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Hypercalcemia of malignancy

Increase in the serum calcium level above the upper limit of normal for a given reference value used in a laboratory.

We have used the acronym HCM ie hypercalcemia of malignancy for our purpose to describe the condition in this review here

 

Also known by other names as
○ hypercalcemia of malignancy ( HCM )
○ malignancy related hypercalcemia
○ humoral hypercalcemia of malignancy ( HHM ) Seen frequently in patients with cancer particularly advanced cancer Can be seen in up to 10 % to 30 % of patient with cancer during the course of their disease 
( can be seen with any type of tumour ) Most common cause of raised calcium in hospitalised patients is malignancy Multiple myeloma is the most common cancer associated with HCM
○ seen in both- patients with solid tumours and haematological malignancies 
○ others include lung and renal , breast and lung
○ squamous cancers ( lymphomas and leukaemias )
○ seen less commonly with prostate cancer ( even with extensive bony metastases )

 

What happens – Metabolic disorder The most common causes of hypercalcemia are hyperparathyroidism and malignancy
 Three main mechanisms of HCM – have been implicated
○ excessive secretion of parathyroid hormone related protein
○ local osteolytic hypercalcemia
○ production of 1,25-dihydroxy vitamin ( calcitriol )
 About 80 % of cases are due to systemic secretion of parathyroid hormone related protein ( PTHrP ) by a malignant tumour
○ excessive PTHrP is also called as humoral hypercalcemia
○ under normal circumstances PTHrP participates in development of various tissues , facilitates transplacental calcium transport and promotes calcium transfer to breast milk
○ ↑↑ PTHrP increases bone resorption & reduced renal clearance of calcium leading to HCM
 Local osteoclastic hypercalcemia ( LOH ) responsible in about 20 % of cases
○ bony metastases causing ↑ Ca seen in patients with multiple myeloma & solid organ tumours which metastasize to bones such as breast cancer
○ local release of cytokines → recruits / promotes osteoclast differentiation and function leading to ↑↑ bone resorption and kidneys capacity to clear Ca is overwhelmed
 1,25 ( OH )2 vitamin D secreting lymphomas or dysgerminomas are responsible for less than 1 % cases ( ↑ ed intestinal absorption of Ca + enhanced osteoclastic bone resorption )

 

poor prognostic sign -HCM typically seen in advanced malignancy patients with HCM tend to have limites survival of several months prognosis for solid tumours is generally poor once hypercalcemia occurs – tumour load is already extensive it is not clear if asymptomatic hypercalcemia heralds the onset of cancer later

 

Assessment – manifestation depend on degree of hypercalcemia and rapidity of development levels > 3.0 mmol/L are significant ↑ Calcium can affects several organ systems presentation can be non-specific – often develops gradually and may resemble the symptoms of the underlying malignancy and its treatment it is generally noted that HCM patients have a higher degree of hypercalcemia & this develops over a shorter period of time the severity of symptoms are not necessarily indicative of the level of hypercalcemia presenting symptoms can include nausea , vomiting , abdominal pain , constipation ,bone pain , fatigue ,confusion , polyuria , polydipsia in severe degree of hypercalcemia confusion and coma may happen.

 

Renal – polydipsia , polyuria , nephrogenic diabetes insipidus , renal insufficiency , distal tubular acidosis ( RTA ) secondary to nephrolithiasis polyuria along with ↓↓ intake can lead to hypovolemia

 

Gastro-intestinal mild elevation causes anorexia & constipation larger elevation can lead to nausea and vomiting peptic ulcers due to gastrin secretion pancreatitis can also happen – mechanism of this is unknown.

 

Neurological – anxiety , mood changes , ↓↓ in cognitive function , fatigue severe cases change in mental state , coma posterior reversible leukoencephalopathy ( PRES ) -headaches , seizures and imaging findings of subcortical edema

 

Cardiological – short QT interval in severe ↑↑ ST segment myocardial infarction mimic , malignant ventricular arrhythmias and hypertension

 

cancer patients with hypercalcemia can present with severe symptoms and this is often a true oncological emergency thorough history and physical full medical hx ( ? known bone / liver metastases ) assess fluid balance ( BP , pulse ) previous lab results to gauge baseline level and duration / rapidity dietary ( is the patient able to eat and drink ) vomiting / bowel movements mental state ? sudden onset confusion medications ( check all OTC and prescribed medications for e.g thiazides , oral calcium , Vit A or D supplements ) in presence of hypercalcemia a normal or raised PTH is pathological dehydration – body tries to excrete calcium causing polyuria and loss of Na , K+ & Mg+ in the proximal renal tubule – nephrons loose concentrating ability leading to dehydration acute kidney injury is likely the most frequently encountered manifestation of end organ damage if left untreated calcium level of > 4 mmol/L can be rapidly fatal.

 

There are no standard guidelines for management of HCM in primary care. If in doubt seek advice / help 
The management of patients in a hospital settings would be managed
 by a multi-disciplinary team.

 

Elevated PTHrP with a depressed or low normal PTH suggests humoral hypercalcemia or malignancy
 A low to normal phosphorus and low 1,25-dihdroxyvitamin D confirms the diagnosis.

 

adrenal insufficiency crohn’s disease electrolyte disturbances as hyperkalaemia , hypermagnesemia , hypernatremia , hyperphosphataemia hyperparathyroidism hyperthyroidism.

 

Take into account factors as
○ balance of benefits versus burden of treating hypercalcemia
○ stage of the disease 
○ care setting
○ patient preferences / acceptance / carer’s family wishes – is the patient willing to have intravenous treatment and blood tests in hospital environment Consider reversible causes – for e,g stop thiazide diuretuc / any calcium / Vit D supplements Review any drugs which may affect renal flow eg NSAIDs , diuretics , ACE inhibitors , ARBs If the patient is dying imminently focus on symptom control Mild to moderate hypercalcemia in an asymptomatic patient does not require immediate management -advice the patient about diet ( low calcium diet ) , medications and avoiding dehydration and physical inactivity Sternlicht H and Glezernab IG in their article ” Hypercalcemia of malignancy and new treatment options ” quote that patients with asymptomatic or mildy symptomatic disease
( serum calcium < 3 mmol / L ) should be managed supportively until a definitive diagnosis has been obtained and chemotherapy initiated.

 

It is important to consider the fact symptomatology is a function of both the absolute serum calcium conentration and the rate of rise of the serum calcium . Any level of 3.0 mmol or more is significant ( likely to be symptomatic ) and you should consider seeking advice / admission based on circumstances

 

Patient is symptomatic ie moderate to severe symptoms as polyuria , dehydration , renal failure , drowsiness , mental dullness , confusion , worsening of underlying cancer pain , delirium , coma ,myoclonus

 

Acute management is in hospital 
setting with fluid resuscitation as patients are dehydrated and Na depleted

 

Once patient has stabilised
 The management options for patients with hypercalcemia are
○ calcitonin
○ bisphosphonates
○ desnosumab
○ gallium nitrate
○ prednisolone
○ haemodialysis
 Treatment is rapidly effective and good symptom control can be achieved

 

Oncological emergency

 

Once patient has stabilised
 The management options for patients with hypercalcemia are
○ calcitonin
○ bisphosphonates
○ denosumab
○ gallium nitrate
○ prednisolone
○ haemodialysis
 Treatment is rapidly effective and good symptom control can be achieved

References

  1. Vakiti A, Mewawalla P. Malignancy-Related Hypercalcemia. [Updated 2021 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482423/
  2. Zagzag, J., Hu, M.I., Fisher, S.B. and Perrier, N.D. (2018), Hypercalcemia and cancer: Differential diagnosis and treatment. CA: A Cancer Journal for Clinicians, 68: 377-386. https://doi.org/10.3322/caac.21489
  3. Scottish Palliative Care Guidelines Hypercalcemia Scottish Palliative Care Guidelines – Hypercalcaemia
  4. Mirrakhimov, Aibek E. “Hypercalcemia of Malignancy: An Update on Pathogenesis and Management.” North American journal of medical sciences vol. 7,11 (2015): 483-93. doi:10.4103/1947-2714.170600
  5. Sternlicht H, Glezerman IG. Hypercalcemia of malignancy and new treatment options. Ther Clin Risk Manag. 2015;11:1779-1788
    https://doi.org/10.2147/TCRM.S83681
  6. Onco-Nephrology: The Pathophysiology and Treatment of Malignancy-Associated Hypercalcemia
    Mitchell H. RosnerAlan C. Dalkin
  7. Specialist Palliative Care advice and Guideline Group – Management of Hypercalcemia in pregnancy Palliative Care Shared Care Guidelines (wmcares.org.uk)

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