An interesting case of Hypercalcemia of malignancy.

Original case by Cheng Cheng, Jose Kuzhively, and Sanford Baim

A 26-year-old African American male, with no significant past medical history, presented to the emergency department in early November 2016 with complaints of fever, malaise, 18 lb weight loss over 2 weeks, and multiple neck masses

Q  What is definition of clinically significant weight loss ?

>5% weight loss over period of 6-12 months

Q  What is Cachexia and Sarcopenia ?

  1. Sarcopenia- reduction in muscle mass, strength or function with or without weight loss- eg: Sarcopenia can also occur in obese
  2. Cachexia= weight loss + loss of muscle mass

Q  Enlist the causes of unintentional weight loss ?

VINDICATE

  1. Vascular- CCF- Cardiac cachexia
  2. Infective- HIV, tuberculosis
  3. Neoplasm – malignant – GI and Non GI malignancies
  4. Drugs
  5. Autoimmune – Lawrence syndrome- acquired generalized lipodystrophy
  6. E- Endocrinopathies- see next page
  7. Non maligant GI disorder
  8. Pulmonary disorder- COPD, Pulmonary chachexia
  9. Pyschiatric problems- anorexia nervosa, depression
  10. Neurological disorders
  11. Rheumatological disorders
  12. CKD
  13. CLD

Q  What are endocrine causes of weight loss ?

  1. Adrenal insufficiency
  2. Hyperthyroidism
  3. Type 1 diabetes
  4. Glucogonoma
  5. Pheochromocytoma
  6. Endocrine malignacies

Medications prior to admission consisted of cyclobenzaprine, meloxicam, tramadol, and recreational use of marijuana. Initial imaging revealed an anterior mediastinal mass with intrathoracic lymphadenopathy, bilateral pulmonary nodules, and spine lesions on CT

Q Name some important causes of anterior mediastinal mass ?

  1. Thymic mass- thymic enlargement or thymic carcinoma
  2. Lymphoma
  3. Substernal/ ectopic goiter
  4. Germ cell tumor- mediastinum is the most common site for extragonadal germ cell tumors

Q Which endocrine related condition must be ruled out in case of mediastinal germ cell tumors ?

  • Klienfelter syndrome

Physical exam demonstrated bilateral supraclavicular lymphadenopathy that was tender to palpation, pain on palpation of the cervical and lumbar spine, and normal neurological exam.

Labs on admission were notable for corrected total calcium (Calc) of 15.1 mg/dL, ionized calcium (iCa) of 1.59 mg/dL (ref: 0.95–1.32 mg/dL), PTH of 4.8 pg/mL (ref: 8–85 pg/mL), phosphorus (Phos) of 2 mg/dL (ref: 2/5–4.6 mg/dL), creatinine of 1.16 mg/dL (ref: 0.75–1.2 mg/dL), and blood count with no atypical cells seen on the differential

Q What is your interpretation of the cause of hypercalcemia in this case ?

  • This is hypercalcemia with clearly suppressed PTH.
  • This is most certainly a case of PTH independent hypercalcemia.
  • Q What PTH value suggest PTH independent hypercalcemia ?
  • Typically PTH <20 pg/ml generally suggest PTH independent hypercalcemia ?

Aggressive IV hydration with normal saline at a rate of 250 cc/hr was promptly started and maintained throughout this admission with administration of pamidronate 90 mg on hospital day 2.

Q Give the proposed line of treatment for severe hypercalcemia ?

  • Injection Normal Saline
    • 250 ml/hr for 2 hrs followed
    • 150 ml/hr for next 20 hrs
    • 100 m/hr for next 24 hrs
    • Diuretics not used routinely and given only if the patient develops fluid overload or has congestive cardiac failure.
  • Inj CALCITONIN (inj BIOCALCIN)
    • TEST DOSE : 4 units / kg subcutaneously stat (Approximately 200 units) – repeat serum calcium after 3 hrs. If there is no fall in calcium or patient has reaction to calcitonin then it is not continued any more – If the response is seen then give a dose of 4 units/kg subcutenously every 12 hrs
    • Increase the dose to 8 units/kg every 12 hrs if little response seen in 1-2 days. The dose and frequency may be further increased upto maximum dose of 8 units/kg every 6 hrs
    • Effect seen for generally 3-5 days only . After this tachyphylaxis to calcitonin often develops
    • Patient may develop nausea and vomiting with calcitonin. Inj EMSET (ondensatron) may be given sos if nausea/ vomiting develops
  • Inj Zolendronic acid (Inj NATZOLD)
    • Given on first or second day itself
    • Avoided if Parathyroid surgery is planned within 1-2 days
      • 150 ml of Normal saline f/b
      • Inj NATZOLD 5 mg (100ml) infusion over 15 min f.b
      • 150 ml of normal saline
    • W/f fever, joint pain etc for 24 hrs- if this develop NSAIDs may be given
    • Take 2-5 days for onset of effect
    • Effect lasts for 2-8 weeks. In patient with malignancy associated hypercalcemia which cannot be treated otherwise- the dose may be repeated after 1 month
  • CINACALCET (Tablet PTH)
    • 30 mg OD starting dose ( Maximum of 90 mg QID)
    • Given as alternate to Zolendronate in patients with hyperparathyroidism in whom surgery is planned
  • Hemodialysis
    • Considered in patients with acute renal failure and/or Serum Calcium >18 mg/dl with neurological symptoms
  • Denusomab
    • Indications
      • Hypercalcemia with renal failure
      • Hypercalcemia refractory to bisphosphonates
    • Dose
      • Inj XGEVA – 120 mg subcutaneously weekly for 4 weeks followed by monthly
    • Glucocorticoid
      • Inj Hydrocortisone (Inj Effcorlin) 100 mg IV /8hrly
      • Or if patient takes orally T. Prednisolone ( Wysolone) 40 mg per day
      • Given in case of vitamin D toxicity or granulomatous disease associated hypercalcemia
    • Once the patient becomes better and the etiology for hypercalcemia not treated then patient advice
      • Good oral hydration- 6-8 glasses of water /day
      • Low calcium diet
      • Avoid prolonged bedrest
      • Avoid thiazide diuretics
    • Check serum calcium and serum creatinine daily

Additional studies included supraclavicular lymph node and bone marrow biopsies consistent with Epstein-Barr virus positive metastatic undifferentiated, non-keratinizing, lymphoepithelioma-like carcinoma of thymic origin. After undergoing staging with additional imaging, the patient completed his first cycle of chemotherapy with cisplatin, doxorubicin, and cytoxan in the next 2 weeks. His Calc decreased to 10.5 mg/dL at the time of discharge.

Approximately 2 weeks after discharge, the patient was readmitted for a second admission with increasing somnolence. Laboratory analysis disclosed Calc of 15.4 mg/dL and iCa of 1.72 mg/dL for which IV hydration with normal saline at 250 cc/hr was initiated followed by pamidronate 90 mg and calcitonin 300 U with improvement of iCa to as low as 1.16 mg/dL.

PTH-related peptide (PTHrP) and 1,25-dihydroxyvitamin D (calcitriol) were sent during this admission but results were not available.

Figure 

Q Why did they send 1,25 dihydroxyvitamin D ?

    • Granulomatous disease increase produce of 1 alpha hydroxylase enzyme leading to increase 1,25 dihydroxyvitamin D levels.

Q What is the differene in actions of PTHrP and PTH in relation to calcium and phosphate ?

    • PTHrP does not increase 1,25 dihydroxy vitamin D, however it does cause phosphaturia.
    • Hence in case of a PTHrP producing tumor the typical biochemical picture is as follows:
  1. Serum calcium- high
  2. Serum phosphate- low
  3. PTH- low
  4. 1,25 dihydroxyvitamin D – low

Repeat MRI of the entire spine noted new hyperintense metastatic lesions.

Over the ensuing 3 days, iCa slowly increased to 1.46 mg/dL and required administration of zoledronate 4 mg resulting in normalization of iCa between 1 and 1.1 mg/dL for the rest of the admission (Figure 1). The patient subsequently began cycle 2 of cisplatin, doxorubicin, and cytoxan which was completed prior to discharge with a plan to initiate denosumab as an outpatient

During outpatient follow-up and 5 days after discharge, a rapid rebound in hypercalcemia occurred with Calc of 12.6 mg/dL and iCa of 1.46 mg/dL, requiring administration of denosumab 120 mg which decreased iCa to 1.25 mg/dL (Figure 1). A second dose of denosumab 120 mg was given 1 week later with concurrent Calc of 12.7 mg/dL.

Q What percentage of calcium is ionized  ?

  • 50% of calcium is in ionized form
  • 40% – protein bound
  • 10% – bound to inorganic acids
  • Q In which conditions is measurement of ionized calcium important ?
  1. Acid base disorder
  2. Hypoalbuminemia
  3. CKD

Q How is mmol/l converted to mg/dl ?

  • Mmol/lt = (mg/dl x 10 ) / mol wt

Q What is the conversion for calcium ?

  • Mol wt is 40 and valence is 2
  • Mg/dl divide by 4 = mmol/lt

Q How is calcium adjusted for albumin ?

  • Correct calcium = measured calcium + 0.8 x (4- measured serum albumin)
  • Total calcium falls by 0.8 mg/dl for every 1 g/dl fall in albumin

Q What happens in patients with multiple myeloma ?

  • They have pseudohypercalcemia
  • This is because of increase of calcium bound to myeloma cells
  • Since MM itself may be associated with increase calcium, it is important to use ionized calcium for the same

Q How do acid base disorders change ionized calcium ?

  • Alkalosis – there is increase binding of calcium to albumin thus reducing ionized calcium

Q What is the effect of PTH on ionized calcium ?

  • PTH sepearates calcium from albumin and increases the ionized calcium

Q What is the effect of phosphate on ionized calcium ?

  • Acute hyperphosphatemia will reduce the ionized calcium
  • This is because it will bind with the ionized calcium
  • Gradually the total calcium will also drop

Q Why is total calcium and calcium calculations not reliable in patients with CKD ?

  1. CKD patients have metabolic acidosis hence higher ionized calcium
  2. The albumin correction formula overestimates the ionized calcium in CKD patients

Hence in CKD patients it is preferable to measure ionized calcium directly

Q What is the normal ionized calcium value in adults ?

  • In adults normal values of ionized calcium is  64 to 5.28 mg/dl
  • This is equivalent to 1.15 to 1.3 mmol/ (approx)

One month later, the patient was readmitted with altered mental status with Calc of 13.6 mg/dL, iCa of 1.53 mg/dL, Phos of 1.6 mg/dL, and normal renal function. The patient received prompt administration of IV hydration with normal saline and pamidronate 90 mg. Although iCa level decreased to 1.3–1.4 mg/dL within 2 days, it rebounded over the next 24–48 hours to 1.64 mg/dL, requiring further administration of zoledronate 4 mg

At this time, it was noted that his 1,25-dihydroxyvitamin D level from the previous admission was elevated at 131 pg/mL (ref: 18–64 pg/mL) and PTHrP at 27 pg/mL (ref: 14–27 pg/mL). Methylprednisolone 60 mg per day was subsequently instituted over the next 2 days with decrease in iCa level to 1.3–1.4 mg/dL

However, the patient continued to clinically deteriorate, despite iCa being maintained at 1.3–1.4 mg/dL (Figure 1) with development of multiorgan failure, and he expired shortly after. It is noteworthy that the third admission repeated PTHrP and calcitriol levels that returned to the medical record posthumously were 58 pg/mL and 499 pg/mL, respectively.

Q What will you suspect in a case of hypercalcemia associated in malignancy where PTHrP and 1,25 dihydroxyvitamin D are normal, PTH is suppressed and there is no evidence of osteolytic metastasis ?

  • Think of Hypercalcemia of malignancy associated with cytokine/chemokine associated bone resorption.

Q Enlist the etiologies for hypercalcemia of malignancy ?

  1. Local osteolytic hypercalcemia – due to osteolytic metastasis
  2. Increase 1,25 dihydroxy vitamin D production
  3. Ectopic PTHrP production
  4. Ectopic PTH production
  5. Cytokine/chemokine associated hypercalcemia

https://www.hindawi.com/journals/crie/2017/2608392/tab1/

Q What is the possible etiology of hypercalcemia in this case ?

  • In this case multiple reasons for hypercalcemia may be present either togather or evolving over time.
  • The patient has
  1. Metastasis to the bones which may have been osteolytic (“Repeat MRI of the entire spine noted new hyperintense metastatic lesions)
  2. Increase 1,25 dihydroxyvitamin D levels due to tumor producing 1 alpha hydroxylase.  (it was noted that his 1,25-dihydroxyvitamin D level from the previous admission was elevated at 131 pg/mL (ref: 18–64 pg/mL)
  3. Ectopic PTHrP production (It is noteworthy that the third admission repeated PTHrP and calcitriol levels that returned to the medical record posthumously were 58 pg/mL and 499 pg/mL, respectively)
  4. Hypercalcemia secondary to cytokine / chemokines.

Learning objective

  • In a patient with hypercalcemia of malignancy , multiple causes of hypercalcemia may exist in the same patient.
  • Denusomab is useful in case of hypercalcemia refractory to bisphosphonate therapy.

 

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