Adrenal Insufficiency in the Antiphospholipid Antibody Syndrome

Jbn A. Arnason and Frank M. Graziano

Objective: Adrenal insufficiency (AI) is a rare complication of the antiphospho- lipid antibody syndrome (APS). The objective of this report is to describe a case and review the published literature to enhance recognition of this potentially fatal disorder by emphasizing its course, diagnosis, and cause. Data Sources: A bibliographic database with the indexing terms adrenal insufficiency, adrenal hemorrhage, adrenal thrombosis, APS, systemic lupus erythematosus, with the constraints of human subjects only, was used. Study Selection: All 27 reports meeting the indexing terms were selected for review. Data Extraction: The specific criteria used for data extraction articles included course of the disease, causation, clinical and laboratory diagnostic criteria, and therapeutic intervention. Data Synthesis: Our patient is a previously health woman who developed a respiratory tract infection, followed by a prolonged illness with fever, hypoten- sion, nausea, depression, and venous thromboses. She was found to have AI and APS that was alleviated with hydrocortisone and anticoagulation. Initially, her adrenal glands were normal on CT scan but subsequently became enlarged and later atrophic. Of the 27 previous case reports, a majority had thromboses and typical clinical and laboratory manifestations of AI. Hemorrhagic infarction of the adrenal gland appears to be the mechanism for AI in the APS. IgG and IgM anticardiolipin antibodies are most commonly reported in association with AI in APS. Conclusions: The hypercoagulable state in the APS may lead to adrenal vein thrombosis and subsequently to hemorrhagic necrosis of the adrenal gland. This complication of APS is important to recognize because it may be fatal if untreated. Copyright © 1995 by W.B. Saunders Company

INDEX WORDS: Adrenal insufficiency; antiphospholipid antibody syndrome; systemic lupus erythematosus.

DRENAL insufficiency (AI) is an uncom- mon manifestation of systemic lupus ery-

thematosus (SLE),I, 2 but several cases have been described in which AI occurs in associa- tion with antiphospholipid antibody syndrome (APS), with or without clinical evidence of SLE. 3-22 In this report we describe one such case and review the previous reports in the litera- ture.

CASE REPORT

Our patient is a previously healthy, nulli- gravida 44-year-old white woman, who after a 3-month prodrome of nasal congestion and cough, developed left-sided pleuritic chest pain, fever, and hemoptysis. She was admitted to her local hospital where a chest radiograph showed

an infiltrate and pleural effusion. She was treated with a combination of broad-spectrum antibiot- ics for a presumed pneumonia with a parapneu- monic effusion. A chest tube was placed for drainage of the effusion but cultures and cyto- logical examination of the pleural fluid were

From the Department of Internal Medicine, University of Wisconsin, Madison.

J6n A Arnason, MD: Clinical Fellow, Section of Rheuma- tology; Frank M Grazi.ano, MD, PhD: Professor of Medicine, Chief, Section of Rheumatology.

Address reprint requests to Frank M Graziano, MD, PhD, Professor of Medicine, Chief, Section of Rheumatology, H6/ 367 CSC, University of Wisconsin, 600 Highland Ave, Madi- son, WI53972.

Copyright © 1995 by W.B. Saunders Company 0049-0172/95/2502-000555.00/0

Seminars in Arthritis and Rheumatism, Vo125, No 2 (Octo bet), 1995: pp 109-116 109

110 ARNASON AND GRAZIANO

Table 1 : Demographics and Clinical Features of Patients With APS and AI

Case Reference Age No. of No. No, Year Gender (yr) Prior Diagnosis Miscarriages

1 3 1993 F 30 3 2 4 1993 F 54 Remote TB, cutaneous thrombosis

3 5 1991 M 33 Pneumonia

4 6 1991 F 26 Deep vein thrombosis 7

5 6 1991 F 27 11

6 7 1991 M 42

7 7 1991 M 26 8 7 1991 M 31 SLE

9 7 1991 M 72 Drug-induced SLE 10 8 1991 F 68 SLE

11 9 1990 M 14

12 10 1990 M 68 Antiphospholipid antibody syn- drome, MI

13 11 1990 F 15 AI, SLE 14 12 1990 F 31 Necrotizing vasculitis, SLE

15 12 1990 F 17 Pneumonitis, depression 1 16 13 1990 F 32 Deep vein thrombosis, pulmonary

embolism 17 14 1989 M 46 Arterial thrombus

18 15 1989 M 42

19 15 1989 M 27 Deep vein thrombosis, pulmonary embolism

20 15 1989 F 67 Discoid lupus 21 16 1989 20 Superficial arterial thromboses 22 17 1988 M 34 Deep vein thrombosis

23 18 1988 F 37 Deep vein thrombosis 4

24 19 1988 M 43 Deep vein thrombosis, pulmonary embolism

25 20 1988 F 10 AI, pneumonia 26 21 1980 M 37 Deep vein thrombosis

27 22 1973 F 26 SLE

Abbreviations: APS, antiphospholipid antibody syndrome; SLE, systemic lupus erythematosus; TB, tuberculosis; MI, myocardial infarction; blank, not reported; AI, adrenal insufficiency.

AI AND ACA SYNDROME 111

Table 1: (Cont'd)

Thrombosis Symptoms of AI Comments SLE

Superficial thromboses, pulmonary embolism

Deep vein thrombosis, pulmonary embolism

Deep vein thrombosis, cerebral embolism

Deep vein thrombosis

Deep vein thrombosis, pulmonary embolism

Deep vein thrombosis

Cerebral embolism

Cerebral embolism

Deep vein thrombosis

Deep vein thrombosis

Pulmonary embolism

Deep vein thrombosis Deep vein thrombosis,

pulmonary embolism

Abdominal pain, nausea, vomiting Abdominal pain, depression, hyperpig-

mentation Vomiting, hypotension

Abdominal pain, nausea, vomiting, hypo- tension

Headache, fever, hyperpigmentation, hypotension

Abdominal pain, fever, hypotension

Abdominal pain, fever, hypotension Abdominal pain, fever, esoinophitia,

hypotension Abdominal pain, fever Fever, weakness, hypotension

Abdominal pain, vomiting, weight loss

Nausea, vomiting, weakness, weight loss, hypotension

Abdominal pain, nausea, vomiting, hypo- tension

Back pain, nausea, vomiting, hypotension Abdominal pain, nausea, vomiting, fever,

hypotension Abdominal pain Abdominal pain, weakness, weight loss,

hyperpigmentation Abdominal pain, fever, nausea, vomiting,

weakness, hypotension Abdominal pain, nausea Abdominal pain, fever, weakness Abdominal pain, fever, weakness, hypo-

tension, hyperpigmentation Nausea, weakness, hyperpigmentation,

hypotension Hyperpigmentation

Headache, hypotension

Back pain, vomiting, fever, hyperpigrnen- tation, eosinophilia, hypotension

Improved 3 months later Antithrombotic agents before AI

Heparin before AI

Heparin and warfarin before AI

Heparin before AI

Heparin before AI

Warfarin before AI Multiple complications after

diagnosis; death Mesangioproliferative glomerulo-

nephritis

Anticoagulation before A!

Heparin before AI

Warfarin before AI

N N

N

N

N

N

N Y

Y Y

N

N

N Y

Y N

N N

N

N N N

N

N

N N

Y

112 ~,RNASON AND GRAZIANO

Table 2: Test Results of Patients With Antiphospholipid Antibody Syndrome and Adrenal Insufficiency

Platelet Partial Thrombo- Case Reference Count Anticardio- Lupus Anti- Antinuclear Other Prothrombin plastin Time No. No. xl031~L lipin Antibody coagulant Antibody AB Time (s) (s) VDRL

1 3 IgM N 28 N 2 4 43 P N N 17 65 N 3 5 292 IgG 1:40 N 22 68 4 6 IgG, A, M P N N 11.5 32 P 5 6 IgG, A, M P N ds DNA 15 95 P 6 7 P P PROL 7 7 P P PROL 8 7 P P P PROL P 9 7 P PROL

10 8 NL IgM P 1:20,480 N PROL 11 9 90 P 40 DNA 14 58 P

12 10 32 P 10 N 15.5 50

13 11 IgG, M 1:1,280 N PROL 14 12 62 IgG, M P N N 14.1 52 15 12 109 IgA, M P 1:160 N 14.9 47 P

16 13 IgG P NL 41.8

17 14 45 P N NL 32 18 15 P N 66

19 15 P P 20 15 P

21 16 P 22 17 154 P P 1:1,280 N 13.9 101.5 P 23 18 62 IgG, M P P N 15 67 24 19 56 IgG P N N PROL 25 20 <100 IgG, M P P N PROL P 26 21 89 P N 55 P 27 22 118 P P 52 61.9 P

Abbreviations: Ig, immunogiobulin; P, positive; N, negative/no; dsDNA, double stranded DNA; PROL, prolonged; NL, normal; H, high; L, low; Y, yes; blank, not reported; ACLA, anticardiolipin antibody; LA, Lupus anticoagulant.

negative. Other pertinent laboratory data on admission included white blood cells 10,200/ ixL, hematocrit 29.8 mL/dL, platelets 79,000/ixL. Electrolytes and chemistry panel were normal.

Over the next 3 weeks the infiltrate and the effusion gradually cleared, but she became de- bilitated from intermittent hypotension and de- veloped clinical depression. She also continued to have a fever, abdominal pain, nausea, and vomiting. Bacterial and fungal cultures of spu- tum, blood, and pleural fluid and serum titers

for human immunodeficiency virus and hepati- tis viruses A, B, and C were all negative. A tuberculin skin test was negative with positive controls. Ultrasound examination and com- puted tomography (CT) scan of the abdomen showed a hemangioma-like lesion in the liver but no other abnormalities (adrenal glands appeared normal). The antinuclear antibody test was 1:40 with a homogenous pattern, and the double-stranded DNA was 279 IU (nega- tive < 100 IU). Rheumatoid factor, Smith, RNP,

AI AND ACA SYNDROME 113

Table 2: (Cont'd)

Hyponatremia or Cortisol

H!yperkalemia (Unstimulated)

Adrenocorti- cotrophic Hormone

Stimulation Test

Computed Tomography Magnetic Resonance

Imaging Biopsy

,y

Y Y

Y Y L Y L

Y L Y L

Y L

H H

N H

H

H

Y L H

L Y L

Y L Y L Y L

L Y L

L Y L

H

Bilateral adrenal enlargement Bilateral adrenal hemorrhage

NL Right adrenal enlargement Bilateral adrenal hemorrhage Bilateral adrenal hemorrhage Bilateral adrenal hemorrhage

Bilateral adrenal hemorrhage Bilateral adrenal enlargement,

later atrophy Bilateral adrenal enlargement,

later atrophy

NL, right adrenal not seen Bilateral adrenal enlargement,

right hemorrhagic Bilateral adrenal enlargement,

later atrophy Bilateral adrenal hemorrhage Left adrenal calcification, right

adrenal enlargement Right adrenal enlargement Bilateral adrenal enlargement

Bilateral adrenal hemorrhage

NL Small adrenal glands

Hemorrhage Atrophy, thrombus

Hemorrhagic infarct

Hemorrhagic infarct, thrombus

Scl 70, centromere, SSA, SSB, c-antineutrophil cytoplasmic antibody (ANCA), p-ANCA, and cold agglutinins were all negative and the complement profile was normal. Other perti- nent laboratory data included: prothrombin time 13 (11.2 to 13.2), partial thromboplastin time 36 (20-30), Na + 128 mmol/L, K + 6.2 retool/L, glucose 108 mg/dL, blood urea nitro- gen (BUN) 30 mg/dL, creatinine 1.9 mg/dL.

In the third week of the hospital stay, a left-sided neck mass was noted caused by throm- boses in the internal jugular and subclavian veins. A central venous catheter had been placed into the subclavian vein on admission.

Echocardiogram and ventilation/perfusion lung scans were normal. Subcutaneous heparin was started. Her symptoms continued and a week later, she was given one dose of prednisone (20 mg) for presumed SLE and transferred to our institution.

Two days after admission she developed right thigh and calf deep vein thromboses. Rheuma- tology consultation found the patient intermit- tently obtunded and complaining of nausea. She had a fever of 39.2°C, tachycardia, tachypnea, and a blood pressure of 110/70 mm Hg. A previous history of Raynaud's syndrome, inter- mittent arthralgia, and hair loss was obtained.

114 ,~,RNASON AND GRAZIANO

Hyperpigmentation was noted, but no skin rash, mucosal ulcers, or signs of arthritis were found.

The diagnoses of APS and AI were consid- ered. Immunoglobulin (Ig)G anticardiolipin an- tibody (ACA) was 621 U ( < 10), but IgA ACA and IgM ACA were below the detection limit of the assay. The lupus anticoagulant test results were positive, and the veneral disease research laboratory was positive with a nonreactive fluo- rescent treponemal antibody. A cortisol level was low normal at 6.9 ~g/dL (am 6 to 24), but without an increase after an injection of cosyn- tropin. Adrenocorticotrophic hormone (ACTH) was 21 ng/mL (range, 7 to 51) but aldosterone was undetectable. Thyroid function test results were normal. A repeat CT scan of the abdomen now showed a diffusely thickened right adrenal gland and a 2.8-cm mass in the left gland. On magnetic resonance imaging (MRI) scan, the left adrenal mass appeared cystic. The patient was fully anticoagulated and started on hydro- cortisone, which led to resolution of symptoms; after appropriate adjustment of anticoagulation she was discharged from the hospital.

On a follow-up evaluation 3 months later, a cosyntropin stimulation test result was still with- out a cortisol response but aldosterone levels were normal. Two months later, however, nei- ther cortisol nor aldosterone increased in re- sponse to stimulation, and ACTH was elevated. CT of the abdomen showed involution of both adrenal glands. The IgG and IgA ACA were now both markedly elevated above the upper limits of the assay and IgM ACA was 19 U (range, 0-10).

LITERATURE REVIEW

AI in a patient with SLE and a circulating anticoagulant was first described by Eichner in 1973, 22 and in association with ACA by Pel- konen et al 2° in 1988. Table 1 lists the reported clinical findings of the 27 patients previously reported with ACA or lupus anticoagulant and AI. The gender ratio is fairly equal, and the mean age is 36 years. Although the full details of the clinical features of each case were seldom reported, the majority of patients did not meet the 1982 ARA criteria for SLE. 23 In several cases, there was a pre-existing clinical illness consistent with APS, with a history of deep vein thrombosis in 7, pulmonary embolism in 3, and

another form of thrombosis in 3. Three of the 14 women (Table l; numbers 1, 15, and 23) had a history of second or third trimester spontaneous abortions, but early abortions, not a feature of APS, were reported in two other women (Table 1; numbers 4 and 5).

The symptoms of AI in these patients are fairly typical, with abdominal pain, nausea, vomiting, fatigue, fever, and hypotension being common. One patient had hypertension, 9 but his illness was complicated by coexisting glo- merulonephritis. Hyperpigmentation, indicat- ing a longstanding AI, was reported in four patients. The laboratory features of this group of patients were consistent with AI (Table 2). Hyponatremia and/or hyperkalemia were the most common laboratory abnormalities, being observed in 18 patients. Hypoglycemia was less commonly found, and only two patients were reported to have eosinophilia. Baseline cortisol levels were subnormal, and cosyntropin stimula- tion test results were always without a sufficient increase in cortisol levels, diagnostic for AI. Aldosterone levels were infrequently reported, but w e r e low 4,8'9'12 or normal 22 where com- mented on. In 10 of the 27 cases reported, treatment with some form of anticoagulant or antithrombotic agent before the clinical onset of AI raised the possibility of intra-adrenal bleeding as a complication of anticoagulation. Only one patient, however, had bleeding de- tected elsewhere. I9 All of the others developed AI without a concurrent hemorrhagic complica- tion, but often associated with another major thrombosis (in some cases despite anticoagula- tion). Thus, adrenal bleeding caused by anti- coagulants was an unlikely cause of AI in these individuals.

The adrenal glands have a rich arterial supply but have limited venous drainage by a single vein. 24 Anatomic features peculiar to the adre- nal vein are thought to make it susceptible to thrombosis, following which hemorrhagic infarc- tion of the adrenal gland often occurs. 24,25 This appears to be the mechanism for AI in APS and is supported by histological findings. In histologi- cal studies, thrombi, 8 hemorrhage, 7 or hemor- rhagic infarction 14,a5 rather than vasculitis have been observed. CT or MRI studies of the adrenal glands typically show intra-adrenal

AI AND ACA SYNDROME 115

bleeding initially, but later atrophy, consistent with the course of hemorrhagic necrosis.

IgG and IgM ACA are most commonly re- ported in association with AI, but many of the case reports do not indicate the isotypes of ACA. How ACA and other antiphospholipid antibodies lead to hypercoagulability has not been unequivocally established. However, they are more likely to be directly responsible, rather than just an epiphenomenon. 26

DISCUSSION

Before this illness, our patient enjoyed good health with only nonspecific symptoms attribut- able to connective tissue disease. We do not know if she previously had ACA. When she be, came ill with an upper respiratory tract infec- tion, and later pneumonia, no etiologic agent was identified. The pneumonic infiltrate cleared in response to antibiotics, making SLE-related pneumonitis unlikely. However, despite radio- logic improvement, she remained severely ill, had metabolic evidence of AI, and developed venous thromboses. The hyperpigmentation in-

dicates at least a subclinical AI before this illness, with precipitation of the symptoms caused by the stress of the infection. Such a presentation is indeed typical for AI. 16,27 Hypo- volemia, hypotension, and prostration during her illness, as well as the presence of intrave- nous catheters are likely to have contributed to the hypercoagulable state (in the presence of ACA) that caused the major vessel thromboses. The adrenal glands were normal on initial imaging, but later they were asymmetrically enlarged and finally atrophic. This is consistent with thrombosis of the adrenal vein and subse- quent hemorrhagic necrosis of the adrenal glands.

Although a recovery of adrenal function may occur in patients with APS and AI, 3 and our patient transiently regained aldosterone secre- tion, a permanent loss of adrenal gland function is more common. AI probably is a rare complica- tion of APS but needs to be considered in the appropriate clinical context. Although poten- tially fatal, it is usually easily treated.

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