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.

 

CASE 5- A CASE OF HYPERCALCEMIA

Original Case by Kuhadiya et al (AACE Case reports)

A 49-year-old Caucasian female with no significant medical history was referred for evaluation of primary hyperparathyroidism. She reported increased thirst and urination and weight gain of 10 lbs in the previous year.

Q What are clinical features of Hypercalcemia ?

  1. GI symptoms
    1. vomiting
    2. constipation
    3. anorexia
    4. abdominal pain (? Pancreatitis)
  2. Renal Symptoms- because of nephrogenic Diabetes insipidus
    1. Polyuria
    2. Polydipsia
  3. CNS symptoms
    1. Confusion
    2. Agitation
    3. Delirium
    4. Loss of consciousness
  4. CVS symptoms
    1. Bradyarrhythmia
    2. Hypertension

Paired corrected calcium, albumin, and intact PTH levels measured on 2 separate days 3 months apart were 9.82 mg/dL, 4.6g/dL, and 63.9 pg/mL and 10.0 mg/dL, 5.0 g/dL, and 58.9 pg/mL, respectively (normal ranges: 8.6–10.2 mg/dL, 3.5–5.2 g/dL, and <65 pg/mL). Her vitamin D-25 OH level was 31 ng/dL. Measurements for 24-hour urinary calcium and phosphate levels were 400 mg (normal: <250) and 1,169 mg (normal: 170–1,200). Urinary calcium/creatinine ratio was 299 mg/g (normal: <275). Serum total calcium levels obtained on 5 different occasions ranged from 9.7 to 10.8 mg/dL with inappropriately high PTH levels ranging from 53.3 to 97.7 pg/mL. A sestamibi scan did not reveal a parathyroid adenoma, but there was radioligand uptake in the midline at the skull base, a location consistent with a pituitary adenoma. (Figure)

Q Can a Sestamibi scan detect a Pituitary adenoma ?

Yes. Kojima et al have shown that Tc99 sestamibi can accumulate the in the Pituitary adenoma where as the tracer does not accumulate in normal pituitary.

Serum cortisol levels (7:15 am) 17.4 mcg/dL and 24-hour urinary free cortisol (UFC) levels were found to be elevated on 2 occasions 150 and 135.8 mcg (normal: <50). Her cortisol level was not suppressed after 1-mg overnight dexamethasone suppression test (DST) (presuppression: 18.3, postsuppresion: 6.3 mcg/dL). Measurements of 11 pm salivary cortisol levels on 2 separate days were elevated at 0.35 mcg/dL (normal: <0.09) and 0.14 mcg/dL (normal: <0.09).

Q What is your inference of the above cortisol reports ?

These reports suggest presence of Cushing’s syndrome.

Q What is the normal response expected in case of 1 mg overnight dexamethasone suppression test ?

The cortisol should be less than 1.8 ug/dl

Q What would you do further for evaluation of Cushing’s syndrome ?

Eventhough there is already a presence of a Pituitary tumor detected assuming we donot have an evidence of that I would check the ACTH level next.

Her baseline ACTH was 30 pg/mL.

Q What is interpretation of her ACTH level ?

ACTH <10 pg/ml suggest ACTH independent Cushing’s syndrome while level >25 pg/ml is suggestive of ACTH dependent Cushing’s. I would think this is ACTH dependent Cushing’s .

Q Again, forgetting that we already have a Pituitary tumor, what would be the next step in this case ?

Since we are suspected ACTH dependent Cushing’s I would a high dose dexamethasone suppression test.

With the high-dose overnight 8-mg DST, the cortisol levels were suppressed to 1.2 mcg/dL from 15.9 mcg/dL.

Q What is the interpretation of this high dose dexamethasone suppression test and what would be your next step ?

I would think we are dealing with either a Pituitary microadenoma or a rare possibility of Bronchial carcinoid secreting ACTH. My next step would be a MRI Pituitary protocol.

Pituitary MRI was unremarkable (Figure) (Sagittal view)  

Q What would your next step be ?

We would probably consider doing a Bilateral inferior petrosal sinus sampling (BIPSS)

IPSS Data (click here)

Q What is your interpretation of IPSS data ?

Basal Central : Peripheral ratio (right) 2.5 :1
Basal Central : peripheral ratio (left) 1.25: 1
Stimulated Central : Peripheral ratio (right) 15.5 :1 (highest ratio is taken)
Stimulated Central : Peripheral ratio (right) 1.5 :1
Basal right:left 2:1
Stimulated Right : Left 10:1

From this IPSS report my interpretation is that we are dealing with a Right sided Pituitary microadenoma.

Note on Interpretation of IPSS

  1. Basal ratio ACTH – from central : peripheral > 2:1 – s/o of pituitary Cushing’s ie IPSS positive
  2. Post stimulated- take the highest ratio – central : peripheral > 3:1 – Positive IPSS
  3. For lateralization Central : peripheral ratio > 1.4:1 (both basal and stimulated) suggests Tumor of that side

 

Q So what is your interpretation at this stage ?

Since we are dealing with a Hyperparathyroidism with probably a Pituitary microadenoma (Cushing’s syndrome) I would think a possibility of MEN1 syndrome.

Q How will you explain the absence of any uptake on Sestamibi parathyroid scan ?

MEN1 syndrome patients often have Parathyroid hyperplasia and may not have a parathyroid adenoma. In presence of hyperplasia, the Parathyroid scan may not pick up any tracer uptake.

Contrast-enhanced CT scan of chest, abdomen, and pelvis did not reveal an ectopic ACTH source. A dual-energy X-ray absorptiometry scan performed in 2011 had revealed osteopenia of lumbar spine, osteoporosis of the right femoral neck, and osteopenia of left femoral neck (T-scores of –2.2, –2.5, and –2.1, respectively). The patient’s preoperative luteinizing hormone and follicle-stimulating hormone levels were 44.3 mU/mL and 50.1 mU/mL, respectively, confirming menopause. Her fasting glucose levels were consistently <100 mg/dL; therefore, no oral glucose tolerance test was performed.

Q What treatment would you offer here ?

I would refer to the neurosurgeon for a Transphenoidal hemi-hypophysectomy of the right side

Transsphenoidal resection of 40% of the pituitary gland revealed an ACTH-producing corticotroph adenoma.

Q What is the definition of remission after transsphenoid surgery for Cushing’s disease ?

Remission is defined as post operative Cortisol levels of <5 ug/dl within 7 days of surgery.

Q What the chances of remission in this case ?

Since this was a microadenoma, chances of remission are around 70% .

Q How long would glucocorticoid replacement be required in this case ?

It would be require till HPA axis recovers which could take 6-12 months.

Q Why do patients with Cushing’s who undergo a surgery feel worse after the surgery ?

This is because of sudden withdrawal of glucocorticoids (Glucocorticoid withdrawal syndrome) . It can last for upto 1 year after the surgery.

Q What is the dose of Hydrocortisone given at discharge in such patients ?

Hydrocortisone is given in the dose of 10-12 mg/m2/day in 2-3 divided doses

Q How do you taper the steroid dose in such a patients ?

  1. Patient is discharged on dose as mentioned above
  2. He is asked to get a morning cortisol done before the next steroid dose
  3. If the morning cortisol is <5 ug/dl then the same dose is continued and patient is rested after 3-6 months
  4. If the morning cortisol is >7.4 ug/dl then perform a ACTH stimulation test after stopping all glucocorticoids.
  5. If either the Baseline of post stimulated cortisol is >18 ug/dl – then the steroids may be stopped.

Q When should GH Levels be tested in adults with Cushing’s ?

Cushing’s also suppresses the GH axis. Hence the GH axis is tested 1 year after treatment of Cushing’s .

Q What else would you do for this patients ?

I would do a genetic testing for MEN1 syndrome. I would also consider doing a 3.5 resection of the parathyroid gland (since the patient has PTH dependent hypercalcemia)

The patient required postoperative steroids for 4.5 months before hypothalamic-pituitary-adrenal axis recovery. At 22 months after pituitary surgery, the patient is in remission with a normal 11 pm salivary cortisol level of 0.06 mcg/dL (normal: ≤0.09), normal plasma ACTH level of 9 pg/mL (normal: 6–50), and a normal 24-hour urinary cortisol level of 20.4 mcg/24 hours (normal: 4–50). Her body mass index had decreased from 27.1 to 25.6. Eight months after the transsphenoidal resection, her calcium levels remained mildly elevated (10.3 to 10.4 mg/mL). After receiving a second opinion, the patient underwent 3.5-gland parathyroidectomy, and her calcium levels remained mildly elevated (10.3–10.9 with a PTH level of 46.8). In the next few months, her calcium varied from 9.7 to 10.7 mg/mL with a PTH level of 41.1 A follow-up sestamibi scan 1 year after surgery continued to show midline pituitary uptake. Genetic testing for a MEN1 mutation was negative.

LEARNING POINTS FROM THIS CASE

 

  1. Sestamibi scan can pick up Pituitary adenoma especially ACTH producing adenomas
  2. On IPSS, Stimulated central:peripheral ratio of >3:1 is suggestive of Central cause of ACTH secreation (Positive IPSS)
  3. Cortisol level <5 ug/dl within 7 days of Pituitary surgery suggest remission from Cushing’s disease
  4. HPA axis post Cushing’s disease surgery may take 12-18 months to recover.
  5. Baseline and stimulated Cortisol level are tested every 3-6 months on follow up. If baseline or stimulated value are >18 ug/dl then it suggests recovery of HPA axis and glucocorticoids may be discontinued.