E-Poster Presentation 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

Hypercalcaemia is a very common endocrine condition, yet severe hypercalcaemia as a result of fungal infection is rarely described (1-4). 

A 55 year-old woman of Polynesian descent presented 6 weeks after her second liver transplant with tachycardia and rising inflammatory markers.  She had a history of end stage liver disease due to non-alcoholic steatohepatitis cirrhosis, type 2 diabetes mellitus, obesity, hypertension and recurrent perianal abscesses.  Her first liver transplant four months prior had failed as a result of acute rejection, hepatic bilomas, recurrent Enterococcus and Pseudomonas aeruginosa bacteraemia and cytomegalovirus viraemia.

There was no obvious cause of her tachycardia and rising inflammatory markers which were suspicious for infection.  A computed-tomography pulmonary angiogram revealed bilateral air space opacities (Figure 1).  Her Cryptococcus antigen titre was greater than 1 in 2560.  Culture of bronchial washings demonstrated growth of Cryptococcus neoformans.

The patient was commenced on four weeks of induction therapy with intravenous liposomal amphotericin and oral flucytosine.  Despite antifungal treatment, she subsequently developed invasive fungal skin lesions over her abdomen and thighs (Figure 2) with biopsies demonstrating growth of Cryptococcus neoformans.  She transitioned to consolidation therapy with oral fluconazole.  Ten days later the patient developed further skin lesions, raising concerns about disease progression and she recommenced intravenous liposomal amphotericin and oral flucytosine.  A fluorodeoxyglucose positron emission tomography (FDG-PET) scan demonstrated findings in keeping with disseminated cryptococcosis, with FDG-avid lesions in the lungs as well as substantial subcutaneous and muscle tissue avidity (Figure 3).

Three weeks after her presentation, she was noted to have an elevated corrected calcium of 2.79 mmol/L.  Her calcium concentrations were observed and continued to steadily rise.  Further investigations when corrected calcium was 3.17 mmol/L demonstrated that the ionised calcium was 1.69 mmol/L (1.12-1.30), the parathyroid hormone 1.1 pmol/L (0.7-4.1), 25-hydroxy-vitamin D (25-OH D) 59 nmol/L and 1,25-dihydroxy-vitamin D (1,25-OH D) 219 pmol/L (50-190).  The parathyroid hormone was measured on the Diasorin Liaison (1-84) assay which was subsequently found to report falsely high values at the lower end of the reference range.  Her albumin was 35 g/L and estimated glomerular filtration rate was 61 ml/min/1.73m².

The patient was surprisingly asymptomatic from the hypercalcaemia.  She remained alert and oriented, and did not experience polyuria or polydipsia.  Throughout her hospitalisation she remained ambulant, mobile and had consumed a regular diet without any nutritional or calcium supplementation. She was hypervolaemic due to large volumes of intravenous hydration to minimise amphotericin-induced nephrotoxicity.  Consequently, she had signs of mild pulmonary oedema on chest radiography which improved with diuretic therapy.

As the cause of her hypercalcaemia was not immediately apparent, she was observed for several days before treatment with 30mg of intravenous pamidronate.  Despite this, the corrected calcium continued to rise, peaking at 3.82 mmol/L.  The patient received a 48 hour course of intravenous calcitonin 100mg six-hourly followed by 60mg of subcutaneous denosumab.  The calcium slowly decreased, but remained above 3 mmol/L.  Two weeks later, the patient had a liver biopsy demonstrating acute liver rejection and was treated with intravenous pulse methylprednisolone.  The calcium levels sharply declined and normalised within several days (Figure 4).  There were no granulomas on the skin or liver biopsies.

Hypercalcaemia mediated by 1,25-OH D has been described as a rare complication of fungal infections.  There are only two case reports in the literature of hypercalcaemia associated with Cryptococcus neoformans infection (1,2).  In both of these cases, the patients were infected with HIV and had a low CD4 lymphocyte count.  Whilst the case described by Spindel had disseminated multiorgan Cryptococcus infection (1), Ali et al describe isolated pulmonary Cryptococcus neoformans and Coccidioides immitis infection (2).  Both cases had an elevated 1,25-OH D and a peak corrected calcium in the range of 3.30-3.60 mmol/L.  Hypercalcaemia was managed with intravenous fluids, antifungal treatment and one of the cases required intravenous pamidronate and hydrocortisone.  Resolution of the hypercalcaemia coincided with resolution of the Cryptococcus infection.  Tuberculosis and lymphoma were excluded as alternative causes of hypercalcaemia.

Although the mechanism of hypercalcaemia in these infections is not clear, the fact that 1,25-OH D levels were elevated in all three cases suggests that the hypercalcaemia could be at least partly driven by the extra-renal production of 1-alpha-hydroxylase by macrophages in granulomas (1,3).  Indeed, Cryptococcus is known to induce a granulomatous response (5), and granulomas were found in the skin and liver biopsies of the case reported by Spindel (1).  A review has suggested that 1,25-OH D may play a role in regulating immune function (4) so this pathway may become activated through adaptive mechanisms.  However, this theory has not been proven.

Management of 1,25-OH D-driven hypercalcaemia includes restriction of dietary calcium and sunlight exposure (4).  Glucocorticoids inhibit 1-alpha-hydroxylase activity in macrophages as well as 1,25-OH D-mediated absorption of calcium from the gastrointestinal tract, and may also be given.  However, the risks of exacerbating an underlying infection need to be carefully considered against the benefit of controlling the hypercalcaemia.  In our case, methylprednisolone was administered as it was essential for the survival of the liver graft, and fortuitously resolved the hypercalcaemia.

In addition to its antifungal effects, fluconazole inhibits 25-hydroxylase and 1-alpha-hydroxylase, and its use in reducing 1,25-OH D levels in a patient with a CYP24A1 mutation has been described (6).  In our case, the calcium levels dropped during fluconazole therapy, but this may have been confounded by concurrent calcitonin and denosumab therapy.

In summary, Cryptococcus neoformans is a rare cause of 1,25-OH D-mediated refractory hypercalcaemia which in our case required antifungal treatment, pamidronate, calcitonin, denosumab and high dose glucocorticoid treatment.  Hypercalcaemia is a rare complication of disseminated fungal infection, which should be suspected in immunosuppressed individuals.

Take home messages

• In immunocompromised patients with unexplained hypercalcaemia, fungal infections should be considered in the differential diagnoses;
• Glucocorticoids may be considered to treat 1,25-OH D-driven hypercalcaemia, however, the benefits of lowering the calcium need to be balanced against the risk of exacerbating an underlying infection;
• Fluconazole might be an effective therapy for both treatment of the hypercalcaemia by lowering 1,25-OH D levels as well as of the fungal infection.