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Bilateral adrenal hemorrhage

Bilateral adrenal hemorrhage represents a challenging condition which requires multi-modal intervention. Our aim to systematically review the published cased diagnosed with this condition. The method we used is based on PubMed database research. The papers are published between 2005 and 2020. We included articles that follow the subsections: idiopathic type, hemorrhage in patients with adrenal tumors, in subjects with hematologic diseases, with autoimmune/systemic conditions, in COVID-19 positive patients, in subjects using anticoagulants, respective in pregnant females.


INTRODUCTION
Bilateral adrenal hemorrhage represents a challenging condition which requires multi-modal intervention. Our aim to review the published cased with this condition. The method we used is based on PubMed database research. The papers are published between 2005 and 2020.

IDIOPATHIC BILATERAL ADRENAL HEMORRHAGE
Idiopathic bilateral adrenal hemorrhage is bleeding in the absence of any known adrenal pathology and without any predisposing factors or caused at diagnostic or during follow-up (1,2,3). Several cases have been published in the literature. For instance, Ogino et al. reported a case of idiopathic bilateral adrenal hemorrhage of a 54-year old female (1). Computed tomogra-phy (CT) of the abdomen showed left adrenal hemorrhage (2.5x4.2x4.2 cm) and additional right adrenal hemorrhage (2 x 3.6 x 3.4 cm); laboratory investigation released low cortisol levels thus early glucocorticoid replacement therapy was initiated; after one month the patient was discharged (1). Antón et al. published a case of bilateral adrenal hemorrhage, the patient was 80-year old female; predisposing factors were excluded, therefore was diagnosed as spontaneous idiopathic BAH; CT scan of the abdomen showed a bilateral adrenal hemorrhage, enlarged adrenal glands 6.5x5.5 cm (left) and 6x5 cm (right); the patient recovered after the introduction of glucocorticoid replacement therapy (2). Another case was published by Song et al. -this is a 50-year old female who had a spontaneous regression of idiopathic bilateral adrenal hemorrhage (3). Dahiya et al. reported a 46-year old male who was identified with the condition based on autopsy exam (4) (see Table 1).

BILATERAL ADRENAL HEMORRHAGE IN ADRENAL TUMORS
Ali et al. published a retrospective study (between 2012 and 2018) on 11 patients that were included; they presented with non-traumatic acute adrenal hemorrhage in Sheffield Teaching Hospitals; adrenal glands were evaluated based on CT scan (5). Women were 63.6%; median age was 58  years; patients was initially treated without surgery, but after a median of 10 weeks, 5 patients underwent adrenalectomy (pathological examination showed 2 benign, 2 malignant and 1 necrotic tumor) (5). Most of the patients with adrenal hemorrhage had as predisposing factors adrenal tumors and anticoagulant therapy (5). Liu et al. published the case of a 52-year old male with giant bilateral adrenal hemorrhagic myelolipomas as showed by CT with post-operative confirmation (6). The adrenal metastases from non-small cell lung carcinoma (NSCLC) were identified in one case published by Hiroi et al.: this is a 56-year old male, with CT lesions of 5.9x4.2 cm of left and 6x4 cm of right mass (7). Surgery was not preformed because the patient had also bone metastases (7) (see Table 1).

BILATERAL ADRENAL HEMORRHAGE IN HEMATOLOGIC DISORDERS
Myeloproliferative disease increases the risk of thrombo-haemorrhagic events, for instance, a case of bilateral adrenal hemorrhage was published by Mendoza et al., a 71-year female with acute myeloid leukemia, and thrombocytopenia (8). Manganaro et al. published a case of a 65-year old male, with myelodysplastic syndrome, admitted at the emergency room with: acute epigastric pain, vomit, nausea and dyspnea (9). Uminski et al. described a 55-year old female case with myelofibrosis and additional bilateral adrenal hemorrhage demonstrated by CT; laboratory tests showed thrombocytopenia, without evidence of adrenal insufficiency (10). Bhandari et al. described a case of bilateral adrenal hemorrhage on a 64-year old man with polycythemia vera who was admitted for hypotension, tachycardia, hypoglycemia and elevated coagulation parameters; CT showed bilateral adrenal hemorrhage (right adrenal gland of 5.3x3.4x3.8 cm and a left adrenal gland of 6.1x4.3x5.4 cm) (11). Gönen et al. published the case of a 56-year old man who was confirmed with bilateral adrenal hemorrhage and polycythemia; CT showed a right, respective left adrenal gland mass of 4x5x5.5 cm, respective 4x3x2 cm (12) (see Table 1).

BILATERAL ADRENAL HEMORRHAGE IN AUTOIMMUNE/SYSTEMIC CONDITIONS
Antiphospholipid syndrome (APLS) is a pro-thrombotic autoimmune disorder and it is a major risk factor for adrenal hemorrhage (13). Ramon et al. published a retrospective study between 1990 and 2010 on 23 patients with bilateral adrenal hemorrhage secondary to APLS; only 16 patients survived the acute phase; median follow-up of patients was 3.5 years (range 0.3-28.1); median age of adrenal failure was 33.5 years; the adrenal insufficiency was irreversible in majority of patients (13). Aldaajani et al. published a case of bilateral adrenal hemorrhage after discontinuation of warfarin therapy; the patient was a 43-year old male with medical history of APLS secondary to systemic lupus erythematosus; clinical presentation and laboratory examination were consistent with adrenal insufficiency; bilateral adrenal thrombosis lead to hemorrhage and it was confirmed on CT scan (14). Minami et al. reported a case of a 56-year old male with history of follicular non-Hodgking lymphoma and APLS during the development of chronic Graf-versus-host disease complicated by bilateral adrenal hemorrhage (15). Also, Potter et al. presented a case of 57-year old female with medical history of several episodes of thrombosis in addition to adrenal condition and APLS (16). Adrenal hemorrhage is associated with stress caused by sepsis, classically with fulminant meningoccemia (Waterhouse-Friderichsen syndrome); sepsis increasing the risk for adrenal hemorrhage (17). Guarner et al. published a postmortem study on 65 patients with bacterial infections in different tissues, a study between 1998 and 2006 in Centers for Disease Control and Prevention (17). Adrenal glands were evaluated with hematoxylin and eosin stains, the hemorrhage was found in 39 patients (60%) of 65 cases (17). Neisseria meningitidis was the bacteria most frequently associated with adrenal hemorrhage (17). Stojanović et al. described a case of 20-year old male who died and on autopsy revealed hemorrhage in many organs even bilateral adrenal hemorrhage with Waterhouse-Friderichsen syndrome (18 Table 1).

BILATERAL ADRENAL HEMORRHAGE AND COVID-19
Adrenal tissue have a high vulnerability in patients affected by COVID-19 due to the presence of virus receptors at the level of adrenal glands (23-27) (see Table 1).

BILATERAL ADRENAL HEMORRHAGE AND STRESS
Stress can induced adrenal hemorrhage; adrenaline can induced platelets aggregation, turbulence and vasoconstriction that may lead to hemorrhage (41,42). patients with severe burns who died between 1995 and 2005 in Helsinki Burn Centre, and 4 patients had adrenal hemorrhage (3-bilateral adrenal hemorrhage, 1-unilateral adrenal hemorrhage); the cause of death was multiple organ failure (44) (see Table 1).

BILATERAL ADRENAL HEMORRHAGE AND PREGNANCY
Pregnancy is a known, yet very rare, risk factor for adrenal hemorrhage; pregnancy is associated with adrenal cortex hyperplasia and hypertrophy, which may predispose to venous congestion and hemorrhage (45,46) (see Table 1).

DISCUSSIONS
Adrenal hemorrhage represents a condition accompanying local (adrenal) diseases or systemic diseases (71,72). Its recognition is essential since glucocorticoids replacement is lifesaving (73,74). The level of statistical evidence is dominated by case reports rather than vast studies .

CONCLUSION
The importance of recognition a severe condition as bilateral adrenal hemorrhage is based on the fact that multiple medical and surgical practitioners relate to it.