A 42-year-old Sri Lankan grocery shop owner with noninsulin-dependent diabetes mellitus on diet control for three years duration admitted to the medical ward of a tertiary care hospital in central Sri Lanka with generalized malaise and feverish feeling for three weeks' duration. His feverishness was mainly at night, and it was associated with evening sweating and severe anorexia. He has lost three kilograms of body weight during that period. No chronic cough, hemoptysis, or contact history of tuberculosis was noted in the history. He had nausea, but there was no vomiting or abdominal pain. His urinary and bowel habits were normal. There was no arthralgia, morning stiffness, photosensitive rashes, or any other symptoms suggestive of any autoimmune disease.
He was diagnosed to have type 2 diabetes mellitus three years ago and on diet control with good glycemic control. He did not have any micro- or macrovascular complications related to diabetes mellitus. There were no past hospital admissions or episodes of recurrent urinary, respiratory, or skin sepsis. He owns a small grocery shop and works in there. He did not have significant exposures to birds, animals, paddy, and wet soil. His travel history was unremarkable. He had five pack-years of cigarette smoking and consumes alcohol occasionally. He is married and has two children. He denied any high-risk behaviors including sexual promiscuity or intravenous drug abuse.
On examination, he was averagely built, afebrile, and mildly pale. There was no cervical, axillary, or inguinal lymphadenopathy. No skin rashes or mouth ulcers to be seen. His ic fundi were normal. His pulse rate was 72 beats per minute (bpm) and blood pressure was 110/70 mmHg without any postural drop. His cardiovascular and respiratory system examinations were unremarkable. He had mild hepatomegaly which was nontender, and there was no associated splenomegaly or other palpable masses in the abdomen clinically.
Full blood count showed pancytopenia with a white blood cell count of 3 * 109/liter (l), platelet count of 120 * 106/l, and hemoglobin of 10 grams per deciliter (g/dl). C-reactive protein (CRP) was 8 and erythrocyte sedimentation rate (ESR) was 60 mm in the first hour. His liver and renal profiles including serum electrolytes were normal. 2D echocardiogram and chest X-ray were unremarkable. His septic screening including blood and urine cultures were negative. Mantoux test was negative. Hemoglobin A1c (HbA1c) was 6.5%. Ultrasound scan (USS) of the abdomen showed mild hepatosplenomegaly with bilateral hypoechogenic masses in the suprarenal glands with normal kidneys and few enlarged para-aortic lymph nodes. Although blood picture was compatible with pancytopenia, the bone marrow biopsy only showed reactive marrow without any evidence of leukemia, lymphoma, or secondary deposits. Bone marrow biopsy was negative for both fungal studies and tuberculosis.
After admitting to the ward, the patient has felt well with the symptomatic treatment. Meanwhile, an urgent contrast-enhanced computer tomography (CECT) chest and abdomen was arranged suspecting an adrenal neoplasm, but it was delayed due to a technical issue with the computer tomography (CT) machine. Since the patient was stable with the symptomatic treatment, he went home with a plan to review with the CECT report and random serum cortisol levels.
One week later, he was again admitted to the same medical unit with severe nausea, vomiting, diarrhea, abdominal pain, and postural dizziness for three days' duration. There was no associated fever or a history of food poisoning. On examination, he was dehydrated, and his pulse rate was 100 bpm, and blood pressure was 90/60 mmHg with 30 mmHg of postural drop in systolic blood pressure. The rest of the examination was normal. He was initially resuscitated with intravenous fluid boluses, but even after correcting his dehydration, his blood pressure remained low. Since he had bilateral adrenal masses, an Addisonian crisis was suspected, and he was started on intravenous hydrocortisone 200 mg bolus followed by 200 mg 8 hourly. With that, his blood pressure picked up and stabilized. His serum sodium value was 114 mmol/l, and serum potassium value was 5 mmol/l. Random blood sugar was 80 mg/dl, and corrected serum calcium level was marginally elevated. His random cortisol level was very low at 1.32 mug/l. His full blood count showed improving pancytopenia. His renal functions and inflammatory markers were within normal range. An urgent CECT chest and abdomen revealed bilateral well-defined homogenously enhancing adrenal masses (left side-6.9 * 3.7 * 5 cm and right side-5.3 * 3.4 * 5.4 cm in size) with mild hepatosplenomegaly and patchy para-aortic lymphadenopathy (Figure 1). There were no other mass lesions in the abdomen and chest. Then, adrenocorticotrophic hormone (ACTH) stimulation test was performed after converting hydrocortisone to oral dexamethasone therapy, and it showed a persistently low serum cortisol value less than 1 mug/l even after stimulating with synthetic ACTH preparation. So, Addison's disease was confirmed, and the patient was started on replacement steroid and mineralocorticoid therapy.
USS-guided adrenal mass biopsy reveled a core tissue with necrosis at one end with infiltration of plasma cells and lymphocytes alone with histiocytes in adjacent tissues. With the Gomori-Grocott methenamine silver (GMS) staining, there were numerous fungal spores which were morphologically similar to Histoplasma in the necrotic and adjacent tissues (Figure 2). An upper gastrointestinal endoscopy was performed to see any evidence of disseminated histoplasmosis, and it was normal. His blood and tissue specimen was sent for fungal cultures. We did not do additional diagnostic investigations including serum and urine antigen assays, polymerase chain reaction assay, and specific cultures due to financial limitations and nonavailability of the facilities. His human immunodeficiency virus (HIV) 1 and 2 serology was negative.
The diagnosis of possible disseminated histoplasmosis with adrenal involvement leading to Addisonian crisis was made, and he was started on oral itraconazole 100 mg twice per day in addition to oral fludrocortisone 0.5 mg per day and oral hydrocortisone 10 mg at 6 am, 5 mg at noon, and 5 mg at 6 pm. With the treatment, his symptoms improved, and he started to gain weight. After six months of itraconazole therapy, the CECT abdomen and the adrenal biopsy were repeated, and it showed persistent bilateral adrenal masses and persistent Histoplasma infection histologically. So, the decision was taken to continue itraconazole therapy for at least one-year duration and thereafter to continue it further according to the radiological and histological response. The patient is regularly followed up in a medical clinic, and upto now he does not show any evidence of worsening of Addison's disease or any evidence of hepatotoxicity related to the itraconazole therapy. But he has developed generalized body pigmentation after about three months into the therapy although he was improving symptomatically (without any postural drop in systolic blood pressure, and his serum electrolytes were within normal range).