Definitive Adrenal Insufficiency Due to Bilateral Adrenal Hemorrhage and Primary Antiphospholipid Syndrome
Philippe Caron,
Marie-Hélène Chabannier,
Jean-Pierre Cambus,
Françoise Fortenfant,
Philippe Otal and
Jean-Michel Suc
Service dEndocrinologie (P.C.), Service de Néphrologie
(M.-H.C., J.-M.S.), Laboratoire dHématologie (J.-P.C.), Service
de Radiologie (P.O.), CHU Rangueil, and Laboratoire dImmunologie
(F.F.), CHU Purpan, Toulouse, France
Address all correspondence and reprint requests to: Philippe Caron, M.D., Service dEndocrinologie et Maladies métaboliques, CHU Rangueil, 1, Avenue J. Poulhés, 31054 Toulouse Cedex, France.
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Introduction
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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, 2, 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.
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Case report
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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 Hashimotos 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.

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Figure 1. 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).
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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 Rosners 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-ß2 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.
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.
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Discussion
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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-ß2
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 Hashimotos thyroiditis, but without anti-ß2 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-ß2 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-ß2
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.
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Conclusion
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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-ß2 glycoprotein I antibodies
should be performed, as adrenal insufficiency may be an early and fatal
manifestation of the antiphospholipid syndrome.
Received December 17, 1997.
Accepted February 10, 1998.
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References
|
---|
-
Asherson RA, Khamashta MA, Ordi-Ros J, et al. 1989 The "primary" antiphospholipid syndrome: major clinical and
serological features. Medicine. 68:366374.[Medline]
-
Asherson RA, Hughes GRL. 1989 Recurrent deep vein
thrombosis and Addisons disease in "primary" antiphospholipid
syndrome. J Rheumatol. 16:378380.[Medline]
-
Alarcon-Segovia D, Cabral AR. 1996 The
antiphospholipid/cofactors syndromes. J Rheumatol. 23:13191322.[Medline]
-
Asherson RA. 1988 A "primary" antiphospholipid
syndrome. J Rheumatol. 15:17421746.
-
Alarcon-Segovia D, Perez-Vasquez ME, Villa AR, et
al. 1992 Preliminary classification criteria for the
antiphospholipid syndrome within systemic lupus erythematosus. Semin
Arthritis Rheum. 21:275286.[CrossRef][Medline]
-
Mackworth-Young CG, Loizou S, Walport MJ. 1989 Primary antiphospholipid syndrome: features of patients with raised
anticardiolipin antibodies and no other disorder. Ann Rheum Dis. 48:362367.[Abstract]
-
Ames DE, Asherson RA, Ayres B, et al. 1992 Bilateral adrenal infarction, hypoadrenalism and sphincter haemorrhages
in the "primary" antiphospholipid syndrome. Br J Rheumatol. 31:117120.[Medline]
-
Christopilis MA, Silvestre-Aillaud P, Piquet P, Aillaud
MC, Vialettes B. 1994 Insuffisance surrénalienne et syndrome
des antiphospholipides. Ann Endocrinol (Paris). 55:284287.
-
Viard JP, Amoura Z, Bach JF. 1992 Association of
anti-ß2 glycoprotein I antibodies with lupus-type circulating
anticoagulant and thrombosis in systemic lupus erythematosus. Am J
Med 93:181186.
-
Khamasiita M, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ,
Hugues GRV. 1995 The management of thrombosis in the
antiphospholipid-antibody syndrome. N Engl J Med. 332:993997.[Abstract/Free Full Text]
-
Doppman JL, Gill JR, Nienhuis AW, Earli JM, Long
JA. 1982 CT findings in Addisons disease. J Comput Assist
Tomogr. 6:757761.[Medline]
-
Xarli VP, Steele AA, Davies PJ, Buescher ES, Rios CN,
Garcia-Bunuel R. 1978 Adrenal hemorrhage in the adult. Medicine.
57: 211221.
-
Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike
T. 1994 Anticardiolipin antibodies recognize ß2-glycoprotein I
structure altered by interacting with an oxygen modified solid phase
surface. J Exp Med. 179:457462.[Abstract]
-
McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. 1990 Antiphospholipid antibodies are directed against a complex antigen
that includes a lipid-binding inhibitor of coagulation:
ß2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA. 87:41204124.[Abstract]
-
Paggi A, Caccavo D, Ferri GM, et al. 1994 Anticardiolipin antibodies in autoimmune thyroid disaese. Clin
Endocrinol (Oxf). 40:329333.[Medline]
-
Martinuzzo ME, Forastiero RR, Carreras LO. 1995 Anti ß2 glycoprotein I antibodies: detection and association with
thrombosis. Br J Haematol. 89:397402.[Medline]
-
Piette JC, Wechsler B, Frances C, Papeau T, Godeau
P. 1993 Exclusion criteria for primary antiphospholipid syndrome. J Rheumatol. 20:18021804.[Medline]
-
Komesaroff P, Yung A, Topliss D. 1991 Postoprerative primary adrenal failure in a patient with
anticardiolipin antibodies. J Rheumatol. 18:8890.[Medline]
-
Asherson RA, Hughes GRL. 1991 Hypoadrenalism,
Addisons disease and antiphospholipid antibodies. J Rheumatol. 18:13.[Medline]
-
Alperin N, Babu S, Weinstein A. 1989 Acute adrenal
insufficiency and the antiphospholipid syndrome. Ann Intern Med. 111:950.[Medline]
-
Rao RH, Vagnucci AH, Amico JA. 1989 Bilateral
massive adrenal hemorrhage: early recognition and treatment. Ann Intern
Med. 110:227235.[Medline]
-
Grinspoon SK, Biller BMK. 1994 Laboratory
assessement of adrenal insufficiency. J Clin Endocrinol Metab. 79:923931.[Medline]
-
Wolverson MK, Kannegiesser HK. 1984 CT of
bilateral adrenal hemorrhage with acute adrenal insufficiency in the
adult. Am J Roentgenol. 142:311314.[Medline]