Hypercalcaemia associated with disseminated cryptococcosis

Abstract

We report an elderly man who presented with giddiness and right-sided weakness, constipation and constitutional symptoms for 6 months duration. Blood investigations indicated hypercalcaemia with normal serum phosphate and acute kidney injury. Serum intact parathyroid hormone was suppressed. CT revealed bilateral tiny lung nodules with right upper lobe tree in bud appearance and incidental findings of bilateral adrenal lesion. Tuberculosis was ruled out. CT adrenal showed multiseptated hypodense rim enhancement adrenal lesion bilaterally. Adrenal function tests were normal except for low dehydroepiandrosterone (DHEA). Right-sided cervical lymph node biopsy confirmed fungal infection with the presence of intracellular and extracellular fungal yeast. Serum cryptococcus antigen titre was positive. Our final diagnosis was disseminated cryptococcosis with lungs, bilateral adrenal gland and lymph nodes involvement. The patient was then treated with antifungal treatment. Serum calcium was normalised after 1 month with marked clinical improvement.

Background

Hypercalcaemia is one of the common clinical presentations among admitted patients in hospital. The causes of hypercalcaemia can be divided between parathyroid hormone (PTH)-related or non-PTH-related causes. It is important to establish the cause of hypercalcaemia as it will determine the definitive management of the patients. In this case, treating the cause of hypercalcaemia leads to the resolution of hypercalcaemia.

Case presentation

We report an elderly man with no known medical illness. He initially presented to our centre with giddiness and right-sided hemiparesis 1 month prior to admission. On further history, he complained of constipation for 3 months duration. It was also associated with prolonged fever and loss of weight over the span of 6 months.

On admission, the patient was dehydrated, with blood pressure of 158/91 mm Hg. The patient was cachectic. Further neurological examinations revealed unsteady gait with the power of 3/5 over right upper and lower limbs. The tone and Babinski reflexes were normal for all limbs. CT scan of the brain revealed multifocal old lacunar infarcts with small vessel disease and cerebral atrophy. This was his first presentation with neurological symptoms. Due to our limited resources, the patient was not subjected for further evaluation, for example MRI of the brain or further vascular imaging. This patient was treated as ischaemic stroke by general medical team and started with tablet aspirin 150 mg once a day.

There was incidental finding of hypercalcaemia, with admitting corrected serum calcium of 3.05 mmol/L (normal range: 2.20–2.60 mmol/L) and serum phosphate of 0.91 mmol/L (normal range: 0.78–1.65 mmol/L). Renal profile showed acute kidney injury with serum creatinine of 152 μmol/L (normal range: 54–97 μmol/L) and estimated glomerular filtration rate (eGFR) of 42 mL/min/1.73 m². Serum albumin was 31 g/L (normal range: 32–48 g/L). On further history, he denied any calcium and vitamin D supplements or other herbal treatment. There was no bony pain or abdominal pain. Serum intact parathyroid hormone (iPTH) was suppressed, 0.77 pmol/L (normal range: 1.58–6.03 pmol/L). Serum 25-hydroxycholecalciferol (vitamin D) level was sufficient and not elevated, 172.30 nmol/L (normal range: 75–225 nmol/L). The urine calcium: creatinine clearance ratio was 0.0664, unlikely familial hypocalciuric hypercalacaemia. Ultrasound kidney, ureter and bladder performed revealed left nephrolithiasis with mild hydronephrosis, bilateral renal cysts with left complex renal cyst. Then, we proceeded with CT urography which showed bilateral nephrolithiasis with left upper pole calliectasis, bilateral complex renal cyst and urinary bladder calculus.

The diagnosis of non-iPTH dependant hypercalcaemia was established. In view of history of prolonged constipation, the patient was referred to surgical team for further evaluation. Oesophagoduodenoscopy performed revealed gastric polyp. The histophatological examination confirmed benign fundal polyp. Colonoscopy was normal. Full blood picture showed mild normochromic normocytic anaemia, with haemoglobin of 11.6 g/L (normal range: 13–17 g/L), no rouleaux formation with normal white cells and platelets. Serum protein electrophoresis and urine protein electrophoresis were negative for monoclonal gammapathy. CT thorax, abdomen and pelvis were reported as diffuse bilateral tiny nodules with right upper lobe tree in bud appearance (figure 1), with bilateral lobulated hypodense adrenal lesion, measuring approximately 3.4 cm × 2.4 cm and 2.5 cm × 1.6 cm for right and left, respectively. There was non-obstructive left renal staghorn calculi and bilateral renal cyst with complex left renal cyst.

Figure 1.

CT thorax showed diffuse bilateral tiny nodules with right upper lobe tree in bud appearance.

The serum calcium improved with hydration in which he required 3 L of normal saline infusion over 24 hours. We maintained at least 1 L of positive fluid balance every day. The serum calcium gradually dropped to 2.6 mmol/L. The hemiparesis improved and he regained full power on neurological reassessment after hydration and on normalisation of serum calcium, hence no MRI brain or further vascular imaging was done. In view of presence of pulmonary nodules with tree in bud appearance, he was evaluated for pulmonary tuberculosis. The results were negative, including sputum acid fast bacilli and Mantoux test. He refused bronchoscopy for further evaluation.

CT adrenal protocol showed multiseptated hypodense rim enhancing adrenal lesions bilaterally (figure 2). The right adrenal lesion measured 2.7 cm × 2.4 cm × 3.1 cm, with attenuation of 30 HU (plain phase) and total wash out rate of 90%. The left adrenal lesion measured 2.0 cm × 2.4 cm × 2.6 cm, with attenuation of 22 HU (plain phase) and total wash out rate of 100%. The differentials were tuberculosis, fungal infection or adrenal infiltrations. Adrenal function tests revealed AM cortisol of 466.6 nmol/L (normal range: 145–619 pmol/L), Adrenocorticotropic hormone (ACTH) of 3.2 pmol/L (normal range: 2.2–13.3 pmol/L), aldosterone of 216.8 pmol/L (normal range: 102–859 pmol/L), 24 hour urine metanephrines was not elevated and serum DHEA of less than 0.41 umol/L (normal range: 2.20–15.4 umol/L). All tumour markers were negative.

Figure 2.

CT adrenal protocol showed multiseptated hypodense rim enhancing adrenal lesions bilaterally. The right adrenal lesion measured 2.7 cm × 2.4 cm × 3.1 cm, with attenuation of 30 HU (plain phase) and total wash out rate of 90%. The left adrenal measured 2.0 cm × 2.4 cm × 2.6 cm, with attenuation of 22 HU (plain phase) and total wash out rate of 100%.

Right cervical lymph node was palpable, mobile and firm in consistency, with size of 2 cm × 2 cm diameter. The patient was then subjected for lymph node excision biopsy. Histopathological examination revealed fragments of fibrofatty tissues infiltrated by epithelioid granuloma aggregations, dense lymphoplasmacytic cells, histiocytes and neutrophils (figure 3), (figure 4). Langhans and foreign body type giant cells as well as tissue necrosis were also noted (figure 4). There were numerous small round to oval intracellular and extracellular fungal yeast with peripheral halos seen on Grocott’s methenamines silver stain (GMS) (figure 5) and periodic acid-Schiff (PAS) (figure 6). Possible diagnoses were histoplasmosis, cryptococcosis or penicilliosis. On review of the histopathological examination, the patient was initially treated as disseminated histoplasmosis with lungs, lymph nodes and adrenal involvement. No urine histoplasma antigen test was performed.

Figure 3.

H&E stain ×10 showed granulomatous inflammation.

Figure 4.

H&E high power ×40 showed multiple multinucleated giant cells with intracytoplasmic yeast.

Figure 5.

Fungal yeasts highlighted by Grocott’s methenamines silver stain.

Figure 6.

Fungal yeasts highlighted by periodic acid-Schiff. Yeast cells are coloured in red.

The case was discussed and seen with infectious disease team, in view of his prolonged symptoms and clinical stability prior to presentation, the diagnosis of cryptococcus infection was thought to be most likely. Serum cryptococcus antigen was positive with the titre of 1:10. Lumbar puncture was subsequently performed to evaluate for meningeal involvement of cryptococcus; however, the results were unremarkable and negative for evidence of cryptococcal involvement. The cerebrospinal fluid protein was not elevated, cryptococcal antigen was not detected, acellular and no growth on culture. Although the initial presentation of the patient was right-sided hemiparesis, the neurological deficits resolved after normalisation of serum calcium level before the initiation of treatment for cryptococcosis.

HIV screening test was negative. On evaluation of his immunological status, lymphocyte subset enumeration test reported as reduced total B cells (81×106/ L, normal range 130–716) and CD4 T cells (330×106/ L, normal range 431–1976). There is possibility of primary immunodeficiency, however, further investigations are required. In addition to his elderly age group, low total B cells and low CD4 T cells are possible risk factors for cryptococcosis.

Treatment

Based on the diagnosis of disseminated cryptococcosis, we have started the treatment with combination of intravenous conventional amphotericin B; with test dose of 1 mg; followed by 15 mg once a day, then 30 mg once a day on subsequent days, intravenous flucytocine 1000 mg two times per day and intravenous fluconazole 400 mg once a day. Due to his worsening acute kidney injury after 5 days of treatment, the conventional amphotericin B was changed to intravenous amphotericin B lipid complex 200 mg two times per day. Proper hydration with intravenous normal saline infusion was instituted during the treatment. During readmission for initiation of treatment, his baseline corrected serum calcium was 3.38 mmol/L, and serum creatinine increased to 146 umol/L. On completion of intravenous antifungal treatment for 2 weeks, corrected serum calcium improved to 2.62 mmol/L and serum creatinine level of 124 umol/L. He was discharged well with marked improvement of his general medical condition. He was then discharged with oral flucytosine 1000 mg two times per day and oral fluconazole 400 mg once a day.

The patient was counselled regarding the prevention of recurrence of cryptococcosis, particularly inhalation of the fungus by wearing masks in the high-risk areas. In addition, avoidance of areas that may contain dried pigeon faeces might prevent the disease.

Outcome and follow-up

On clinic review 2 weeks after discharge, he gained appetite and able to perform all his daily activities independently. Corrected serum calcium was 2.38 mmol/L with serum creatinine level of 118 umol/L. Traced fungal culture from lymph nodes biopsy showed no growth.

He was scheduled for repeat CT adrenal after completed 3-month anti-fungal treatment. Total maintenance phase for antifungal treatment was planned for 6–12 months.

Discussion

In this case report, we describe disseminated cryptococcus infection, presented as hypercalcaemia in elderly. Hypercalcaemia is a common disorder among admitted patients in hospitals. The presentation ranges from incidental findings from unrelated symptoms to severe hypercalcaemic symptoms, including stupor, cardiac arrhythmia and acute kidney injury.

Primary hyperparathyroidism and malignancy are the most common causes of hypercalcaemia, accounting for 80%–90% of hypercalcaemia cases.¹ In ambulatory population, primary hyperparathyroidism comprises up to 60% cases of hypercalacaemia.¹ Among hospitalised patients, malignancy is the most common cause of hypercalcaemia, comprises 54%–65% cases.¹ Generally, the causes of hypercalcaemia were divided between parathyroid hormone (PTH)-related or non-PTH-related causes. The most common causes of PTH-related hypercalcaemia is primary hyperparathyroidism, other uncommon causes are PTH-producing tumour and familial hypocalciuric hypercalcaemia.² The causes of non-PTH-related cause are malignancy-associated hypercalcaemia, vitamin D intoxication, granulomatous disease, iatrogenic cause, including calcium supplements, thyrotoxicosis, hypocortisolism, milk-alkali syndrome and immobilisation.³ Malignancy-associated hypercalcaemia can be divided into four groups: (1) overproduction of parathyroid-related peptide (PTHrP) by malignant tumour cells, known as humoral hypercalcaemia of malignancy (HHM) which accounts 80% of cases; (2) local osteolysis by tumour cells which accounts for 20% of cases, for example in multiple myeloma; (3) conversion of vitamin D to active 1,25-dihydroxyvitamin D by lymphomas and (4) ectopic hyperparathyroidism.⁴

In non-PTH-related hypercalcaemia, the serum parathyroid hormones are suppressed as presented in this case.

In view of constitutional symptoms, elderly age and altered bowel symptoms, we focused our initial investigations towards malignancy. The endoscopy examinations are negative for malignancy. After reviewing the CT thorax, abdomen, including adrenal and pelvis, the features involving lungs and bilateral adrenal glands are highly suggestive for granulomatous disorders, including infectious and noninfectious granuloma-forming disorders.

Granulomatous disorders, particularly tuberculosis is common in this region of the world. Due to his elderly age, the risk of fungal infection is also higher. Granulomatous disorders are associated with 1,25-dihydroxyvitamin D-mediated hypercalcaemia.⁵ The causes of non-infectious granulomatous disorders are sarcoidosis, silicon-induced granulomatosis, paraffin-induced granulomatosis, Wegener’s granulomatosis and eosinophilic granulomatosis.⁵ Examples of infectious granulomatous disorders are tuberculosis, histoplasmosis, coccidiomycosis and Bartonella hensalae infection (cat-scratch disease).⁵

Calcium metabolism in physiological condition is mainly regulated by parathyroid hormones and 1,25-dihydroxyvitamin D to maintain normocalcaemia. In granulomatous disorders, the macrophages produce 1α-hydroxylase enzyme, which converted 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D without any homeostatic control.⁶ The inapproapriately increased level of 1,25-dihydroxyvitamin D resulting in hypercalcaemia, which then leads to suppressed PTH.⁷ Serum 1,25-dihydroxyvitamin D should be investigated for this patient, however, due to its inavailabiliy in our laboratory, it was not sent.

Cryptococcus infection is one of the common complications among immunocompromised patients. There were reported cases of hypercalcaemia among immunocompetent patients.^8–10 Hypercalcaemia as initial manifestation of cryptococcus infection, as observed in this patient, is rare. We have collected four cases linking hypercalcaemia as initial presentation of cryptococcus infection, reported by Huang et al,⁸ Spindel et al,¹¹ Wang et al¹² who reported a case in patient with end stage renal failure and Ali et al.¹³ Bansal et al¹⁴ reported hypercalcaemia as a primary manifestation of cryptococcal immune reconstitution syndrome. Common organs involvement for cryptococcosis are lungs and meninges. Cryptococcosis with adrenal gland involvement as seen in this case is rare. Possible spread of cryptococcal infections involving adrenal glands are through haematogenous spread.⁹ Ito et al,⁹ Ranjan¹⁰ et al and Cheng et al¹⁵ reported disseminated cryptococcosis with adrenal insufficiency.⁹ The adrenal cryptococcosis was confirmed by adrenal biopsy in all the cases.^{9 10 15} In our patient, the morning cortisol was normal despite common presentation of adrenal insufficiency as previously reported. No adrenal biopsy was performed in our patient as the diagnosis was confirmed by the lymph node biopsy. If there was no accessible lymph node for biopsy, adrenal biopsy should be considered in this case.

The contrast-enhanced computed tomography (CECT) adrenal findings in cryptococcosis were previously reported as enlarged bilateral adrenal glands with capsular enhancement.9 10 15 16 Our patient’s CECT adrenal also showed same findings of bilateral adrenal enlargement with rim capsular enhancement. Only Ito et al reported enhancing mass both at the margin and inside the adrenal mass.⁹

Based on the diagnosis of disseminated cryptococcosis with adrenal glands, lungs and lymph nodes involvements, we have started the treatment with combination of intravenous amphotericin B, intravenous flucytocine and intravenous fluconazole as inpatient for 14 days. The general condition and serum calcium improved and responded well with treatment.

There is also an option of bilateral adrenalectomy in patient with cryptococcosis with adrenal gland involvement, particularly in patients who failed antifungal therapy. Case reports by Ito et al⁹ and Takeshita et al¹⁷ mentioned about successful treatment of disseminated cryptococcosis with bilateral adrenalectomy in patients with refractory disease despite prolonged treatment with antifungal therapy. Marsuda et al¹⁶ reported a case of cryptococcosis with adrenal gland involvement who failed 4 months of fluconazole and 6 weeks of liposomal amphotericin B treatment, then successfully treated with left adrenalectomy in view of adhesion of right adrenal mass to the liver, with no relapse observed. In this case, we noted resolution of hypercalcaemia and symptoms on systemic antifungal treatment, hence there is no indication for further invasive treatment, including adrenalectomy.

In conclusion, granulomatous disease diagnosis should be considered in patients with non-PTH dependant hypercalcaemia. Histopathological examination combined with demonstration of elevated cryptococcal antigen titre are vital in establishing the diagnosis of disseminated cryptococcal infection. Adrenalectomy may be considered when only adrenal gland is affected and the patient does not respond well with long-term antifungal treatment. In this case, medical therapy with systemic antifungal is the first line treatment as there were other organs involvement.

Learning points.

• In immunocompromised or elderly group patients, uncommon causes of non-intact parathyroid hormone dependent hypercalcaemia, particularly chronic infectious granulomatous diseases should be considered.

• Treating the underlying condition, in this case; infectious granulomatous disease, will lead to normalisation of serum calcium level.

• Systemic antifungal is the treatment of choice in disseminated cryptococcosis.

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