Adrenal Hemorrhage Clinical Presentation

Symptoms of adrenal hemorrhage are nonspecific; they include abdominal, lumbar, pelvic, or thoracic pain and symptoms of acute adrenal insufficiency, such as fatigue, anorexia, nausea, and vomiting. Symptoms associated with the underlying condition(s) also may be present. Rarely, adrenal hemorrhage is entirely asymptomatic, presenting as an incidental finding on imaging studies.

Pain that is nonspecific in location and quality is the most consistent feature of adrenal hemorrhage.

• Nonspecific pain occurred in 65-85% of published cases.

• It can occur predominantly in the epigastrium, flank, upper or lower back, pelvis, or precordium or elsewhere in the thorax.

• Left shoulder pain may occur in association with abdominal pain, likely because of diaphragmatic irritation.

Fatigue, weakness, dizziness, arthralgias, myalgias, anorexia, nausea, vomiting, and diarrhea, which are present in approximately 50% of extensive, bilateral adrenal hemorrhage cases, are indicative of acute adrenal insufficiency.

Symptoms of the underlying condition(s) predisposing to adrenal hemorrhage may be present. For example, patients with Waterhouse-Friderichsen syndrome often experience prodromic, nonspecific symptoms, including malaise, headache, dizziness, cough, arthralgias, and myalgias.

Adrenal hemorrhage may be present in approximately 2 of 1000 newborn infants and may arise spontaneously or in association with birth trauma, asphyxia, sepsis, or hemorrhagic diathesis.

Physical findings in patients with adrenal hemorrhage are nonspecific and vary depending on the extent of adrenal hemorrhage, the bleeding rate, and the underlying cause, as well as according to whether the adrenal hemorrhage is bilateral or unilateral.

Fever (ie, temperature >38ºC) is present in 50-70% of patients with adrenal hemorrhage, representing the most frequent finding in adrenal hemorrhage.

• In reported cases, temperature may range from low-grade fever to high fever with chills.

• In the setting of adrenal hemorrhage, fever may be associated with adrenal insufficiency, the hematoma itself, or the underlying cause of adrenal hemorrhage.

Tachycardia has been reported in approximately 40-50% of patients early in the course of extensive, bilateral adrenal hemorrhage, and without aggressive therapy, it may progress to shock.

Orthostatic hypotension is present in approximately 20% of patients with extensive, bilateral adrenal hemorrhage. This is an early finding that, if there is no specific intervention, usually leads to supine hypotension and shock.

Because shock occurs only late in the course of extensive, bilateral adrenal hemorrhage, its absence should not be used to exclude this diagnosis.

• In addition to acute adrenal insufficiency, shock in patients with extensive, bilateral adrenal hemorrhage may be caused by 1 or more underlying conditions, including sepsis, cardiovascular causes (commonly myocardial infarction and pulmonary embolism), or hypovolemia.

• In Waterhouse-Friderichsen syndrome, activation of several cytokine mediators appears to lead to sepsis and shock. Whether acute adrenal insufficiency has a significant role in the pathogenesis of the Waterhouse-Friderichsen syndrome remains unclear and debatable.

Hypertension has been reported rarely in patients with unilateral adrenal hemorrhage; in one patient it was accompanied by headache and dizziness, leading to an erroneous diagnosis of pheochromocytoma.

Weight loss is very uncommon, but it may occur in cases of adrenal hemorrhage that are recognized several weeks after the event. These patients have a subacute presentation of adrenal insufficiency in association with adrenal hemorrhage, instead of acute adrenal crisis.

Skin hyperpigmentation has been reported rarely in adrenal hemorrhage cases. Its presence indicates late recognition of adrenal insufficiency in association with adrenal hemorrhage.

A characteristic skin rash with a typical evolution occurs in approximately 75% of patients with Waterhouse-Friderichsen syndrome.

• In its early stages, the rash consists of small, pink macules or papules.

• These are rapidly followed by petechial lesions, which gradually transform into large, purpuric, coalescent plaques in late stages of the disease.

Signs of acute abdomen, including guarding, rigidity, or rebound tenderness, have been reported in 15-20% of patients. This relative paucity of physical findings on abdominal examination is likely secondary to the retroperitoneal location of the adrenals.

Confusion and disorientation are present in 20-40% of patients. These findings are also nonspecific, because they may be associated with acute adrenal insufficiency or with the underlying condition(s) precipitating adrenal hemorrhage.

Bilateral adrenal hemorrhage

In at least 50% of cases, bilateral adrenal hemorrhage is associated with an acute, stressful illness (eg, infection, congestive heart failure, myocardial infarction, complications of pregnancy) or event (eg, surgery or invasive procedure). Other frequent associations include hemorrhagic diatheses (eg, anticoagulant use, thrombocytopenia), thromboembolic disease (including antiphospholipid antibody syndrome), blunt trauma, and ACTH therapy. In addition, bilateral adrenal hemorrhage has been reported in patients with tuberculosis, amyloidosis, or metastatic tumors involving the adrenals, including lung adenocarcinoma. A multicenter, hospital-based, case-control study identified thrombocytopenia, heparin exposure, and sepsis as the major risk factors for the development of bilateral adrenal hemorrhage.

• Infections associated with extensive, bilateral adrenal hemorrhage are diverse; they include sepsis, wound infections, pneumonia, pseudomembranous colitis, influenza, varicella, and malaria.

• Waterhouse-Friderichsen syndrome (purpura fulminans) represents hemorrhagic necrosis of several organs, including adrenal hemorrhage, in the setting of overwhelming sepsis. The syndrome frequently is characterized by a distinctly hemorrhagic skin rash. Although Waterhouse-Friderichsen syndrome originally was recognized in association with meningococcal disease, which still accounts for 80% of cases, the syndrome also has been associated with other bacterial pathogens, including Streptococcus pneumoniae, group A beta-hemolytic streptococci, Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae (group B), Salmonella choleraesuis, Pasteurella multocida, Acinetobacter calcoaceticus, and Plesiomonas shigelloides. ^[9]

• Congestive heart failure, myocardial infarction, inflammatory bowel disease, acute pancreatitis, and cirrhosis also have been associated with bilateral adrenal hemorrhage. ^[10]

• Obstetric causes of bilateral adrenal hemorrhage include toxemia of pregnancy, spontaneous abortion, antepartum or postpartum hemorrhage, twisted ovarian cyst (in pregnancy), and primary antiphospholipid antibody syndrome. Spontaneous adrenal hemorrhage during pregnancy has rarely been described. ^[11]

• Coronary artery bypass graft surgery, hip joint replacement, intracranial surgery, and hepatic arterial chemoembolization are procedures associated with bilateral adrenal hemorrhage. ^[12] Heparin-induced thrombocytopenia may predispose to adrenal hemorrhage in some of these patients.

• Hemorrhagic diatheses, including anticoagulant use, thrombocytopenia, and vitamin K deficiency have been associated with approximately one third of bilateral adrenal hemorrhage cases. Heparin use accounts for the majority of cases of anticoagulant-associated, bilateral adrenal hemorrhage. In such cases, bilateral adrenal hemorrhage occurs despite the fact that the activated partial thromboplastin time is almost invariably therapeutic, and adrenal hemorrhage represents an isolated event without evidence of bleeding elsewhere. Heparin-induced thrombocytopenia (HIT) was found to underlie several bilateral adrenal hemorrhage cases, although the precise role of HIT in the pathogenesis of heparin-induced adrenal hemorrhage has not been fully elucidated. ^[13]

• Arterial (eg, pulmonary embolism, cerebrovascular disease, peripheral arterial embolism) and venous (eg, deep venous thrombosis, superficial thrombophlebitis) causes have been associated with bilateral adrenal hemorrhage in one third of cases. Antiphospholipid antibody syndrome (either primary or secondary to systemic lupus erythematosus) has been associated with bilateral adrenal hemorrhage. ^{[14, 15, 16]}

• Blunt trauma of diverse etiologies, ranging from motor vehicle accidents to a truck ride over a bumpy road, has been associated with bilateral adrenal hemorrhage.

• Underlying adrenal pathologic conditions, including granulomatous diseases, amyloidosis, and metastatic cancer (eg, lung or gastric adenocarcinoma), have been associated with bilateral adrenal hemorrhage.

• Treatment with ACTH for multiple sclerosis or inflammatory bowel disease has in some cases been associated with bilateral adrenal hemorrhage.

• Case studies have indicated that an association exists between coronavirus disease 2019 (COVID-19) and adrenal hemorrhage. A report by Frankel et al described a woman aged 66 years who, along with COVID-19, had primary adrenal insufficiency resulting from bilateral adrenal hemorrhage. In addition, she had renal vein thrombosis and a past history of primary antiphospholipid antibody syndrome. The investigators suggested that the combination of COVID-19 (which has been associated with coagulopathy and thromboembolic events) and antiphospholipid antibody syndrome led to the adrenal hemorrhage. ^[17] Another case study, by Álvarez-Troncoso et al, reported test results in a man aged 70 years indicative of both COVID-19 and bilateral adrenal hemorrhage. ^[18]

Unilateral adrenal hemorrhage

Unilateral adrenal hemorrhage most frequently is caused by blunt abdominal trauma (traumatic adrenal rupture), but it also has occurred in liver transplant recipients and in patients with primary adrenal or metastatic tumors. In addition, unilateral adrenal hemorrhage is associated, albeit infrequently, with otherwise uncomplicated pregnancy, neurofibromatosis 1, or long-term nonsteroidal anti-inflammatory drug (NSAID) use. There have been rare reports of idiopathic, spontaneous, unilateral adrenal hemorrhage.

In a retrospective study of 23 patients with adrenal hemorrhage (including 22 with a unilateral condition), Karwacka et al reported that risk factors could not be determined in 13 patients, while risk factors in the rest of the cohort included trauma (5 patients), sepsis (1 patient; bilateral adrenal hemorrhage), concomitant neoplastic disease (2 patients), both anticoagulant drug use and lung cancer (1 patient), and both trauma and chronic oral anticoagulation (1 patient). ^[19]

• Unilateral adrenal hemorrhage secondary to blunt trauma more often involves the right adrenal. Liver hematomas and rib fractures commonly occur in these patients as well. Unilateral adrenal hemorrhage occurs in 2% of patients with penetrating trauma.

• Right adrenal hemorrhage was found in 2% of liver transplant recipients in one study, and it also was reported in 10% of children dying early after orthotopic liver transplantation. In these patients, intraoperative ligation of the right adrenal vein, performed after a limited resection of the recipient's inferior vena cava, has sometimes resulted in venous infarction and adrenal hemorrhage.

• Unilateral adrenal hemorrhage was described in patients with primary adrenal or metastatic tumors, representing hemorrhagic tumor infarction. Primary adrenal tumors associated with adrenal hemorrhage include adrenal adenomas, adrenocortical carcinomas, and pheochromocytomas. In addition, adrenal hemorrhage has been described in patients with metastatic hepatocellular carcinoma or with lung or gastric adenocarcinoma. ^[20]

• In isolated cases, unilateral adrenal hemorrhage may occur in association with long-term NSAID, otherwise uncomplicated pregnancy, and neurofibromatosis 1. ^[21]

• Idiopathic, unilateral adrenal hemorrhage is a rare entity that either may have an acute presentation (eg, idiopathic adrenal rupture) or may present as an asymptomatic adrenal mass. ^[22]