Definitive Adrenal Insufficiency Due to Bilateral Adrenal Hemorrhage and Primary Antiphospholipid Syndrome

ANTIPHOSPHOLIPID syndrome is characterized by multiple and recurrent venous and arterial thromboses accompanied by and probably caused by circulating antibodies directed against a heterogenous group of phospholipids (1–3). Antiphospholipid syndrome has been described in a large variety of conditions such as connective tissue disorders, malignancies, or some prolonged treatments, but has also been recognized in the absence of all those conditions, leading to the concept of primary antiphospholipid syndrome (4). Contrary to neurological, cardiac, hepatic, skin, or renal manifestations associated with antiphospholipid syndrome, which have been extensively described and commented, the adrenal manifestations of the antiphospholipid syndrome have received scare attention or are completely omitted in large series (1, 5, 6). In patients with primary antiphospholipid syndrome, spontaneous bilateral adrenal hemorrhage is an uncommon condition that may lead to acute adrenal insufficiency and death. It was almost exclusively a postmortem diagnosis before computed tomography (CT) scan was developed. Anecdotal cases of survival have recently been reported in patients with bilateral adrenal hemorrhage associated with the antiphospholipid syndrome (7, 8). We describe a new observation of definitive adrenal insufficiency caused by bilateral adrenal hemorrhage in a woman with a primary antiphospholipid syndrome. A 45-yr-old woman with a history of pain to left flank was admitted to our department in May 1996. She has had 11 pregnancies without spontaneous abortions, and the youngest child was 12-yr-old. A hypothyroidism secondary to Hashimoto’s thyroiditis was treated with levothyroxine. She has also a history of proteinuria. On admission she was febrile and hypotensive. She presented with livedo reticularis on her legs and cutaneous ulcers on her right foot. An abdominal CT scan revealed an enlarged dense left adrenal gland consistent with unilateral adrenal hemorrhage (Fig. 1A), whereas the right adrenal gland was normal. Three days after admission, she remained febrile, became confused and developed bilateral abdominal pain. A repeat CT scan of the abdomen showed a bilateral adrenal hemorrhage (Fig. 1B). A possible adrenal insufficiency was suggested and was later confirmed by low cortisol (85 nmol/L, normal range 165 - 550 nmol/L) and undetectable aldosterone (<140 pmol/L) levels. A steroid therapy with hydrocortisone and mineralocorticoids rapidly improved her condition. Subsequently, because of noncompliance to therapy, she presented an acute adrenal insufficiency with hypotension, hyponatremia, and hyperkaliema. Finally, during the next week, she had a transient ischemic cerebrovascular attack. Abdominal CT scan showing bilateral adrenal hemorrhage in a patient with a primary antiphospholipid syndrome (A, at time of admission, B, after 3 days, and C, after 6 months of follow-p). The hemostasis analysis of the patient showed that the extrinsic and intrinsic pathway factors were normal. Antithrombin, protein C and S were normal. Activated protein C resistance was negative. On the other hand, activated partial thromboplastin time (APTT) of the patient was 84 sec (normal 34 sec). The APTT with a mixture of patient and normal plasma was also increased to 60 sec. These results suggested the presence of an anticoagulant antibody, with a Rosner’s index of 31 for a cut-off value equal to 15. Tissue thromboplastin inhibition (TTI) indicated the presence of antiphospholipid antibodies (Table 1). Anticardiolipin antibodies by enzyme-linked immunosorbent assay (Cardilisa test, Biomedical diagnostic, Marne la Vallée, France) were positive. Anti-β2 glycoprotein I antibodies were detected by an ELISA technique described by Viard et al. (9) (Table 1). Therefore, the diagnosis of antiphospholipid syndrome was made, and a warfarin treatment was initiated (10). Based on medical history, clinical examination, biological, and radiologic findings, there was no evidence for antiphospholid syndrome associated with drugs, connective tissue disorders, or malignancies. Pertinent laboratory tests in the patient with a primary antiphospholipid syndrome Pertinent laboratory tests in the patient with a primary antiphospholipid syndrome After 6 months of anticoagulation therapy, the patient was reevaluated by an abdominal CT scan (Fig. 1C), showing a diminution of the adrenal masses. A prolonged ACTH stimulation test (1 mg cosyntropin infused over 6 h, on two consecutive days) was performed while the patient was taking 1 mg/day dexamethasone. Serum cortisol (blood withdrawn every 4 h during 24 h) was low before (<20 nmol/L) and the day after (26 ± 1 nmol/L) ACTH stimulation. Urinary free cortisol levels were undetectable (<20 nmol/day) and did not rise after the two-day ACTH stimulation test. The patient was discharged with a warfarin treatment. At the time of writing this report, she has not experienced any new episode of venous or arterial thrombosis, and she has remained on glucocorticoid and mineralocorticoid therapy. Before development of CT scan, the diagnosis of bilateral adrenal hemorrhage was seldom recognized before death, because signs and symptoms are nonspecific and are easily confused with those of the underlying condition. In the early stage, the symptoms and signs of adrenal hemorrhage are not dramatic: pain of varying severity localized to the abdomen, flank, lower chest, or back is the more consistent feature, whereas the cardiovascular, gastrointestinal, and neurospsychiatric symptoms of adrenal insufficiency occur much less frequently. The two main features of bilateral adrenal hemorrhage are original biochemical evidence of occult hemorrhage, with a fall of hemoglobin and hematocrit, and subsequent hormonal appearance of adrenal insufficiency with hyponatremia and hyperkaliema. Surgical or biopsy proof of adrenal hemorrhage in this patient was lacking, but a firm presumptive diagnosis was made on successive CT scan studies showing, in a few days, the rapid enlargement of the right adrenal gland. To our knowledge, this is the first case in which the two episodes of bilateral adrenal hemorrhage have been visualized. On the other hand, CT scan data exclude other conditions associated with bilateral enlargement, with or without adrenal insufficiency, such as granulomatous infections, malignancies, or autoimmune deficiency syndrome (AIDS) (11). Spontaneous bilateral adrenal hemorrhage usually occurs in association with severe stress such as meningococcemia, surgery, burns, or hypotension (12), but also may complicate a hemorrhagic diathesis, especially that resulting from anticoagulant therapy or acquired coagulation disorders, such as antiphospholipid syndrome. Laboratory tests of the patient revealed the presence of thrombocytopenia, anticardiolipin, and anti-β2 glycoprotein I antibodies, consistent with a antiphospholipid syndrome (13, 14). An increased incidence of anticardiolipin antibodies has been reported in patients affected by autoimmune thyroid diseases (15) such as Hashimoto’s thyroiditis, but without anti-β2 glycoprotein I antibodies, and most of these patients did not present recurrent venous and arterial thromboses. Interestingly, the patient had 11 pregnancies without recurrent spontaneous abortions, and no association between the presence of anti-β2 glycoprotein I antibodies and the prevalence of obstetric complications has been observed in patients with primary antiphospholipid syndrome (16). On the other hand, these authors reported that the presence of anti-β2 glycoprotein I antibodies was associated with venous thromboembolic events in patients with primary antiphospholipid syndrome. Clinical data and laboratory tests of the patient argue for the diagnosis of primary antiphospholipid syndrome (17). In patients with antiphospholipid syndrome, spontaneous hemorragic infarction of the adrenal glands has been observed in the postoperative period (18) or during anticoagulant treatment (19). Hemorrhagic necrosis of the adrenal glands probably results from adrenal vein thrombosis: the adrenal glands show hemorrhagic infarction with fibrin thrombi in the small vascular channels without vasculitis (20). Therefore, adrenal hemorrhage or thrombosis are both possible mechanisms of adrenal insufficiency in patients with antiphospholipid syndrome. The diagnosis of adrenal insufficiency in patients with bilateral adrenal hemorrhage was rarely made before death few years ago, because the signs and symptoms are not dramatic and were nonspecific (21). After an abdominal CT scan showing a bilateral enlargement of the adrenal glands, a presumptive treatment should be started while confirmation of adrenal insufficiency is made by hormonal evaluation: low basal cortisol and aldosterone levels, and the absence of a rise in plasma cortisol after a short corticotropin stimulation test are the most commonly used tools for the diagnosis of adrenal insufficiency (22). While she did not take steroid therapy, the subject of this case report developed hypotension, hyponatremia, and hyperkaliema owing to an acute adrenal insufficiency. After a 6-month follow-up examination, hormonal evaluation of the patient showed no detectable rise in plasma and urinary free cortisol after a prolonged ACTH stimulation test, and the permanent adrenal insufficiency was confirmed. As already observed, after spontaneous bilateral adrenal hemorrhage in acutely ill patients (23), endocrine studies of our subject demonstrate that, in a patient with a primary antiphospholipid syndrome, a definitive loss of adrenal function could be the result of bilateral adrenal hemorrhage and might need long-term steroid replacement therapy. Acute and definitive adrenal insufficiency due to bilateral adrenal hemorrhage can complicate the primary antiphospholipid syndrome. In those patients, the diagnosis of bilateral adrenal hemorrhage might be rapidly made with CT scan of the abdomen in order to initiate a treatment with glucocorticoid and mineralocorticoids. On the other hand, in patients with adrenal insufficiency and enlargement of adrenals suggestive of bilateral hemorrhage, a test for anticardiolipid and/or anti-β2 glycoprotein I antibodies should be performed, as adrenal insufficiency may be an early and fatal manifestation of the antiphospholipid syndrome.