Oral Presentation 33rd ASM of the Australian & New Zealand Bone & Mineral Society 2023

Diagnostic challenges in a case of refractory severe hypercalcemia: case report (#23)

Jeremy A Knott 1 , Myron Lee 2 , Andrea Rita Horvath 2 , Thaw Htet 1
  1. St George Hospital, Sydney, NSW, Australia
  2. Department of Chemical Pathology, NSW Health Pathology, Sydney, NSW, Australia

Introduction:

Hypercalcemia is a common clinical abnormality with 90% of cases attributed to either malignancy or primary hyperparathyroidism[1]. Other causes of hypercalcaemia often require careful consideration, particularly where preliminary tests are inconclusive or calcium levels are refractory to initial therapy for the suspected underlying cause. Although hypercalcemia is a known metabolic complication of sarcoidosis, it is rarely a presenting manifestation and affects up to 10% of cases[2-5]. The primary mechanism of hypercalcaemia is attributed to increased activity of 1α-hydroxylase enzyme from activated granuloma macrophages, resulting in uncontrolled synthesis of 1,25-dihydroxyvitamin D3(1,25-OHD) from 25-hydroxyvitamin D(OHD)[6]. However, utilising vitamin D metabolites to assess disease activity remains challenging. We present a complex diagnostic and management case of sarcoidosis diagnosed on splenic biopsy, in a 60-year-old Caucasian female who presented with asymptomatic severe hypercalcemia, refractory to conventional therapy, on a background of chronic stage IV diabetic nephropathy.

 

Case presentation:

Our patient presented with severe asymptomatic hypercalcemia with paired CrCa 3.50mmol/L/ PTH 1.1pmol/L on routine serology. She had a normal 25-OHD 68nmol/L, and mildly elevated 1,25-OHD 206pmol/L [60-200] on a background of chronically impaired renal function (creatinine 247umol/L). Serum angiotensin-converting enzyme (ACE) level (enzymatic assay) and parathormone-related peptide (PTHrP) were undetectable. A 24-hour urinary calcium was low 2.0mmol/24h [2.5-7.5]. Whilst undergoing further investigations to ascertain the cause of her PTH-independent hypercalcemia, her corrected calcium level remained persistently elevated above 3.0mmol/L for over five weeks despite intravenous fluids and multiple doses of pamidronate, denosumab, and four aliquots of calcitonin. The patient subsequently underwent a PET scan, which revealed FDG-avid lymphadenopathy and splenic uptake suggestive of lymphoma. A splenic biopsy revealed sarcoid-like well-formed, diffuse granulomas and was subsequently diagnosed with extrapulmonary sarcoidosis.

 64c38ff99521e-PET+scan+image.jpg

Treatment:

Despite high-dose prednisolone therapy for two-weeks, severe hypercalcaemia persisted and deteriorated to 3.41mmol/L. Moreover, judicious use of required intravenous fluid therapy was limited due to her chronic renal impairment. Given her hypercalcemia was not responsive to steroid therapy, coupled with a now normalised repeat 1,25-OHD 161pmol/L, the diagnosis of sarcoid-induced hypercalcemia was questioned.  Conversely, while ACE activity level was undetectable using the routine enzymatic assay, ACE mass level using immunoassay showed high-normal level of 189ug/L [37-221] despite steroid therapy and on an ACE-inhibitor. After multi-disciplinary team discussion, second-line ketoconazole therapy was trialled. There was nil initial improvement in serum calcium until two weeks of ketaconazole therapy (dosed at 200mg before increasing to 600mg), which improved her corrected calcium level to 2.74mmol/L. Currently, after five weeks of ketoconazole and seven weeks of prednisone her calcium levels have now normalised (2.20mmol/L).

 

Discussion:

Hypercalcaemia is a common clinical entity, however sarcoidosis as an aetiology for hypercalcaemia is relatively uncommon. The incidence of hypercalcaemia as the presenting symptom in sarcoidosis is 3%[7], which makes the diagnosis challenging particularly when refractory to conventional therapy. Our case is unique, as there was no other clinical feature or radiographic evidence of systemic sarcoidosis, and diagnosis was suggested only by splenic biopsy. Our case displayed important features: (1)markedly elevated serum calcium levels 3.50mmol/L in the absence of overt systemic sarcoidosis, (2)decreased levels of urinary excretion of calcium as well as normal serum ACE and minimally elevated 1,25-OHD, and (3)hypercalcemia unresponsive to corticosteroid therapy.

Sarcoidosis is an idiopathic, multisystem, granulomatous disease, with extrathoracic splenic involvement occurring in up to 40-60% of cases[8]. Hypercalcemia in sarcoidosis is attributed to three potential mechanisms: (1)systemic extrarenal conversion of 25-OHD to 1,25-OHD by 1α-hydroxylase produced by granulomatous macrophages and the consequential increase in intestinal calcium absorption, (2)granuloma production of PTHrP causing increased renal calcium absorption and bone resorption, similar to humoral hypercalcemia of malignancy, and  (3)tissue-level conversion of 25-OHD to 1,25-OHD by local granulomatous macrophages[9]. Interestingly, our case demonstrated only mildly elevated 1,25-OHD levels, in addition to undetectable PTHrP levels.

 There have been similar case reports in the literature illustrating hypercalcemia with inappropriately normal 1,25-OHD levels in the setting of granuloma-forming disorders[10-12]. Proposed contributing factors for normal 1,25-OHD levels may include increased oral calcium intake, dehydration, and decreased calcium excretion, particularly in renal insufficiency[13], as seen in our patient with a baseline serum creatinine of 247umol/L and decreased calcium excretion. The clinical utility of serum ACE levels in sarcoidosis is also limited due to poor sensitivity and specificity, with high ACE levels occurring in up to 75% of cases[14].

 Corticosteroids are considered first-line therapy in treating sarcoidosis-associated hypercalcemia due to their effectiveness in treating granulomatous inflammation and rapidly correcting hypercalcemia due to a relatively swift decrease in 1,25-OHD and calcium levels typically within 3-5 days[15]. As in our case of steroid-resistant sarcoidosis, ketoconazole may be effective in treating hypercalcemia as it inhibits 1α-hydroxylase required in 1,25-OHD synthesis[16]. Additional steroid-sparing agents, such as infliximab, methotrexate and azathioprine, may also help in treating refractory hypercalcemia by reducing granuloma formation[17].

 

Conclusion:

Our case demonstrates an unusual presentation of extrathoracic sarcoidosis, presenting as prolonged, severe hypercalcemia with inappropriately normal or minimally elevated 1,25-OHD, which was refractory to conventional therapies including fluid therapy, anti-resorptive therapies and high dose steroid therapy. This case highlights the importance of multi-displinary team input in managing uncommon causes such as sarcoidosis as a differential diagnosis for PTH-independent hypercalcaemia, as it has a multisystemic and non-specific presentation, with biopsy and radiographic findings as key to diagnosis. Timely recognition and appropriate treatment with second-line therapy may be necessary to avoid prolonged effects of first-line steroid therapy particularly in cases with prolonged refractory hypercalcemia with multiple co-morbidities such as type 2 diabetes and chronic renal failure.

  

Learning Points:

  1. Sarcoidosis-induced hypercalcemia is uncommon and presents diagnostic challenges.
  2. Persistent levels of severe hypercalcaemia can occur in sarcoidosis despite inappropriately normal or minimally elevated 1,25-OHD levels.
  3. Medications such as ACE-inhibitors and prednisolone should be taken into consideration when interpreting ACE activity levels. Utilising ACE mass assay (immunoassay) rather than an enzymatic assay, may be considered more clinically reliable.
  4. Biopsy and radiographic findings are key to diagnosing sarcoidosis, even without overt systemic features.
  5. Refractory hypercalcemia requires timely recognition and consideration of second-line therapies, such as ketoconazole or other steroid-sparing agents. Multidisciplinary input is vital for managing complex cases effectively.
  1. Walker, M.D. and E. Shane, Hypercalcemia: A Review. Jama, 2022. 328(16): p. 1624-1636.
  2. Adams, J.S., Vitamin D metabolite-mediated hypercalcemia. Endocrinol Metab Clin North Am, 1989. 18(3): p. 765-78.
  3. Sharma, O.P., Vitamin D, calcium, and sarcoidosis. Chest, 1996. 109(2): p. 535-9.
  4. Soto-Gomez, N., J.I. Peters, and A.M. Nambiar, Diagnosis and Management of Sarcoidosis. Am Fam Physician, 2016. 93(10): p. 840-8.
  5. Karnchanasorn, R., et al., Severe hypercalcemia and acute renal failure: an unusual presentation of sarcoidosis. Case Rep Med, 2010. 2010: p. 423659.
  6. Zhou, Y. and E.E. Lower, Balancing Altered Calcium Metabolism with Bone Health in Sarcoidosis. Semin Respir Crit Care Med, 2020. 41(5): p. 618-625.
  7. Baughman, R.P., et al., Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med, 2001. 164(10 Pt 1): p. 1885-9.
  8. Raber, E.L., J. Haba, and P. Beck, Splenic sarcoidosis: a case report and review of the imaging findings of multiple incidental splenic lesions as the initial presentation of sarcoidosis. Can J Gastroenterol, 2011. 25(9): p. 477-8.
  9. Berlin, J.L., et al., Serum vitamin D levels may not reflect tissue-level vitamin D in sarcoidosis. BMJ Case Rep, 2014. 2014.
  10. Falk, S., et al., Hypercalcemia as a result of sarcoidosis with normal serum concentrations of vitamin D. Med Sci Monit, 2007. 13(11): p. Cs133-136.
  11. Gwadera, Ł., et al., Sarcoidosis and calcium homeostasis disturbances-Do we know where we stand? Chron Respir Dis, 2019. 16: p. 1479973119878713.
  12. Unsal, A., et al., Renal sarcoidosis with normal serum vitamin D and refractory hypercalcemia. Int Urol Nephrol, 2013. 45(6): p. 1779-83.
  13. Volpicelli, G., A. Mussa, and M. Frascisco, A case of severe hypercalcemia with acute renal failure in sarcoidosis: a diagnostic challenge for the emergency department. Eur J Emerg Med, 2005. 12(6): p. 320-1.
  14. Ungprasert, P., et al., Diagnostic Utility of Angiotensin-Converting Enzyme in Sarcoidosis: A Population-Based Study. Lung, 2016. 194(1): p. 91-5.
  15. Sharma, O.P., Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulm Med, 2000. 6(5): p. 442-7.
  16. Adams, J.S., et al., Ketoconazole decreases the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia. J Clin Endocrinol Metab, 1990. 70(4): p. 1090-5.
  17. Kiltz, U. and J. Braun, Use of methotrexate in patients with sarcoidosis. Clin Exp Rheumatol, 2010. 28(5 Suppl 61): p. S183-5.