. Inhibits parathyroid hormone secretion by the parathyroid gland due to excess calcium and may also lead to metabolic alkalosis [srs] and diabetes insipidus.)
    • Aluminium intoxication

       

When PTH is low and calcium is normal or high (non-parathyroid-related reasons for the elevated calcium)

  • Viral infection, such as by herpes family viruses
  • Hypercalcaemia of malignancy – Tumours secreting PTH related peptide which mimics PTH – squamous cell tumours of head, oesophagus, neck lung, renal cell carcinoma and breast cancer. Associated with weight loss and presented with elevated calcium and normal or low PTH
  • PTH-Independent hypercalcemia due to lymphoma, granuloma or paraneoplastic hypercalcemia caused by parathyroid related peptide (PTHRP)
  • An autoimmune disorder
  • Excess calcium has been ingested over a long period of time (from milk or certain antacids)
  • Low levels of magnesium in the blood
  • Radiation exposure
  • Vitamin D intoxication
  • Magnesium deficiency [srs] Low magnesium levels inhibit PTH release and can mimic hypoparathyroidism
  • Sarcoidosis – inflammation in the lymph nodes, lungs, liver, eyes, skin, or other tissues
  • Thiazide diuretics can cause elevated calcium levels in blood by decreasing the amount of calcium excreted in urine
  • Dehydration
  • Inherited metabolic or kidney conditions
  • Oxidative stress promotes inflammation, which triggers osteoclasts that break down the bone, increasing calcium levels
  • Mutations of the Ca2+ or PTH receptors cause suppressed PTH secretion by the hypercalcemia and evidence of increased bone resorption

Symptoms

  • Headaches
  • Anxiety [srs]
  • Depression
  • Lethargy and fatigue
  • Cognitive dysfunction
  • Loss of appetite, nausea, bloating due to decrease in decrease in peristalsis
  • Abdominal pain
  • Frequent urination, including night-time urinating (Polyuria due to promotion of renal clearance thru osmotic diuresis)
  • Thirst, dehydration (due to polyuria and renal impairment causing water reabsorption)
  • Constipation due to polyuria which leads to dehydration and hypercalcemia causing a raised action potential (AP) threshold moved away from resting potential (RP) causing decrease in peristalsis (intestinal contraction)
  • Fatigue, decreased stamina, restlessness
  • Anorexia
  • Nausea or vomiting
  • Muscle weakness
  • Muscle, bone and joint aches
  • Numbness
  • Irregular but strong or rapid heartbeat, palpitations
  • Kidney pain due to increased excretion of excess calcium

Complications

  • Low vitamin D levels in blood
  • Magnesium deficiency
  • Hypokalemia
  • Corneal calcification
  • Pancreatitis or pancreatic insufficiency by secretory block, build up of secretory proteins, activation of proteases
  • Stomach peptic ulcers due to increase of gastrin production
  • Kidney stones and possibly kidney failure

Testing

The typical representation of hypercalcemia is generally raised PTH levels, hypophosphataemia and an increase in 24-hour urinary calcium excretion, increased serum creatinine levels.

Parathyroid hormone (PTH) values should be interpreted together with serum calcium and phosphorus levels, and the clinical presentation and history of an individual.

  • Calcium and magnesium can be measured by a mineral hair analysis test. Note that calcium levels may appear lower on the mineral hair test if magnesium levels are low, as deficiency in magnesium may reduce excretion of calcium.
  • Magnesium blood levels can be measured via blood serum testing, however, the redulst can be misleading since only about 1% of magnesium is found in blood, and about 0.3% is found in blood serum, therefore clinical blood serum testing may not successfully identify magnesium deficiency.
  • Calcium blood levels may reflect a minimal relationship between symptoms of hypercalcemia and the actual level of calcium. Calcium in serum is bound to proteins, principally albumin. As a result, total serum calcium concentrations in patients with high or low serum albumin levels may not accurately represent the physiologically important ionized or free calcium concentration. In patients with hypoalbuminemia for example, total serum calcium concentration may be normal when serum ionized calcium is elevated.
  • Phosphorus
    • A low PTH and high phosphorus levels  in hypercalcemia suggests that hypercalcemia is not caused by a transitional increase in levels of parathyroid hormone or PTH-like substances.
    • An low PTH level with a low phosphorus level in hypercalcemia suggests the diagnosis of paraneoplastic hypercalcemia caused by parathyroid related peptide (PTHRP). PTHRP shares N-terminal homology with PTH and can transactivate the PTH receptor. This can be produced by different tumor types.
  • Parathyroid hormone-related protein (PTHrP) must be evaluated if cancer is suspected. When a tumor secretes PTHrP, this can lead to hypercalcemia.

About 90% of the individuals with primary hyperparathyroidism have elevated PTH levels. The rest, have normal (inappropriate for the elevated calcium level) PTH levels. About 40% of individuals with primary hyperparathyroidism have serum phosphorus levels <2.5 mg/dL and about 80% have serum phosphorus <3.0 mg/dL.

The following table may be helpful in interpreting laboratory results:

Interpreting Hypercalcaemia Laboratory Values
Condition Serum Phosphate Serum Alkaline Phosphatase Urine Calcium Urine Phosphate PTH
Hyperparathyroidism Low Normal-high High (in 67% of patients) High High
Vitamin D excess Normal-high Low High High Low
Malignancy Often low High (except in haematological malignancy, when normal) Variable High Variable
Granulomatous disease Normal-high Normal-high High Normal Low
Milk alkali syndrome Normal-high Normal Normal Normal Low
Familial hypocalciuric hypercalcemia Normal or low Normal Low (<200 mg/day) Normal High

Treatment of hypercalcemia

The goal is to first reduce the blood concentration of calcium and treat the underlying cause immediately after.

Decreasing calcium concentrations

  • Strength training, weight bearing – lifting weights and performing muscle development exercises can reduce calcium levels in the blood by strengthening the bones.
  • Dietary adjustments and supplements
    • Increase fluids intake to promote calcium excretion via urine
    • Increase dietary salt intake (use sea salt only). Increased sodium intake will help to increase the body fluid retention, while increasing urinary sodium excretion along with calcium excretion as sodium and calcium are handled similarly by kidneys.
    • Supplements
      • Magnesium 400-800 mg, daily, in divided doses or magnesium oil. Note, when deficient, magnesium oil may cause itching. Supplementing with magnesium orally for a few days prior to using magnesium oil, may help reduce itching. It may take up to 12 months to normalize magnesium levels when supplementing orally. Transdermal magnesium oil may restore magnesium levels within a few weeks.
      • Potassium excretion is elevated when calcium levels are high. A banana per day can be sufficient to keep the potassium levels in check. Over supplementing on potassium can also cause magnesium deficiency.
      • Vitamin K2 200-1000 mcg in divided doses daily. Deficiency is implicated in deposition of calcium on artery walls and other tissues. Vitamin K2 is required to carboxylate vitamin K-dependent Gla-proteins, including essential for bone health osteocalcin and matrix-Gla protein that prevents calcification of soft tissues. Vitamins A, D and magnesium should also be taken as a complex with K2.
      • Probiotics of wide spectrum may be necessary if intestinal flora is not balanced, which will further hinder the absorption of B group vitamins and vitamin K2.
      • Strontium Citrate (if deficient only) boosts osteoblast production and bone synthesis and helps to maintain a more alkaline pH whereas an acidic pH causes activation of osteoclasts that break down the bone, releasing more calcium into the blood. Strontium may slightly lower PTH and calcium levels.
    • Avoid
      • Vitamins A, D supplementation without co-factors of Vitamin K, boron and magnesium [srs]. Vitamin D uses vitamin K-dependent proteins, therefore in case of vitamin K deficiency, the malformed proteins may be formed causing vitamin D toxicity and ultimately hypercalcemia.
      • Calcium supplements as they increase calcium levels
      • Glycine supplementation – increases intracellular calcium concentration [srs]
      • Zinc supplementation – reduces magnesium and potassium levels
      • Dairy (except cottage cheese)
      • Nightshade vegetables as they are rich in calcitriol which raises blood calcium. Naturally ripen nightshade vegetables are better than commercially gas ripen.
      • Molasses
    • Limit
      • Vegetables: arugula, broccoli, chard or okra, spinach
      • Fruits: figs, oranges
      • Legumes: tofu, soybeans
      • Grains: cereals and breads (calcium fortified)
      • Oatmeal (instant)
      • Nuts & seeds: sesame, almonds, sunflower
      • Fish: Mackerel (canned), salmon, sardines
  • Calcium intake should not be drastically limited and must meet daily requirements but not exceeded

    Age

    Calcium (mg)  

    1 – 3 year old

    500 mg    

    4 — 8 year old

    800 mg

    9 – 18 year old

    1300 mg

    19 – 50 year old

    1000 mg

    51 – 70 year old     

    1200 mg

    70 and older

    1200 mg

Drugs

  • Calcitonin, a hormone produced by the thyroid gland, can reduce bone reabsorption and slow bone loss
  • Glucocorticoids (corticosteroids) to help counter the effects of too much vitamin D in blood if present
  • Cinacalcet (Sensipar), has been shown to lower calcium levels in the blood by reducing production of parathyroid hormone, may be effective for some people with hyperparathyroidism.
  • Alendronate (Fosamax), risedronate (Actonel) or ibandronate (Boniva) — in case of osteoporosis may preserve bone mass in spine and hip, reducing risk of fractures.

Surgery

In case of hyperparathyroidism, abnormal parathyroid gland(s) are advised to be removed for long term benefits.

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