arrangoiz – Rodrigo Arrangoiz MS, MD, FACS, FSSO

Malignancy-Associated Hypercalcemia (MAH) – Epidemiology
- Occurs in 20% to 30% of patients with cancer during their disease course
- Accounts for roughly 90% of hypercalcemia cases in hospitalized patients
- Most common cause of hypercalcemia in hospitalized patients:
  - Whereas primary hyperparathyroidism is most common in the outpatient setting
- Most common cancers Table 1
- Overall prognosis:
  - Median survival after diagnosis of MAH – 3 to 4 months
    - Indicates advanced malignancy
Mechanisms of Hypercalcemia in Malignancy:
- Humoral Hypercalcemia of Malignancy (HHM):
  - Accounts for ~ 80% of cases
  - Pathophysiology:
    - Tumor secretes PTH-related peptide (PTHrP)
    - PTHrP mimics PTH actions:
      - ↑ osteoclastic bone resorption
      - ↑ renal calcium reabsorption
      - ↓ phosphate
    - Laboratory profile Table 2
    - Common cancers:
      - Squamous cell lung carcinoma
      - Head and neck squamous cell carcinoma
      - Renal cell carcinoma
      - Bladder cancer
      - Ovarian cancer
  - Clinical features:
    - Rapid onset
    - Often severe hypercalcemia
    - Advanced malignancy
- Osteolytic Metastases:
  - ~ 20% of cases
  - Pathophysiology:
    - Direct tumor invasion of bone:
      - Stimulate osteoclast activity via the release of:
        
        IL-1
        
        IL-6
        
        TNF
        
        RANKL
        
        These cytokines stimulate osteoclasts → localized bone destruction → calcium release
    - Direct bone destruction → calcium release
  - Typical malignancies:
    - Breast cancer
    - Multiple myeloma:
      - Myeloma cells activate osteoclasts
      - Suppress osteoblast activity
      - Produce osteolytic lesions
    - Lymphoma
    - Metastatic prostate (less common cause of hypercalcemia)
  - Laboratory profile Table 3
- Vitamin D–Mediated Hypercalcemia:
  - Rare (less than 1% to 2% of the cases)
  - Pathophysiology:
    - Tumor produces 1-alpha hydroxylase
    - ↑ conversion of 25-OH vitamin D → 1,25-OH vitamin D
  - Seen in:
    - Hodgkin lymphoma
    - Non-Hodgkin lymphoma
    - Some granulomatous tumors
  - Laboratory profile Table 4
- Ectopic PTH Production:
  - Extremely rare (< 1%of the cases)
  - True PTH secretion by tumor
  - Seen in:
    - Small cell lung cancer
    - Ovarian carcinoma
Clinical Manifestations:
- Symptoms depend on rate of rise and level of calcium
  - Neurologic:
    - Confusion
    - Lethargy
    - Coma
  - Gastrointestinal:
    - Nausea
    - Constipation
    - Pancreatitis
  - Renal:
    - Polyuria
    - Dehydration
    - Acute kidney injury
  - Cardiac:
    - Shortened QT interval
    - Arrhythmias
Laboratory Clues Distinguishing MAH from PHPT Table 5
Treatment:
- Immediate Management:
  - Aggressive IV hydration (normal saline)
  - Calcitonin:
    - Rapid onset (4 to 6 hours):
      - Temporary effect
  - IV bisphosphonates:
    - Zoledronic acid
    - Pamidronate
      - Onset:
        
        24 to 48 hours
- Refractory Hypercalcemia:
  - Denosumab
  - Glucocorticoids (vitamin D–mediated cases)
  - Dialysis (severe renal failure)
Key Teaching Points for Residents:
- Malignancy = most common cause of hypercalcemia in hospitalized patients
- PTH is suppressed
- PTHrP accounts for ~ 80% of cases
- Severe calcium (>14 mg/dL) should raise suspicion for malignancy
- Median survival ~ 3 to 4 months → poor prognostic marker
Key References:
- Stewart AF. Hypercalcemia associated with cancer. N Engl J Med. 2005;352:373–379.’
- Clines GA. Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes.2011;18:339–346.
- Goldner W. Cancer-related hypercalcemia. J Oncol Pract. 2016;12:426–432.
- Mirrakhimov AE. Hypercalcemia of malignancy: pathogenesis and treatment. North Am J Med Sci.2015;7:483–493.

Cancer Type	Frequency of MAH
Lung cancer (especially squamous cell)	~25–30%
Breast cancer	~20–25%
Multiple myeloma	~15–20%
Renal cell carcinoma	~5–10%
Head and neck squamous cell carcinoma	~5–10%
Others (ovarian, lymphoma, bladder)	<5%

Table 1: Cancers most commonly associated with Malignancy-Associated Hypercalcemia

Test	Result
Calcium	↑
PTH	Suppressed
PTHrP	Elevated
Phosphate	Low
1,25-vitamin D	Low/normal

Table 2: Laboratory Profile of Humoral Hypercalcemia of Malignancy

Test	Result
Calcium	↑
PTH	Suppressed
PTHrP	Normal
Vitamin D	Normal

Table 3: Laboratory Profile of Osteolytic Bone Metastases

Test	Result
Calcium	↑
PTH	Suppressed
1,25-OH vitamin D	Elevated

Table 4: Laboratory Profile of Vitamin D–Mediated Hypercalcemia

Feature	Primary Hyperparathyroidism	Malignancy Hypercalcemia
PTH	High or inappropriately normal	Suppressed
Calcium level	Mild–moderate (10.5–12 mg/dL)	Often >13–14 mg/dL
Symptom onset	Chronic	Acute / severe
PTHrP	Normal	Elevated (HHM)
Vitamin D	Normal	May be elevated in lymphoma

Table 5: Laboratory Clues Distinguishing MAH from PHPT

Thyroglobulin (Tg):
- Is a large glycoprotein that is stored as colloid:
  - The primary storage form of thyroid hormone, in the lumen of thyroid follicles
- It is continuously secreted into circulation from the thyroid gland:
  - Thereby reflecting the mass of normal and malignant thyroid tissue
Higher serum concentrations result from:
- TSH stimulation and / or injury of thyroid tissue:
  - However, for the individual with an intact thyroid gland:
    - Its clinical value for evaluating thyroid dysfunction or goiter is limited in the era of modern serum thyroid function testing and imaging
    - However, the demonstration of a suppressed serum Tg level in such a patient can be useful in differentiating factitious thyrotoxicosis (from exogenous thyroid hormone ingestion) from excessive endogenous thyroid hormone release of any etiology:
      - In this situation, when thyrotoxicosis is due to ingestion of exogenous thyroid hormone:
        
        Normal thyroid hormone production is suppressed and serum Tg levels are decreased
      - In contrast, if excess thyroid hormone is produced from the thyroid:
        
        Serum Tg levels are elevated
In current clinical practice:
- The primary use of serum Tg concentrations is as a tumor marker in patients with differentiated thyroid cancer:
  - That is obtained to detect persistent and / or recurrent disease after a total thyroidectomy and radioactive iodine (131I) ablation
Most Tg assays have only first-generation functional sensitivity between 0.5 and 1 ng/mL:
- But the second generation Tg assays are rapidly becoming the standard and have an improved functional sensitivity of 0.05 to 0.1 ng/mL
The Tg assay can be made more sensitive to detect persistent or recurrent tumor:
- After stimulation by TSH:
  - Either endogenously by withholding thyroxine treatment in an athyreotic patient or with administration of recombinant human TSH (rhTSH):
    - The latter of which results in an approximate tenfold increase in basal serum Tg concentrations
Detection of persistent and / or recurrent disease in thyroid cancer depends on the performance of Tg immunometric assays:
- Which currently have suboptimal sensitivity and high interassay variability
Virtually all immunometric methods:
- Will report an undetectable Tg level in euthyroid Tg Ab positive controls:
  - Approximately 25% of patients with differentiated thyroid cancer have a positive serum TgAb titer:
    - Thus when a suspicious lymph node or neck mass is detected in an individual who has undergone a total thyroidectomy:
      - An unmeasurable basal or rhTSH-stimulated Tg in the setting of a positive serum TgAb level:
        
        Does not necessarily exclude thyroid cancer recurrence
    - It is reasonable in this relatively uncommon situation to measure Tg instead by Tg Ab-resistant radioimmunoassay (RIA) or liquid chromatography tandem mass spectrometry:
      - Which are available at some specialty endocrine laboratories.
When the serum Tg Ab titer is positive:
- It may also be used as a surrogate marker of tumor persistence / recurrence
In one study, a > 50% decrease of Tg Ab levels within the first year after a total thyroidectomy:
- Was associated with the absence of tumor recurrence / persistence in all patients studied
- Tumor recurrence / persistence was present in 37% of patients who had any rise of serum Tg Ab within the same period
Thus thyroid cancer patients with rising Tg antibody levels:
- Are at high risk for disease persistence / recurrence and should be evaluated promptly
- In addition, the sensitivities and absolute values reported by different methods of measuring Tg and TgAb are highly variable:
  - It is essential to always use the same Tg and TgAb method when following an individual over time for tumor persistence/recurrence
Finally, the presence of interfering heterophile antibodies (antibodies against the animal-derived antibodies used in the immunometric assay):
- May rarely result in abnormally high or low serum Tg levels
- The most common interfering antibodies are HAMAs:
  - Clinically, this should be suspected when an elevated serum Tg level is inappropriate for the clinical situation and does not increase with rhTSH stimulation
  - When heterophile antibody is suspected, the clinician should repeat the test using a commercially available heterophile-blocking tube (HBT) or measure Tg with an RIA assay

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Malignancy-Associated Hypercalcemia (MAH)

Diagnostic Thyroid Testing: Serum Thyroglobulin

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