In October 2006, a 56-year-old woman was referred to the Diabetes/Endocrine Center at Ohio University Heritage College of Osteopathic Medicine in Athens for evaluation of an incidental 2.7-cm left adrenal adenoma. A few weeks before this visit, the adenoma had been found incidentally by her primary care physician on magnetic resonance images when the patient was being evaluated for abdominal pain.
Her medical history included the following: hypertension, hypothyroidism caused by Hashimoto thyroiditis, macular degeneration, osteopenia, otosclerosis, vitiligo, and several posttraumatic fractures. Her past surgeries included tonsillectomy and adenoidectomy, lumbar disk surgery, bilateral patellar tendon releases, total right knee replacement, and right wrist surgery with metal plate placement. Her current medications were as follows: levothyroxine sodium, 50 μg daily; meloxicam, 7.5 mg twice daily; valsartan/hydrochlorothiazide, 160 mg/12.5 mg daily; and a daily over-the-counter vitamin supplement.
The patient's social history indicated that she was married, had 1 adult child, and worked as a switchboard operator at a local hospital. She had never smoked, she consumed alcohol rarely, and she drank 2 cups of coffee per day. She walked occasionally for exercise. Her family history was significant for type 2 diabetes mellitus, hypertension, hyperlipidemia, and an adrenal cyst.
Review of the patient's systems revealed intermittent, episodic hypertension, headaches, dizziness, and 1 episode of near syncope. She also complained of hot flashes, some flushing, and rapid pulse. Physical examination revealed moderate obesity and a mild Cushingoid appearance, including a slight fat pad seen posteriorly at the cervicothoracic junction, increased supraclavicular fat pads, and white abdominal striae. She also had vitiligo on the extensor surfaces of her hands and elbows, as well as mild ecchymosis of the upper extremities.
Laboratory evaluation (
Table) revealed elevated levels of 24-hour urinary free cortisol on 2 separate occasions, in March 2006 (159 μg/24 h) and November 2006 (158 μg/24 h). Separate tests for fractionated plasma catecholamines revealed slightly elevated levels of vanillyl-mandelic acid, at 7.8 mg/24 h (in November 2006), and norepinephrine, at 524 pg/mL (in January 2006). Morning serum cortisol levels were found to be in the high range of normal on 2 occasions, in January 2006 (18.9 μg/dL) and November 2006 (20.7 μg/dL), and the morning level of serum corticotropin was suppressed (<5 pg/dL in November 2006). Levels of serum and 24-hour urine aldosterone were normal (2.1 ng/dL in January 2006 and 5 μg/24 h in November 2006, respectively).
Because of the patient's mild adrenergic symptoms and elevated urine catecholamine levels, a meta-iodobenzylguanidine scan was ordered as a precaution before surgery. The scan result was negative for pheochromocytoma. With the presumptive diagnosis of an adrenal-dependent cortisol-secreting adrenal adenoma, the patient was referred for surgery. A left laparoscopic adrenalectomy was performed without complication at The Ohio State University Medical Center in early March 2007. Approximately 2 months after the procedure, the patient's morning serum cortisol level was 0.2 μg/dL. The pathology report for the adrenal tissue revealed macronodular cortical hyperplasia with a dominant hyperplastic nodule and no evidence of malignancy (
Figure 1).
At discharge from the medical center in March 2007, the patient was given hydrocortisone glucocorticoid, 25 mg twice daily, for several weeks, with the dose tapered to 10 mg twice daily over the next 6 weeks. The patient tolerated this medication and dose without apparent difficulty. During the first several months after surgery, the patient reported feeling much better, she regained muscle strength, and she lost about 22 pounds. Between May and November 2007, a complete weaning from oral steroids was attempted several times without success, and periodic morning serum cortisol levels were checked (
Table). The patient continued to have low morning serum cortisol levels—presumably from either overreplacement with oral steroids or autoimmune destruction of her adrenal glands, causing less production of endogenous hormone. An alternate-day steroid taper was attempted in early December 2007 with hydrocortisone.
During the period from June to November 2007—when attempts to wean the patient from the steroid were attempted—the patient again reported feeling unwell, experiencing generalized myalgia, joint pain, and salt cravings. These symptoms were especially bad on the alternate days when she took the lower hydrocortisone doses or no hydrocortisone at all. Because the patient was still symptomatic despite about 6 months since her adrenalectomy and several trials of steroid weaning—and considering her known history of Hashimoto thyroiditis and vitiligo—the possibility of permanent adrenal insufficiency from coexistent autoimmune destruction of the adrenal gland was seriously contemplated. Consequently, a test for serum anti-21-hydroxylase antibodies was performed in January 2008, yielding positive results for these antibodies. The patient was subsequently switched from alternate-day low-dose hydrocortisone to daily low-dose dexamethasone for slightly less than 1 week.
In December 2007, on a morning in which she had received no dexamethasone for 48 hours, her morning cortisol level was found to be low (1.1 μg/dL), and her morning corticotropin level was found to be high (76 pg/dL) (
Table). The patient showed no response to the Cortrosyn stimulation test, which measures how well the adrenal glands respond to corticotropin. This result was highly suggestive of Addison disease, though it could also be the result of using high-dose oral replacement steroid.
The presence of anti-21-hydroxylase antibodies was suggestive of an autoimmune destructive process of the adrenal gland, rather than chronic hypothalamic-pituitary-adrenal suppression from the previous cortisol-secreting adrenal tumor or recent exogenous glucocorticoid replacement. To determine if an autoimmune inflammatory process was destroying adrenal tissue unaffected by the macronodular hyperplasia, thereby causing permanent adrenal insufficiency, paraffin sections from the patient's previously resected adrenal tissue were reanalyzed. Hematoxylin and eosin staining of the adrenal tissue adjacent to the tumor revealed pathologically significant infiltration of the parenchyma by mononuclear inflammatory cells (
Figure 2). The inflammatory cells predominated in association with capillaries within the connective tissue tracts in the gland.
Immunostaining revealed high levels of TLR4 in the dominant nodule (
Figure 3A) and in the cytoplasm of adrenal epithelial cells that were being infiltrated by the inflammatory cells (ie, the sites of active adrenalitis) (
Figure 3B). Test results for TLR4 were slightly positive in the inflammatory cells and endothelial cells of the capillaries and in the larger vessels within the adrenal gland. There was some positive TLR3 immunoreactivity in the adrenal epithelial cells, but there was no such immunoreactivity in the endothelial cells or inflammatory cells infiltrating the adrenal gland (
Figure 3C). Immunostaining for Wnt5a (wingless-type MMTV integration site family, member 5A) showed negative results in the tumor tissue and adrenal epithelial cells (
Figure 3D).
At her last follow-up appointment, in mid-2008, the patient was doing well. She remained asymptomatic about 1 month later, in July 2008. The patient, unfortunately, did not keep her subsequent follow-up appointments or complete ordered laboratory work.