Hypercalcaemia of malignancy
Hypercalcaemia of malignancy

Hypercalcaemia of malignancy

Hypercalcaemia of malignancy (HCM) is a severe metabolic complication of cancer patients. HCM occurs when the the serum calcium levels exceed the normal limit of 2.6mmol/L. This is due to dysregulation of calcium homeostasis seen in malignancy. It is usually an indicator of advanced disease. It most commonly occurs in breast cancer, lung cancer, multiple myeloma and renal cell carcinoma. It is important to treat aggressively due to the life-threatening complications that may occur if untreated.

Pathophysiology

HCM can be a multifactorial process - lets take a look at the 5 causes of HCM:

  1. Humoral hyprcalcaemia of malignancy

      2. It is the most common cause of HCM (seen in about 80% of cases). Parathyroid hormone-related protein (PTHrP) is a protein secreted by tumour cells and mimics the action of parathyroid hormone (PTH). PTHrP works by:

    1. Enhancing osteoclastic resorption of bone
    2. Suppressing osteoblastic bone formation
    3. Increasing renal calcium reabsorption
    4. Reducing phosphate reabsorption - leading to hypophosphataemia and hyperphosphaturia.

      5. It is common in renal cancer, breast cancer, ovarian cancer, endometrial cancer and squamous cell carcinoma (lung, head & neck, oesophagus).

  2. Osteolytic hypercalcaemia

    3. Local bone destruction by metastatic cancer cells or in cases of multiple myeloma leads to osteoclast activation and release of calcium from the bone matrix. Cytokines such as IL-6 and IL-1 and hormones such as PTHrP causes osteoclast activation and bone resorption.

    It is seen in cancers such as multiple myeloma, breast cancer and lymphomas.

  3. Vitamin D-mediated hypercalcaemia

    4. The enzyme which converts vitamin D from its inactive calcifediol form (25-hydroxyvitamin D) to its active calcitriol form (1,25-dihydroxyvitamin D) is 1-alpha-hydroxylase. This enzyme is over-expressed by malignant cells or by the adjacent non-malignant cells. This leads to to excessive calcitriol which works by increasing calcium absorption from the intestines, enhance bone resorption and reduces calcium excretion.

    It occurs in all types of lymphoma, and granulomatous diseases (sarcoidosis and tuberculosis).

  4. Ectopic hyperparathyroidism

    5. A rarer cause in which the tumour cells secreter PTH to mimic primary hyperparathyroidism.

    It is seen in small cell lung cancer and ovarian cancer.

  5. Immobility-induced hypercalcaemia

    6. In advanced cancer patients immobility leads to increased osteoclastic activity and reduced osteoblastic activity which results in hypercalcaemia.

🔢 Classification

Severity
Level (mmol/L)
Clinical significance
Normal
2.2 - 2.6
N/A
Mild
2.6 - 3.0
Often asymptomatic, sometimes may have mild fatigue.
Moderate
3.0 - 3.5
Symptoms present, needing prompt management.
Severe
>3.5
Medical emergency - at risk of arrhythmias and coma.

😷 Presentation

  • Hypercalcaemia features:

      • Remember that hypercalcaemia causes: “stones, bones, abdominal groans, moans, thrones and psychic overtones”.

    1. Stones: 
      • Renal stones (nephrolithiasis) causing pain, and nephrocalcinosis (Albright calcinosis) which is the deposition of calcium oxalate/calcium phosphate in the kidneys.
    2. Bones:
      • Bone related complications like bone pain, arthralgia, myalgia.
      • Hypercalcaemia can lead to osteoporosis, osteomalacia, arthritis and pathological fractures.
    3. Abdominal groans:
      • Gastrointestinal symptoms like pain, nausea, vomiting and constipation.
      • Hypercalcaemia can lead to peptic ulcer disease and acute pancreatitis.
    4. Moans: 
      • Fatigue and malaise.
    5. Thrones (sitting on the toilet - referring to the toilet as a throne):
      • Polyuria, polydipsia (sitting on the toilet as you are sitting on a throne), because hypercalcaemia impairs urine concentration that is refractory to ADH administration → nephrogenic diabetes insipidus.
    6. Psychic overtones: 
      • Lethargy, confusion, depression and memory loss.

🔍 Investigations

  • Bloods
    • Total serum calcium & serum ionised calcium
    • Albumin - as albumin binds calcium, so low free albumin may suggest hypercalcaemia
    • Comprehensive metabolic panel - may show elevated urea or bicarbonate in AKI.
    • PTH - elevated in PTH-mediated hypercalcaemia, suppressed in malignancy-associated hypercalcaemia unless concurrent primary hyperparathyroidism or ectopic PTH are present.
    • PHTrP - should be ordered if initial PTH level is low or if PTH level is normal to high despite the presence of a known malignancy. It is low in humoral hypercalcaemia of malignancy.
    • Phosphorus - should be ordered if initial PTH level is low in the presence of lymphoma and/or granulomatous disease is suspected. Raised in humoral hypercalcaemia of malignancy, as PTHrP acts at the level of the kidney to reduce calcium clearance, as well as to reduce the renal phosphorus threshold.
    • Calcitriol - elevated in calcitriol-mediated hypercalcaemia. Should be ordered if initial PTH level is low in the presence of lymphoma and/or granulomatous disease.
    • 25-hydroxyvitamin D - for therapeutic reasons as administration of subcutaneous denosumab or IV bisphosphonates necessitate normal vitamin D levels due to risk of hypocalcaemia and BRONJ.
  • ECG - to assess the QT interval which may be shortened. J waves (Osborn waves) may be present in severe hypercalcaemia.
    • 💡 The normal QT interval is 350-450 ms for adult men and from 360-460 ms for adult women.
      • image

Consider doing some imaging such as:

  • Skeletal survey - if suspecting MM, bone metastases, leukaemia. May show osteopenia, osteolytic bone lesions, pathological fractures.
  • CXR - may show typical findings of lung cancer, sarcoidosis or tuberculosis.

🧰 Management

🧰

Management of hypercalcaemia in malignancy:

  • Mild/asymptomatic HCM
    • Manage the underlying malignancy.
    • Monitor - the calcium levels should go down over 5 days.
    • Supportive measures - primarily emphasising adequate fluid intake and stopping medications that may worsen the hypercalcaemia (such as thiazide diuretics, vitamin D and calcium supplements, antacids and lithium).
  • Moderate-severe/symptomatic HCM:

      • The same principles apply as with mild/asymptomatic HCM, but we can also provide:

    1. IV fluids - 1 litre of sodium chloride 0.9% over 4 hours.
    2. Bisphosphonates - bisphosphonates are the most effective agent for HCM. They work by preventing osteoclastic bone resorption, by binding to the osteoclast and inhibiting their resorptive function. They also inhibit farnesyl synthase enzyme, and this inhibits cholesterol synthesis which in turn inhibits resorption, bone turnover, and osteoporotic fracture risk. Reducing resorption means less calcium secretion from bone and control of the hypercalcaemia.
      • IV pamidronate disodium or IV zoledronic acid
      • Subcutaneous denosumab - may be given if bisphosphonates are not suitable (such as in cases of chronic kidney disease (CKD)).

        • If the patient has advanced CKD then in addition to the denosumab we should also provide dialysis.

    3. Prednisolone - if there is vitamin-D mediated hypercalcaemia (as seen in lymphoma or granulomatous disease). Glucocorticoids work by inhibiting 1-alpha-hydroxylase and as such prevent excessive vitamin D formation and its effects on calcium.
💡
A bit about bisphosphonates and denosumab…

Bisphosphonates

Bisphosphonates work by inhibiting bone resorption by osteoclasts. They work by binding to hydroxyapatite at sites of remodelling. When osteoclasts bind to these sites they take up bisphosphonates intracellularly. Inside the cell they inhibit the enzyme farnesyl diphosphate synthase. Farnesyl synthase is an important enzyme in the mevalonate pathway - a pathway that is crucial for the prenylation (adding a lipid group to a protein to allow it to attach to cell membranes) of small GTPase proteins that are integral to osteoclast function and survival.

🚨 Adverse effects/complications:

Bisphosphonates have poor bioavailability, so very high oral doses need to be given. This may result in:

  • Oesophageal corrosion
  • Peptic and duodenal ulcers
  • Osteonecrosis of the jaw (BRONJ)
  • Prolonged treatment of >5 years may result in low-impact femoral fractures.

⚠️ It cannot be used in patient with an eGFR <30.

💡 Patients should be counselled on on taking bisphosphonates due to the risk it poses of oesophageal corrosion. Patients should be advised on taking the tablet with a large glass of water and remaining upright for 30 minutes after ingestion. It should be taken in the morning 30 minutes prior before any food or beverage.

Denosumab

RANKL (receptor activator of nuclear factor kappa-ß ligand) produced by osteoblasts and osteocytes promotes osteoclastic differentiation (osteoclastogenesis) when bound to the RANK receptor. Osteoprotegrin (OPG) is a decoy receptor that may intercept RANKL to prevent it binding to the RANK receptor thus inhibiting osteoclastogenesis and osteoclast activity.

Denosumab is a monoclonal antibody that binds to RANKL to prevent it binding to the RANK receptor. It acts similarly to how osteoprotegrin naturally acts.

🚨 Complications

  • Renal failure (nephrocalcinosis)
  • Cardiac arrhythmias - such as shortened QT-interval and sudden death.
  • Osteoporosis and fractures
  • Neurological dysfunction - such as seizures and coma.