Adrenal Hemorrhage in Patients with Systemic Lupus Erythematosus and Antiphospholipid Syndrome: A Case Report and Literature Review

Antiphospholipid syndrome (APS) is an autoimmune disorder while adrenal hemorrhage could be its rare complication. Herein, we report the case of a 32-year-old unmarried woman with a history of systemic lupus erythematosus (SLE) who was hospitalized after complaints of upper abdominal pain, limb weakness, and loss of appetite for 2 weeks. Laboratory examination revealed hyponatremia, low plasma cortisol levels, increased adrenocorticotropic hormone levels, and a positive anticardiolipin antibody status. Furthermore, computed tomography (CT) revealed the presence of bilateral adrenal masses. Ultimately, based on dynamic changes in CT images, these masses were diagnosed as adrenal hemorrhage owing to APS. A computer-assisted literature search was conducted to identify cases of primary adrenal insufficiency associated with APS and/or SLE. The clinical features, laboratory examination, treatments, and outcomes of these cases were summarized. Our findings emphasize the importance of screening for adrenal insufficiency in patients with SLE or APS who present with abdominal complaints, asthenia, and hyponatremia. It is also recommended to test for APS all patients with adrenal hemorrhage.


Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by damage to targeted tissues or organs owing to an aberrant immune response.Te typical manifestations of SLE are malar rash, discoid lupus, and multiorgan disorders.Te antiphospholipid antibodies are detected in the serum of approximately 20%-30% of patients with SLE, who tend to sufer from antiphospholipid syndrome (APS) during the faring phase [1].APS, a noninfammatory autoimmune disorder, is characterized by recurrent thrombogenesis, abortion, and a decreased platelet count.In individuals with APS, thrombogenesis can occur in any blood vessel, leading to ischemia and organ dysfunction [2].Bilateral adrenal hemorrhage is the most common mechanism of Addison's disease in APS patients, but the possibility of an autoimmune origin of adrenal insufciency should also be kept in mind [3].Studies have reported that there are <1% of cases of APS-associated adrenal hemorrhage, with adverse outcomes such as adrenal insufciency and adrenal crisis [4].However, gastrointestinal complaints and musculoskeletal symptoms could be the only features of adrenal failure.Hyponatremia is the most common laboratory fnding, refecting mineralocorticoid defciency.Te main fndings that led to the diagnosis of adrenal failure in newly diagnosed APS patients were hyponatremia and abdominal pain [3].Adrenal hemorrhage secondary to APS is difcult to identify because of atypical symptoms such as abdominal pain, fever, altered mental status, and dynamic imaging presentations of the hematoma located in the adrenal glands.
Herein, we described the case of a 32-year-old Chinese woman with primary SLE who presented with adrenal insufciency.After examinations, she was diagnosed with APS-associated adrenal hemorrhage.Furthermore, we reviewed existing literature on patients with SLE and/or APS and adrenal insufciency.

Case Report
A 32-year-old unmarried woman with a history of SLE was admitted to a local hospital on October 27, 2021, owing to complaints of severe upper abdominal pain, limb weakness, and low appetite.She took hydroxychloroquine and prednisone for the treatment of SLE before and had discontinued the drugs for 1 year.She did not complain of nausea, vomiting, and fever.Her blood pressure, heart rate, and temperature were normal at the time of admission; however, serum sodium levels had decreased to 128 mmol/L.She was initially diagnosed with gastroenteritis.Although she received intravenous antibiotics, she continued to complain of upper abdominal pain and limb weakness.Tereafter, whole abdominal computed tomography (CT) revealed bilateral adrenal masses (see Figure 1(a) for the CT image taken at a local hospital).Spiral CT of these bilateral adrenal masses revealed that the center of the right mass was signifcantly strengthened, with a mean CT value of approximately 58 Hounsfeld units (HU); the left mass had a CT value of 30 HU. Abnormal adrenocortical hormone levels were noted, with cortisol levels decreasing to 8.43 nmol/L (reference range, 185-624 nmol/L) at 8 AM and adrenocorticotropic hormone (ACTH) being >1250 pg/mL (reference range, 5-46 pg/mL) at 8 AM (refer to Table 1 for laboratory blood test results); therefore, the patient was diagnosed with adrenal insufciency.Te autoimmune workup confrmed the presence of lupus anticoagulant (LA) and anti-dsDNA, antihistone, anticardiolipin (aCL), and anti-β2 glycoprotein I antibodies (Table 2).Te next day, her abdominal pain spontaneously disappeared; however, limb weakness and loss of appetite did not improve.Surgery was suggested by the doctor in local hospital to identify the nature of the bilateral adrenal masses.She refused to undergo surgery and was discharged with a prescription for hydrocortisone 20 mg at 8 AM and 10 mg at 4 PM.
On November 10, 2021, the patient was admitted to our hospital for further treatment.At the time of admission, she still complained of weight loss and limb weakness; however, she did not have a fever, abdominal pain, and hypotension (blood pressure, 111/89 mmHg).Physical examination revealed hyperpigmentation on her fnger joints.However, no facial rash, oral ulceration, or Raynaud's phenomenon was observed.Meanwhile, her body and sexual organs had developed normally (height and weight were 155 cm and 50 kg, respectively).Examinations revealed hyponatremia, decreased plasma cortisol levels, and increased ACTH and renin levels.Also, the aldosterone level was normal (Tables 1  and 2).Furthermore, abnormal coagulation status was confrmed based on the signifcantly high activated partial thromboplastin time of 100.9 s (reference range 28.0-40.0s).Meanwhile, erythrocytes, leucocytes, platelets, liver enzymes, creatinine, T-spot test, tumor and infammatory makers, testosterone, estradiol, follicle-stimulating hormone, progesterone, luteinizing hormone, and 17hydroxyprogesterone (17-OHP) were all within normal limits.A rheumatologist was consulted.Subsequently, abnormal autoimmune antibody and coagulation status fndings confrmed the diagnosis of APS secondary to SLE [1].She was administered hydroxychloroquine 100 mg two times a day and aspirin 0.1 g once a day.Furthermore, a prescription for hydrocortisone was provided to her as before.Moreover, instead of performing puncture surgery of the adrenal masses, repeated enhanced bilateral adrenal CT was performed, which revealed two low-density nodular shadows located on both adrenal glands; the right shadow was 30 × 20 mm and the left shadow was 20 × 15 mm (Figure 1(b)), with mean CT values of 15 and 12 HU, respectively.In other words, her adrenal glands were cystic rather than normal because the optimal critical value of the adrenal glands is 10 HU.Referring to ESE and ENSAT guidelines, if CT demonstrates a homogeneous adrenal mass with unenhanced HU between 11 and 20 and a tumor size <4 cm, an immediate additional imaging to avoid any follow-up imaging can be performed.Te use of adrenal biopsy is recommended if clinical management would be altered by knowledge of the adrenal mass histology [5].
After carefully comparing these adrenal CT images, the patient was diagnosed with adrenal hemorrhage associated with APS secondary to SLE.Irregular antirheumatic therapy was considered a risk factor for adrenal hemorrhage for her.Nevertheless, weakness and anorexia gradually improved after hydrocortisone treatment during hospitalization.Finally, the patient was discharged with a prescription for hydrocortisone, hydroxychloroquine, and aspirin, as mentioned above.
During the third follow-up visit, on February 24, 2022, the patient was undergoing steroid replacement, antirheumatic, and aspirin therapy and remained in a good condition.Repeat CT scan values of the left and right adrenal glands were 30 and 38 HU, respectively (Figure 1(c)).However, laboratory tests still revealed decreasing serum cortisol and increasing ACTH levels at both 8 AM and 4 PM (Table 1).Considering hydrocortisone might not provide a sufcient suppression of the ACTH levels for its short-acting feature, the patient was prescribed prednisone 5 mg bid, hydroxychloroquine 100 mg bid, aspirin 0.1 g qd, and atorvastatin 20 mg qn.On March 21, 2022, she was confrmed to be 5 weeks pregnant.During her pregnancy, she stopped taking atorvastatin but continued taking prednisone, hydroxychloroquine, and aspirin without decreasing the dosage.Fortunately, in November 2022, she gave birth to a healthy baby girl without spontaneous abortion, thrombocytopenia, or recurrent thrombosis.She continued taking prednisone, hydroxychloroquine, and aspirin after delivery.However, she refused a reevaluation of adrenal function and imaging.Nevertheless, she required long-term follow-up.
Tere were 13 (59%) men and 9 (41%) women.Te mean age of the patients was 39.5 (28.75-49.75)years.Eight (36%) patients had connective tissue disease (CTD) before adrenal insufciency, and fve of these patients were diagnosed with SLE.Furthermore, in nine (41%) patients, adrenal insufciency was the frst manifestation of CTD.Four (18%) patients had hypothyroidism, with two of these patients having thyroiditis.Pulmonary embolism or deep venous thrombosis was observed in four (18%) patients.In one patient (patient 14), adrenal insufciency was diagnosed 1 week after inguinal hernia surgery; on the other hand, in two patients, adrenal insufciency was diagnosed after anticoagulant therapy was discontinued [6,7].
Fever was observed in nine (41%) patients, hyperpigmentation in nine (41%), nausea or vomiting in seven (32%), abdominal pain in six (27%), fatigue or depression in fve (23%), and weight loss in four (18%).Meanwhile, hyponatremia and hypotension were the key signs for doctors to diagnose adrenal insufciency, which were observed in seven (32%) patients.Fifteen (68%) patients were positive for antinuclear antibody, and 11 (50%) patients were positive for LA.Of the 13 (59%) patients who were positive for aCL antibodies, seven had an isotype of aCL: three (43%) were positive for the IgG isotype, three (43%) for the IgM isotype, and one for both isotypes.
In most patients, CT or magnetic resonance imaging fndings of the adrenal glands were diferent.Enlarged adrenal glands were observed in nine (41%) patients, adrenal atrophy in fve (23%), and adrenal hemorrhage in six (27%), similar to adrenal masses.In three patients, adrenal gland images were normal.
As for the etiology of adrenal insufciency, in many cases, owing to the unique and fragile vascular anatomy, adrenal hemorrhage secondary to a hypercoagulant state caused by SLE and/or APS was considered the reason, and patients who discontinued anticoagulants were high-risk groups.Eleven (50%) patients had a confrmed diagnosis of adrenal hemorrhage.Nevertheless, among these patients, autoimmune disorders of the adrenal glands could not be eliminated.In one study, a 21-hydroxylase antibody examination could not be conducted, and in another study, four patients were complicated with hypothyroidism [6,8].Te latter fnding is vital information for diagnosing the possibility of multiple endocrine organ dysfunction as a result of an autoimmune disorder.
All patients received steroid therapy, and hydrocortisone was the most commonly used medication (∼69%).Furthermore, 12 (55%) patients were administered anticoagulants.Patients undergoing long-term anticoagulant therapy remain well.

Discussion
Primary adrenal insufciency is caused by the destruction of the adrenal cortex, leading to the insufcient secretion of glucocorticoids and mineralocorticoids.Here, we reported a case of adrenal insufciency secondary to adrenal hemorrhage associated with APS that was confrmed via aPL testing and adrenal CT.SLE is a chronic autoimmune disease caused by the loss of self-tolerance and organ dysfunction.Bilateral adrenal hemorrhage is the most common mechanism of Addison disease in APS patients, but the possibility of an autoimmune origin of adrenal insufciency should also be kept in mind [3].However, when patients with SLE develop adrenal insufciency with abnormally enlarged adrenal images, they cannot be diagnosed with adrenal hemorrhage owing to APS.Te antiphospholipid antibody is an important diagnostic maker of APS and a risk factor for thrombosis and pregnancy complications [20].Te aPL test includes the evaluation of LA, aCL antibodies, and anti-β 2 glycoprotein antibodies (IgG, IgM, and IgA).A positive LA test with or without a moderate-to-high titer of aCL or anti-β 2 GPI IgG or IgM is defned as a high-risk profle, providing additional confdence in the diagnosis [1].
Studies have reported that there are <1% of patients with APS who present with adrenal hemorrhage; therefore, it is a rare phenomenon during the course [4].However, the main fndings that led to the diagnosis of adrenal failure in newly diagnosed APS patients were hyponatremia and abdominal pain [3].In particular, it is hard to identify this condition during the silent period.Nevertheless, continuous imaging may help in the diagnosis of this condition.Te etiology of abnormally enlarged adrenal images in patients with adrenal insufciency encompasses congenital adrenal hyperplasia (CAH), tuberculosis, autoimmune defciency, tumor metastasis, infection, and hemorrhage [21].On the other hand, patients with adrenal insufciency generally have a chronic course because the clinical manifestations present only after there is ∼90% of adrenal cortex damage.However, bilateral adrenal hemorrhage or thrombosis may lead to acute adrenal insufciency.During our literature review, we encountered a case of bilateral adrenal     hemorrhage associated with APS that was reported by Bansal R et al. [9].After carefully comparing the frst adrenal CT image with the second, the evolvement of adrenal images was similar to the development of a hematoma.Considering the patient was diagnosed with APS and had an abnormal coagulation status, an APS-associated adrenal hemorrhage was identifed.At present, the pathogenesis of APS-associated adrenal hemorrhage remains unclear.One possible mechanism is associated with the unique vascular anatomy of the adrenal glands, making the organ vulnerable, particularly in the APS-induced hypercoagulable state.In bilateral adrenal, there are three arteries with tens of branches, and the transition from arteries to capillary is extremely rapid.Meanwhile, the single vein of the adrenal gland, comprising longitudinal muscle bundles, can hardly expand easily.Terefore, bilateral adrenal vein thrombosis may be the frst pathological change during adrenal insufciency secondary to APS, subsequently resulting in swollen adrenal glands.Finally, adrenal hemorrhage infarction is induced because of the occlusion of the vascular branches [20,22].Te second possible mechanism is associated with the cellular characteristics of the zona fasciculata.Te cells in this zone are rich in cholesterol owing to a high density of late endosomes.Te membranes of these organelles contain lysophosphatidic acid, a target of antiphospholipid antibodies.Tese antiphospholipid bodies react locally and lead to cholesterol accumulation within the cell; this, in turn, leads to cell death and the release of lysosomal proteinases, activating endothelial cells, favoring coagulation, and causing microthrombosis [23].
Te manifestations of APS-associated adrenal insufciency are always typical, with abdominal pain, nausea or vomiting, hypotension, fever, and weakness being common symptoms.Most patients sufer from primary APS, and adrenal insufciency may be the frst manifestation of APS.Similar to most reported cases, our patient began complaining of abdominal pain, weakness, and anorexia.She was diagnosed with APS along with adrenal insufciency.However, she did not have hypotension or fever.Furthermore, diferential diagnosis was possibly difcult because the frst CT scan values of the adrenal glands were not typical values indicative of adrenal hemorrhage.Given that imaging remains the most important tool in adrenal hemorrhage diagnosis, with CT scan being an important modality, the appearance of imaging varies with the age of the hematoma.Fresh hematomas usually demonstrate high attenuation which decreases over time.Magnetic resonance imaging in these cases can be useful in the diferential diagnosis.Still, it cannot be available everywhere.In our case, it is possible that adrenal hemorrhage was the frst manifestation of APS in our patient.
Te treatment goals for APS include thrombogenesis prevention and pregnancy failure; furthermore, individual therapy is warranted.Terapeutic doses of low-molecularweight heparin and subsequent vitamin K antagonists are frst-line treatment options for frst or recurrent APS-related venous thrombotic events (VTEs) [24].According to European League Against Rheumatis recommendations, patients with APS and frst unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists with a target international normalised ratio (INR) of 2-3.In patients with APS with frst arterial thrombosis, treatment with VKA with INR 2-3 or INR 3-4 is recommended, considering the individual's bleeding/thrombosis risk [25].On the other hand, glucocorticoid therapy is recommended for all patients with primary adrenal insufciency.Guidelines for primary adrenal insufciency suggest the use of hydrocortisone (15-25 mg) or cortisone acetate (20-35 mg) in two or three divided oral doses per day; the highest dose should be given in the morning at awakening [26,27].Nine patients had a history of thrombosis, and seven of them were treated with anticoagulants before the diagnosis of adrenal insufciency [3,6,[8][9][10][11].In six (50%) of the twelve patients, heparin was the most commonly used anticoagulant.Among seven patients who received anticoagulants before adrenal insufciency, the CT scan of only two patients revealed adrenal hemorrhage.Consistent with the guidelines, although heparin may cause adrenal hemorrhage, it should still be recommended to patients with APS-related VTEs owing to the extremely low incidence.However, based on the recommendations for the management of APS in China, we prescribed low-dose aspirin instead of heparin to our patient for primary prevention, complying with the primary prevention of APSrelated VTEs [28].During the follow-up, the patient was well without abortion or recurrent thrombotic events.Due to the potential-at least partial-recovery of adrenal insufciency and regression of adrenal lesions, long-term reevaluation of adrenal function and imaging is necessary.However, due to the patient's own reasons, she refused to reexamine.Long-term follow-up should be necessary in the future.
In summary, primary adrenal insufciency secondary to adrenal hemorrhage is a rare complication of SLE or APS.It is important to screen for adrenal insufciency patients with SLE or APS presenting with symptoms of abdominal pain, weakness, and hyponatremia.On the other hand, it is also recommended to test for APS all patients with adrenal hemorrhage.

Figure 1 :
Figure 1: Enhanced bilateral adrenal CT: (a) bilateral adrenal masses with a signifcantly strengthened signal at the center of both the glands at onset; CT scan values on the left and right adrenal glands were 30 HU and 58 HU, respectively.(b) Two low-density nodular shadows located on both adrenals 4 days later.CT scan values on the left and right adrenal glands were 15 HU and 12 HU, respectively.(c) Atrophy of adrenal glands in the third-month follow-up.CT scan values on the left and right adrenal glands were 30 HU and 38 HU, respectively.

Table 1 :
Laboratory data at the time of admission.

Table 3 :
Summary of the clinical features, diagnosis data, treatment, and etiology of all cases.