Hypercalcemia

Created on Thu, 06/25/2015 - 17:57
Last updated on Sun, 09/25/2016 - 03:24

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The hypercalcemia questions in the CICM fellowhsip exam are numerous, and largely focused on the treatment strategies available. Only the question from 2000 went indepth into the investigations of it, and in 2011 some detail about the mechanism of malignancy-associated hypercalcemia was expected.

  • Question 9 from the second paper of 2013 (clinical features and management)
  • Question 18.1 from the first paper of 2011 (diagnostic tests, management, and the mechanism of hypercalcemia associated with malignancy)
  • Question 14.2 from the first paper of 2009 (correction of calcium for albumin, and management)
  • Question 5 from the first paper of 2001 (management)
  • Question 6 from the second paper of 2000 (diagnostic pathway, and management)

Oh's manual only dedicates two short paragraph to this electrolyte disturbance. The LITFL page is an excellent replacement. If one has all the time in the world, one may also wish to explore the world literature, which is best represented by Carroll et al (2003)  and the more detailed Shane et al (1999).

Causes of Hypercalcemia, by Pathophysiology

Primary endocrine causes

  • Primary hyperparathyroidism
  • Thyrotoxicosis
  • Adrenal insufficiency

Paraneoplastic causes

  • PTH-related protein
    • carcinoma of lung
    • oesophageal carcinoma
    • head and neck SCC
    • renal cell carcinoma
    • Breast cancer
    • Ovarian cancer
    • Bladder cancer
  • Ectopic 1,25-dihydroxyvitamin D
    • Lymphoma
  • Lytic bone lesions
    • Multiple myeloma
    • Breast cancer
    • Hematological malignancies
  • Phaeochromocytoma
  • VIP-secreting gastric adenoma

Granulomatous disease

  • Sarcoidosis
  • HIV
  • Tuberculosis
  • Histoplasmosis
  • Coccidioidomycosis
  • Leprosy

Drug-induced hypercalcemia

  • Vitamin D oversupplementation
  • Thiazide diuretics
  • Lithium carbonate
  • Oestrogens and HRT
  • Androgens
  • Theophylline and aminophylline
  • Vitamin A
  • Aluminum toxicity
  • Total parenteral nutrition (TPN)

Random miscellaneous causes

  • Immobilization (eg. spinal injury)
  • Chronic renal failure
  • Milk alkali syndrome
  • Rhabdomyolysis*

*Yes, rhabdomyolysis is usually associated with hypocalcemia initially. However later in the evolution of the AKI there is hypercalcemia. This paper by Shane and Irani (2006) lists it as one of the causes in their table 2 on page 177. Looking deeper into it, one can find that this happens because sequestered calcium is released from the complexes which had formed in the injured muscle, during the convalescent phase of trauma.

It is also possible (perhaps, desirable) to organise the causes of hypercalcemia according to the tests which end up being abnormal. Classically, this is done by separating them into PTH-related and PTH-unrelated causes.

Causes of Hypercalcemia with a High Parathyroid Hormone Level
  • Primary hyperparathyroidism
Causes of Hypercalcemia with a Low Parathyroid Hormone Level

With raised PTH-related-protein:

  • carcinoma of lung
  • oesophageal carcinoma
  • head and neck SCC
  • renal cell carcinoma
  • Breast cancer
  • Ovarian cancer
  • Bladder cancer

With raised 25-hydroxyvitamin D levels

  • Vitamin D oversupplementation
  • Lymphoma

With lytic bone lesions, and normal PTHrp/Vit D

  • Multiple myeloma
  • Breast cancer
  • Hematological malignancies
  • Phaeochromocytoma
  • VIP-secreting gastric adenoma

With raised 1,25-dihydroxyvitamin D levels

  • Extra-renal production of Vit D:
    • Sarcoidosis
    • HIV
    • Tuberculosis
    • Histoplasmosis
    • Coccidioidomycosis
    • Leprosy
  • Could still be primary hyperparathyroidism

Random miscellaneous causes without malignancy or Vit D disturbances

  • Thiazide diuretics
  • Lithium carbonate
  • Oestrogens and HRT
  • Androgens
  • Theophylline and aminophylline
  • Vitamin A
  • Aluminum toxicity
  • Total parenteral nutrition (TPN)
  • Immobilization (eg. spinal injury)
  • Chronic renal failure
  • Milk alkali syndrome
  • Rhabdomyolysis

Clinical manifestations of hypercalcemia

In brief, in the exam one should write something about the following classical features:

Early manifestations (levels < 3.5mmol/L)

  • Constipation
  • Peptic ulcer exacerbation
  • Polyuria
  • Nephrogenic diabetes insipidus
  • Nephrolithiasis
  • Type 1 (distal) renal tubular acidosis
  • Shortened QT interval
  • Bone pain

Late manifestations (levels over 3.5mmol/L)

  • Pancreatitis
  • Renal failure (due to vasoconstriction)
  • Hypertension
  • Delirium, progressing to coma
  • Arrhythmia
  • Muscle weakness

If one has the appetite for detail, Table 1 from Shane et al (1999) offers an abundance of it. It has been reproduced below, with some omissions which the author thought were reasonable (for instance, "cardiac arrest" and "death" were omitted from the list of cardiovascular manifestations).

Clinical Manifestations of Hypocalcemia

Cardiovascular

  • Shortened QT interval on ECG
  • Arrhthymias (rare unless on digitalis)
  • Bradycardia
  • Hypertension
  • Bundle branch/AV blocks

Neuromuscular

  • Emotional lability
  • Confusion
  • Delirium
  • Psychosis
  • Stupor
  • Muscle weakness
  • Headache
  • Seizures (rare)

 Renal

  • Polyuria
  • Polydispsia
  • Nocturia
  • Hypercalciuria
  • Nephrolithiasis
  • Nephrocalcinosis
  • Renal failure

Gastrointestinal

  • Nausea/vomiting
  • Anorexia
  • Constipation
  • Abdominal pain
  • Peptic ulcers
  • Pancreatitis
  • Skeletal
  • Bone pain/arthralgia
  • Osteopenia/osteoporosis in cortical bone (often seen in wrist)

Investigation of hypercalcemia

Causes such as renal failure and prolonged immobility can usually be ruled out (or in) immediately after meeting the patient. Similarly, one can easily look at their drugs and see whether something iatrogenic is responsible. Then, one is left with primary endocrine disturbances and malignancy.

Thus, one may wish to launch the following investigations:

  • Alkaline phosphatase
  • Serum PTH level
  • CK
  • Parathyroid hormone related peptide (PTHrp)
  • Serum Vitamin D metabolite levels
  • CXR - or better yet, CT chest - to look for obvious malignancy and granulomatous disease.

Correction of total calcium for a low albumin

The following formula was first described by Payne et al in 1973.

Corrected calcium = (0.02 × (normal albumin - patient's albumin)) + serum calcium

This issue has come up in Question 14.2 from the first paper of 2009.

Management of hypercalcemia

The management of hypercalcemia follows a stepwise pattern, progressing from mild inoffensive interventions to invasive and dangerous methods. This chapter focuses on the management of the numerical calcium abnormality, because after all its all about the numbers. Particularly, numbers like 3.5mmol/L and other numbers of greater magnitude. Though the pursuit of numerical normality may seem meaningless to the non-critical-care physician population, the number representing calcium concentration does in fact have certain physiological correlations- such as coma and death- and so perhaps there is perhaps some value in paying attention to this isolated numerical abnormality.

In brief, these are the physiological aims for management of hypercalcemia, and the means to achieve them:

  • Dilute serum calcium
    • Rehydration with IV fluids
  • Decrease calcium resportion from bone
    • Calcitonin
    • Bisphosphonates
    • Gallium nitrate
    • Mithramycin (for malignant disease)
  • Decrease calcium resportion from renal tubule
    • Loop diuretics (this has fallen out of favour)
    • Calcitonin
  • Decrease calcium absorption from the gut
    • Corticosteroids (also they decrease the 1,25-dihydroxyvitamin D production by monocytes within granulomae)
  • Forcibly remove excess calcium from the circulation
    • Haemodialysis
    • EDTA administration (as chelating agent)

Rehydration

Dehydration could be contributing - perhaps not to the genesis of the hypercalcemia, but at least to its maintenance. The restoration of intravascular volume will bring about better renal perfusion, and with it perhaps some sort of tubular sanity. Calcium should start to be excreted. This intervention is cheap, largely harmless, and the results should be seen within hours.

Bisphosphonates

If one is convinced that the source of the extra calcium is bone (which is usually the case - where else would it come from) then the inhibition of osteoclast activity is a sensible response. Locally, pamidronate infusion is used, and a protocol exists whereby a dose is calculated according to the magnitude of hypercalcemia. A range of 30-90mg is administered. This is not an intervention which favours immediate gratification - up to 3 days may pass before a meaningful decrease in calcium levels is observed.

 

References

UpToDate has a nice chapter on this topic, for the paying customer.

Stewart, Andrew F. "Hypercalcemia associated with cancer." New England Journal of Medicine 352.4 (2005): 373-379.

Zawada Jr, E. T., D. B. Lee, and C. R. Kleeman. "Causes of hypercalcemia."Postgraduate medicine 66.4 (1979): 91-7.

Shane, Elizabeth, and I. Dinaz. "Hypercalcemia: pathogenesis, clinical manifestations, differential diagnosis, and management." Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Favus MJ (ed.). Philadelphia: Lippincott, Williams &Wilkins (1999): 183-87.

Endres, David B. "Investigation of hypercalcemia." Clinical biochemistry 45.12 (2012): 954-963.

UpToDate has a nice summary of this topic for the paying customer.

Stewart, Andrew F. "Hypercalcemia associated with cancer." New England Journal of Medicine 352.4 (2005): 373-379.

Shane, Elizabeth, and I. Dinaz. "Hypercalcemia: pathogenesis, clinical manifestations, differential diagnosis, and management." Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Favus MJ (ed.). Philadelphia: Lippincott, Williams &Wilkins (1999): 183-87.

Edelson, Gary W., and Michael Kleerekoper. "Hypercalcemic crisis." The Medical Clinics of North America 79.1 (1995): 79-92.

Carrol, Mary F., and David S. Schade. "A practical approach to hypercalcemia." Am Fam Physician 67 (2003): 1959-1966.

(for malignant disease)

Graziani, Giorgio, et al. "Life-threatening hypercalcemia in patients with rhabdomyolysis-induced oliguric acute renal failure." J Nephrol 24.1 (2011): 128-31.