Addison's disease due to histoplasmosis of bilateral adrenal glands in a previously treated extrapulmonary tuberculosis case

A 38 yr old female† presented to the department of Medicine at All India Institute of Medical Sciences (AIIMS), New Delhi, India, in August 2015, with pyrexia of unknown origin, splenomegaly and bicytopenia. All investigations including bone marrow biopsy were negative, except for metabolically active splenic lesions on 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) (Fig. 1A). All abnormalities responded to empirical nine months of anti-tuberculosis (TB) treatment. A follow up ultrasound from September 2017, revealed bilateral adrenal gland enlargements (Fig. 1B) with normal plasma adrenocorticotrophic hormone (ACTH) (37 pg/ml; normal range: 0-46 pg/ml) and normal morning and evening plasma cortisol levels. On one year follow up she presented with hyperpigmentation over knuckles, palm creases, face, lips and gums that were suggestive of Addison's disease (Fig. 2A-D). Histoplasma antibody (complement fixation) was positive (1:16, reference range <1:8). Investigations revealed plasma ACTH level of 1139 pg/ml and subnormal plasma cortisol levels [morning: 0.143 μg/dl (normal: 3.7-19.4 μg/dl) and evening: 0.136 μg/dl (normal: 2.9-17.3 μg/dl)]. ACTH stimulation test with cosyntropin revealed no stimulation of adrenal glands (cortisol values at baseline: 7.0 μg/dl, 30 min; 6.6 μg/dl and 60 min: 6.3 μg/dl). A CT-guided adrenal gland biopsy revealed diagnosis of histoplasmosis (Figs 3-5). The patient was administered intravenous liposomal amphotericin B (total dose: 3.3 g) and prescribed oral itraconazole 200 mg twice daily along with daily dose of 7.5 mg prednisone and fludrocortisone 0.2 mg. Clinically, the patient has showed improvement (Fig. 6). The PET-CT done in November 2019 (Fig. 7) shows decrease in 18F-fluorodeoxyglucose uptake. In December 2019, her plasma ACTH levels (5.18 pg/ml) and cortisol hormone levels (morning: 0.4 μg/dl and evening; 1.92 μg/dl) revealed improvement.

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Fig. 1

(A) 18F-fluorodeoxyglucose positron emission tomography-CT scan (2017), showing bilateral adrenal enlargement (R>L) with hypermetabolism (arrows). (B) Ultrasonograph showing bilateral adrenal gland enlargements.

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Fig. 2

Pre-treatment hyperpigmentation over (A) knuckles, (B) palmar creases, (C) face, lips and (D) gums.

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Fig. 3

Histopathological slides of adrenal glands showing multiple cores with inflammation and necrosis in histoplasmosis (H and E, ×4, ×10, ×20 and ×40).

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Fig. 4

Presence of (A) retractile and (B) maltese cross on polarization (H and E, ×40).

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Fig. 5

Differential diagnosis of histoplasmosis using different stains. (A and B) Yeast forms are positive with silver methenamine (×20 and ×40) and (C) periodic acid-Schiff-diastase stain (×40) but (D) negative with acid-fast bacilli stain (×40).

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Fig. 6

(A-D) Reversal of hyperpigmentation following treatment with anti-fungal treatment.

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Fig. 7

18F-fluorodeoxyglucose positron emission tomography-CT scan (November 2019) showing bilateral adrenal enlargement (R>L) with mildly increased fluorodeoxyglucose uptake (arrows), definite decrease in fluorodeoxyglucose uptake.

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While autoimmune aetiology is the most common cause of Addison's disease in high-income countries, TB is the most frequent cause of Addison's disease in high TB-burden countries. The present case emphasizes importance of follow up and appropriate investigations to rule out an alternate diagnosis.