A 49-year-old Japanese man had been in good health until 2 months prior to admission to the Japan Self Defense Forces Central Hospital, Tokyo, Japan, in July 2014. During those two months, he developed anorexia, weight loss, and increased skin pigmentation.
A physical examination at the time of admission revealed a dehydrated man with generalized pigmentation and hepatic enlargement without any skin changes, chest symptoms, or a stiff neck. He was 174 cm tall and weighed 66 kg. His blood pressure was 93/57 mmHg; pulse rate, 109 beats per minute; and temperature, 36.7 C. His other vital signs were normal. A neurological examination revealed no focal or lateralizing deficits.
The laboratory data on admission were as follows: sodium, 132 mEq/L; potassium, 5.6 mEq/L; chloride, 92 mEq/L; creatinine, 1.57 mg/dL; and urea nitrogen, 36 mg/dL. The BUN/creatinine ratio was 22, which suggested possible dehydration. His white blood cell count, hematocrit, liver function tests, albumin, total protein, calcium, and inorganic phosphate values were normal (Table 1). The plasma adrenocorticotropic hormone (ACTH) level and plasma renin activity (PRA) were elevated at 707.5 pg/mL (normal <63.3 pg/mL) and 51.3 ng/mL/h (normal <4.0 ng/mL/h), respectively. The plasma cortisol and plasma aldosterone levels were both lower than normal at 2.9 mug/dL (normal <21.1 mug/dL) and 3.5 ng/dL (normal <24.0 ng/mL). The tentative diagnosis on admission was adrenal gland insufficiency (Table 1).
Further examinations were performed to differentiate primary adrenal insufficiency from secondary adrenocortical insufficiency. An ACTH stimulation test (250 mug of intramuscular cosyntropin), which measures the response of the adrenal glands to adrenocorticotropic hormone, failed to induce a rise in the serum or urinary cortisol levels. Magnetic resonance imaging (MRI) of the head demonstrated normal findings. No pituitary tumor was detected.
A diagnosis of primary adrenocortical insufficiency was made, and the patient was started on a daily dose of 15 mg hydrocortisone, according to the treatment for adrenal insufficiency (2). Additional tests were performed to determine whether his primary adrenal insufficiency was caused by an autoimmune disorder, tuberculosis, or metastasis of a malignant tumor. The QuantiFERON-TB Gold test (QIAGEN, Osaka, Japan) for tuberculosis was negative.
An abdominal ultrasonography showed bilateral adrenal enlargement, with the glands measuring approximately 55x33x14 mm (left side) and 56x25x49 mm (right side). No calcification was seen on either adrenal gland (Fig. 1). A computed tomography (CT) scan of the abdomen also demonstrated bilateral adrenal enlargement. Tumors or metastases were not found on a CT or Positron emission tomography-computed tomography (PET-CT) scan. However, the CT scan showed nodular shadows around both lungs (right S1, left S1+2, left S6) (Fig. 2). The nodules were 9, 3, and 8 mm in diameter. The serum anti-nuclear antibody, anti-ds DNA antibodies, C3, C4, and rheumatoid factor, beta-D-glucan levels were all within the normal range.
Based on this evidence, tuberculosis, collagen diseases, and metastasizing tumors were excluded from the possible diagnosis. Subsequently, a CT-guided biopsy of the right adrenal gland was performed to obtain tissue for culture and a histologic evaluation. Cryptococcus spp. were identified within the necrotic adrenal tissue (Fig. 3). The tissue fragments were cultured for bacteria, fungi, and acid-fast organisms. None of the cultures yielded any growth. The adrenal gland cytology was class II.
Ultimately, a diagnosis of primary adrenal insufficiency due to a cryptococcal infection was reached. Lumbar puncture yielded colorless cerebrospinal fluid (CSF) with a leukocyte count of 151/mm3. The CSF protein level was elevated to 72.3 mg/dL with a concurrent serum glucose level of 30 mg/dL. These findings suggested meningitis; Cryptococcus spp. were seen in the CSF on a smear culture (Fig. 4).
Nevertheless, a culture of the CSF revealed no growth of Cryptococcus spp., and the CSF and serum cryptococcal antigen titers were 1:8 and 1:4,096, respectively. Bronchial lavage fluid and sputum cultures for fungus were negative. We strongly suspected that this patient was suffering from disseminated cryptococcosis, which causes primary adrenal insufficiency and meningitis. Therefore, we evaluated the patient's immunological status. The results revealed that the serum IgG level was 822 mg/dL, IgM was 1,290 mg/dL, C3 was 166 mg/dL, and C4 was 36 mg/dL. Antibodies for HIV were not detected on either of two separate examinations approximately two months apart. The CD4 count was 1,324 cells/mm3. Additionally, a bone marrow aspiration sample showed a normal distribution with no amplifier plasma cells and an IgM level below 1,500 mg/dL, which led us to conclude that the patient was not immunocompromised. Based on the diagnosis of cryptococcal infection, intravenous liposomal amphotericin B (300 mg daily) and oral flucytosine (7,000 mg daily) were administered.
After five days of therapy, the combination of liposomal amphotericin B and flucytosine was discontinued because liposomal amphotericin B had an adverse effect on the patient's renal function. We started hydration and restarted the combination of intravenous liposomal amphotericin B and oral flucytosine at a daily dose of 200 mg and 6,000 mg, respectively. After two weeks of therapy, consolidation therapy was started with oral fluconazole at 800 mg daily. He was treated for 5 months, at the end of which his medication dosages were fluconazole, 11.2 g; amphotericin B, 3,600 mg; and flucystosine, 126 g in total. However, the serum cryptococcal antigen titers did not decrease, and the patient's symptoms did not improve. A repeat abdominal CT scan showed that the adrenal enlargement was unchanged.
Due to the ineffectiveness of the therapy and the patient's deteriorated condition, bilateral adrenalectomy was performed. The glands were approximately 7.5x4.5x4.5 cm (left side) and 6.5x4.0x4.0 cm (right side) (Fig. 5). A histological analysis of the resected adrenal glands showed massive noncaseating necrosis containing yeast-like particles, which was diagnostic for a Cryptococcus spp. infection (Fig. 6).
Oral fluconazole at a dose of 800 mg daily was continued after adrenalectomy. At 10 months after adrenalectomy, the serum cryptococcal antigen titer had decreased to 1:128 (Fig. 7). Repeated lumbar punctures were performed, revealing no detected CSF cryptococcal antigen titer, and a CSF culture revealed no growth of Cryptococcus spp. The patient is currently taking 800 mg of daily oral fluconazole, and he is being followed up every 2-3 months to check for any relapse.
Computed tomography image of the lung nodules from the patient. The right S1, left S1+2, and left S6 nodules were 9, 3, and 8 mm in diameter, respectively.