Continuing Education Activity

Adrenal hemorrhage represents a rare disease of variable etiologies. The disease often presents in a wide variety of clinical settings and presents a challenging diagnosis due to nonspecific signs and symptoms. This activity will demonstrate how a high index of suspicion, coupled with an interprofessional approach is crucial for improving patient outcomes.

Objectives:

• Outline the most common etiologies of adrenal hemorrhage.
• Describe the most common presenting signs and symptoms of adrenal hemorrhage and outline investigations for its diagnosis.
• Summarize the treatment modalities available for adrenal hemorrhage.
• Explain how an interprofessional approach is vital for the effective management of patients of adrenal hemorrhage.

Introduction

Adrenal hemorrhage is an uncommon disorder characterized by bleeding into the suprarenal glands. The hematoma may be unilateral or bilateral, and the clinical presentation can range from nonspecific abdominal pain to catastrophic cardiovascular collapse. The etiologies for this unusual disorder are diverse. Potential causes include blunt abdominal trauma, septicemia, coagulopathies, anti-coagulant use, pregnancy, stress, antiphospholipid syndrome, and essential thrombocytosis.[1][2][3][2][4][5][6][7]

A high index of clinical suspicion is necessary for prompt diagnosis. A plethora of clinical presentations makes the diagnosis challenging. The signs and symptoms range from nonspecific abdominal pain to acute adrenal insufficiency, depending on the site and extent of hemorrhage. Imaging and biochemical evaluation provide the mainstay for diagnosis.

The adrenal glands are a pair of endocrine organs located in the retroperitoneum on the upper poles of the kidneys. They comprise two embryologically and functionally distinct parts, the outer mesodermally derived adrenal cortex, which produces glucocorticoids, mineralocorticoids, and adrenal androgens, and the inner adrenal medulla, which originates from the neural crest secretes catecholamines. The suprarenal glands are one of the most well-perfused organs in the human body. The superior, middle, and inferior adrenal arteries originate from the inferior phrenic artery, the abdominal aorta, and the renal artery, respectively, form the chief arterial supply. In contrast, the venous drainage is limited and often utilizing a single adrenal vein, which drains into the inferior vena cava on the right and the renal vein on the left. This difference between the arterial inflow and venous drainage may explain the anatomic predisposition to developing hemorrhagic infarction.[8]

Etiology

The etiology of adrenal hemorrhage is diverse. It can be classified as:

1. Primary or idiopathic in which there is no obvious cause
2. Secondary. The etiologies associated with the latter are:[9][10][11][12]
   • Abdominal trauma
   • Infections
   • Septicemia
   • Anticoagulant use
   • Pregnancy
   • Acute stress
   • Neonatal stress
   • Surgery
   • Neoplastic diseases
   • Autoimmune diseases like systemic lupus erythematosus and antiphospholipid syndrome

Any stressful condition placed on the body can lead to physiological hyperplasia of the glands and concomitant increased vascularity.[13] These, together with the already rich arterial supply and the relatively restricted venous drainage may contribute to hemorrhagic infarction. Adrenal congestion is often seen on computed tomography (CT) scans in patients who subsequently develop adrenal hemorrhage and may provide a vital clue to early diagnosis.[14]

Epidemiology

Adrenal hemorrhage is a relatively rare disorder, estimated to be present in roughly 0.14% to 1.8% of postmortem examinations.[15] Overall, it is associated with a 15% mortality rate, which varies according to the severity of the underlying cause of hemorrhage. A 55-60% mortality rate has been reported in patients with Waterhouse-Friderichsen syndrome (adrenal hemorrhage is frequently due to meningococcal sepsis).[16] Though the actual incidence may be much higher since the vague presentation, associated comorbid conditions and variable lab findings can make diagnosis difficult. A higher male preponderance has been reported, probably reflecting the increased frequency of underlying etiologies. The disease is seen in neonates and middle-aged individuals.[17][18]

Pathophysiology

The exact pathophysiology of acute adrenal hemorrhage remains uncertain. It has been hypothesized that certain specific anatomic and physiological characteristics predispose to bleeding into the adrenals.

The adrenals derive rich arterial supply from three main arteries, the superior, middle, and inferior suprarenal arteries, which are usually branches of the inferior phrenic, the abdominal aorta, and the renal artery respectively. In contrast, the outflow of blood is limited to a single adrenal vein draining directly into the inferior vena cava on the right and into the left renal vein on the left.[8] Furthermore, the pattern of blood vessels within the adrenals and the rich subcapsular plexus drained by limited venules have been described as a vascular dam. The term “adrenal dam” is attributed to vascularities within the adrenal glands, implying the large degree of adrenal vascularities that are susceptible to hemorrhage due to their distinct anatomical attributes.[19] This may predispose to venous congestion and consequent hemorrhage in times of stress.[14]

The adrenal gland functionally and embryologically comprises two distinct parts, the cortex, and the medulla. In times of stress, excess trophic stimulation by adrenocorticotropic hormone (ACTH) causes hypertrophy and hyperplasia of the glands with increased vascularity, contributing to hemorrhage predisposition.[13] Furthermore, the release of catecholamines into the adrenal veins promotes vasoconstriction and further compromising the venous outflow leading to hemorrhage.

Histopathology

The histopathological analysis demonstrates hyperplasia of the adrenal glands along with congestion and focal or extensive hemorrhage. A clue to the etiology may also be present such as foci of neoplastic deposits, primary tumor, or infectious agent that may be observed on staining in cases of fatal infections.[6] Histopathology is used to confirm and determine the origin of the non-functioning adrenocortical carcinoma (ACC) and can provide relevant prognostic information.[20]

History and Physical

Adrenal hemorrhage can present in a myriad of clinical contexts, and diagnosis remains challenging. Disease familiarity and a high index of suspicion are required for early diagnosis and prompt treatment. Since critically ill individuals represent a subset of patients who are at risk of developing adrenal hemorrhage, early recognition is crucial in these subsets of patients.

The majority of the cases are discovered incidentally, however, nonspecific abdominal, or loin pain is an important presenting symptom. Other nonspecific symptoms include malaise, weakness, lethargy, nausea, vomiting, and diarrhea.[10] Symptoms may correlate to the severity of hemorrhage with extensive bilateral hemorrhage heralding the development of acute adrenal insufficiency.[21]

The examination may reveal signs of exsanguination such as tachycardia and hypotension, or nonspecific findings like abdominal or flank tenderness.[22] The release of cortisol and catecholamines by the expanding hematoma may present with elevated blood pressure, especially if the underlying etiology is a pheochromocytoma.

Evaluation

The majority of patients have normal lab parameters, possibly reflecting minor bleeding into the adrenals. Leukocytosis and anemia may be present. Biochemical markers of adrenal insufficiency such as hyponatremia, hyperkalemia, hypoglycemia may also be detected. Other important derangements include excess cortisol and elevated catecholamine levels, which may reflect the transient release from the gland destruction. Low cortisol with elevated ACTH is also an important diagnostic clue signifying extensive cortical involvement.[23]

Imaging remains the most important diagnostic tool, with computed tomography (CT) scan being an important modality. The appearance of imaging varies with the age of the hematoma.[24] Adrenal hemorrhage on CT scan appears as a round to ovoid lesion. There may be peri-adrenal fat stranding, and bleeding may extend into the peri-nephric space. Fresh hematomas demonstrate high attenuation, which decreases over time. Ultrasonography is the modality of choice in infants due to their small body size and relatively large adrenal size.[25] Contrast-enhanced ultrasound (CEUS) is being used in pediatrics to assess and follow-up of adrenal trauma and to differentiate between an adrenal hemorrhage and a mass.[26] Magnetic resonance imaging (MRI) is the most accurate diagnostic modality. It can differentiate acute from chronic hematomas and can also ascertain the presence of an underlying tumor.[27][28]

Treatment / Management

Treatment modalities are variable and depend on the extent of hemorrhage and degree of hormonal insufficiency. Conservative management with serial imaging and close monitoring is now being referred to as a more traditional interventional approach.[29][30]

Assessment for hemodynamic instability and adrenal insufficiency should guide treatment. Individuals who have massive retroperitoneal bleeding unresponsive to transfusions and conservative management are candidates for intervention. Angiography and embolization of the bleeding lesion may provide better outcomes compared with traditional surgical laparotomy.[27][31]

Adrenal insufficiency due to bilateral extensive hemorrhage should be managed with corticosteroids. As such, it may be useful to recognize computed tomography (CT) features of adrenal congestion as a sign for potential adrenal dysfunction and subsequent adrenal hemorrhage, so early steroid replacement therapy can be commenced to prevent death from adrenal insufficiency.[14] Pre-emptive use of steroids can prevent death from bilateral massive adrenal hemorrhage in high-risk patients presenting with clinical and laboratory findings.[32]

Adrenal hemorrhage may be the initial presentation of underlying adrenal mass lesions, with pheochromocytoma being the most common. Initial stabilizing therapy with antihypertensive treatment and alpha-blockers with definitive management once etiology is ascertained is advisable in these cases.[33]

Differential Diagnosis

The vague presentation may make differentiation from the primary course of critical illness difficult. Other differentials include aneurysm of the renal artery, metastatic deposits in adrenals and, renal tumors.[33] Suprarenal area masses in neonates can be differentially diagnosed in relation to clinical, laboratory, and radiologic findings. Neonatal neuroblastoma in situ is self-limiting and can be diagnosed by the measurement of the 24-hour urinary excretion of vanillylmandelic acid.[34] Simultaneous occurrence of neonatal suprarenal hemorrhage and neuroblastoma can be diagnosed by serial ultrasonography.[35] Right adrenal hemorrhage was diagnosed in a patient suffering from COVID-19 by triple-phase abdominal computed tomography (CT) imaging with normal adrenal function.[36] Accurate and timely diagnosis of adrenal abscesses is essential to exclude malignancy and to ensure appropriate management.[37] Although adrenal masses are uncommon and rarely present with bleeding, yet they are important in the differential etiology for adrenal bleeding.[38]

Prognosis

Prognosis is variable depending on the underlying etiology, the extent of hemorrhage, and the overall health status of the patient. Waterhouse Friderichsen syndrome has a mortality approaching 60% despite adequate medical management with fluids, antibiotics, and glucocorticoids.

Complications

Extensive adrenal hemorrhage may lead to the development of adrenal insufficiency which may be transient or permanent. Extensive hemorrhage can lead to the development of retroperitoneal hemorrhage and hypovolemic shock.

Deterrence and Patient Education

Though no specific measure prevents the development of adrenal hemorrhage, a high index for diagnosis and early diagnostic workup are key to improving prognosis.

Enhancing Healthcare Team Outcomes

Adrenal hemorrhage, apart from being a rare disease, is seldom considered on one's list of differentials. This situation, combined with the fact that presentation is often vague with no exceptional signs or symptoms, may lead to a missed diagnosis. A high index of suspicion, together with timely radiological and biochemical testing is the key to prompt diagnosis and treatment. An interprofessional team approach is required with the primary provider, intensivist, radiologist, endocrinologist, interventional radiologist, and surgeon to provide comprehensive management.

Prompt management of hemodynamic instability, the institution of timely adrenal replacement, and intervention for ongoing hemorrhage, whether angiographically or via laparotomy, may provide the best possible outcomes.

In essence, a patient-centered, team-oriented approach to diagnosis, evaluation, and management is necessary to provide the best outcomes.