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Adrenal Insufficiency From Bilateral Adrenal Hemorrhage

1990; Elsevier BV; Volume: 65; Issue: 5 Linguagem: Inglês

10.1016/s0025-6196(12)65129-5

1942-5546

Samuel C. Siu, Dalane W. Kitzman, Patrick F. Sheedy, Robert C. Northcutt,

Hormonal Regulation and Hypertension

Bilateral adrenal hemorrhage is a rare cause of adrenal insufficiency in adults. Because of the nonspecific manifestations of adrenal insufficiency, antemortem diagnosis is difficult. Serial computed tomographic scans of the abdomen are a valuable adjunct in confirming the diagnosis of bilateral adrenal hemorrhage, which manifests as round or oval adrenal masses of high density that subsequently decrease in both size and density. The diagnosis should be suspected in any complex highly stressful illness, in the postoperative period, or in the presence of a coagulopathy in conjunction with hypotension, fever, or electrolyte disturbances. Herein we describe five patients in whom the computed tomographic scans suggested or confirmed the presence of bilateral adrenal hemorrhage. In three of the five patients, the presence of a circulating lupus anticoagulant was demonstrated. Once the diagnosis of adrenal hemorrhage is suspected, steroid replacement therapy should be initiated promptly. Bilateral adrenal hemorrhage is a rare cause of adrenal insufficiency in adults. Because of the nonspecific manifestations of adrenal insufficiency, antemortem diagnosis is difficult. Serial computed tomographic scans of the abdomen are a valuable adjunct in confirming the diagnosis of bilateral adrenal hemorrhage, which manifests as round or oval adrenal masses of high density that subsequently decrease in both size and density. The diagnosis should be suspected in any complex highly stressful illness, in the postoperative period, or in the presence of a coagulopathy in conjunction with hypotension, fever, or electrolyte disturbances. Herein we describe five patients in whom the computed tomographic scans suggested or confirmed the presence of bilateral adrenal hemorrhage. In three of the five patients, the presence of a circulating lupus anticoagulant was demonstrated. Once the diagnosis of adrenal hemorrhage is suspected, steroid replacement therapy should be initiated promptly. Bilateral adrenal hemorrhage is a rarely recognized cause of adrenal insufficiency in adults. The diagnostic difficulty is likely related to the nonspecific clinical manifestations of adrenal insufficiency within the context of a major concurrent illness. Corticotropin stimulation and anticoagulation therapy have been identified as risk factors that predispose to adrenal hemorrhage.13Clark OH Hall AD Schambelan M Clinical manifestations of adrenal hemorrhage.Am J Surg. 1974; 128: 219-224Abstract Full Text PDF PubMed Scopus (37) Google Scholar The diagnosis has most often been made during postmortem examination because of the failure to suspect it during life. With the recent availability of computed tomography (CT), the clinician now has a safe and rapid adjunctive diagnostic procedure.2Anderson KC Kuhajda FP Bell WR Diagnosis and treatment of anticoagulant-related adrenal hemorrhage.AmJHematol. 1981; 11: 379-385PubMed Google Scholar, 4Ling D Korobkin M Silverman PM Dunnick NR CT demonstration of bilateral adrenal hemorrhage.AJR. 1983; 141: 307-308Crossref PubMed Scopus (50) Google Scholar, 5Liu L Haskin ME Rose LI Bemis CE Diagnosis of bilateral adrenocortical hemorrhage by computed tomography.Ann Intern Med. 1982; 97: 720-721Crossref PubMed Scopus (30) Google Scholar, 6Lundstrom GK Chen PS Bilateral adrenal hemorrhage associated with prior steroid use: CT diagnosis.J Can Assoc Radiol. 1985; 36: 58-60PubMed Google Scholar, 7Marcus AO Duick DS Little D Waldmann EB Bilateral adrenal hemorrhage during anticoagulant therapy.Ariz Med. 1982; 39: 575-577PubMed Google Scholar, 8Scott Jr, WW Fishman EK Siegelman SS Anticoagulants and abdominal pain: the role of computed tomography.JAMA. 1984; 252: 2053-2056Crossref PubMed Scopus (40) Google Scholar, 9Swift DE Overholt EL Travelli R Methods of diagnosis of acute adrenal hemorrhage complicating anticoagulant therapy—abdominal CAT scanning.Wis Med J. November 1981; 80: 25-28PubMed Google Scholar, 10Wolverson MK Kannegiesser H CT of bilateral adrenal hemorrhage with acute adrenal insufficiency in the adult.AJR. 1984; 142: 311-314Crossref PubMed Scopus (62) Google Scholar In this article, we report five cases of adrenal insufficiency attributable to bilateral adrenal hemorrhage in which the diagnosis was confirmed by CT and endocrine testing. Four of the patients described in this report received direct medical care from one or more of the authors. A review of the Mayo Clinic medical records and the CT records of the Department of Diagnostic Radiology resulted in the discovery of the other case. All five patients had CT evidence of either recent or resolving bilateral adrenal hemorrhage as well as clinical or biochemical evidence (or both) of adrenocortical insufficiency. Cases of unilateral hemorrhage, pediatric patients, postmortem diagnoses, and posttraumatic adrenal hemorrhage were excluded from this study. An otherwise healthy 70-year-old man came to our medical center for evaluation of gross hematuria. Cystoscopy revealed an invasive transitional cell carcinoma of the bladder. After preoperative administration of radiotherapy, a radical cystectomy, lymphadenectomy, and ileoconduit urinary diversion were performed. On the fifth postoperative day, fever, nausea, vomiting, and increased wound drainage developed. He became hypotensive and was found to have leukocytosis, thrombocytopenia (35,000 platelets/mm3), hyponatremia, and hyperkalemia. Intra-abdominal sepsis causing disseminated intravascular coagulation was suspected. Antibiotic therapy, vigorous replacement of fluids, and platelet transfusions were given. After an episode of vomiting, he was given 1,000 mg of methylprednisolone intravenously for treatment of possible aspiration pneumonitis. Within hours, his blood pressure, serum sodium and potassium, and platelet count had returned to normal, and he was afebrile. CT examination revealed bilateral high-density adrenal gland masses, characteristic of recent adrenal hemorrhage (Fig. 1A). Before initiation of long-term replacement therapy for adrenal insufficiency, the basal corticotropin was 240 pg/ml, and the Cortisol level was 6.3 μg/dl and remained so after an intravenous bolus of250 μg of cosyntropin. A follow-up CT scan obtained 13 days after the initial scan showed a slight decrease in the size and density of the adrenal masses (Fig. 1 B). The cardiovascular and electrolyte status of the patient remained stable for the rest of the hospital course. At the time of dismissal, he was receiving replacement doses of prednisone and fludrocortisone acetate. Nine months before his referral to the Mayo Clinic, a 55-year-old man was admitted to his local hospital because of a pulmonary embolus, for which he received intravenous treatment with heparin. On the third day of heparin therapy, acute abdominal pain and hypotension developed. CT of the abdomen revealed bilateral dense adrenal masses and an associated retroperitoneal hemorrhage. Corticosteroid therapy was initiated, and rapid improvement ensued. His medical regimen at the time of dismissal was cortisone acetate (37.5 mg/day) and fludrocortisone acetate (0.1 mg/day). Subsequently, symptoms and signs of left temporal lobe infarction developed. Prednisone (60 mg/day) was added to the medical regimen, and the patient was referred to the Mayo Clinic for assessment. On admission, he had neurologic deficits in association with a left temporal lobe infarction, and he was noted to be mildly cushingoid. Results of routine laboratory determinations, including serum sodium and potassium, were within the normal range. A CT scan of the abdomen again showed the bilateral adrenal masses. Celiac angiography revealed these lesions to be avascular. The regimen of fludrocortisone acetate and cortisone acetate was discontinued, and the dose of prednisone was rapidly tapered and then discontinued. A replacement dose of dexa-methasone (0.25 mg twice daily) was initiated. Testing of the adrenocortical status of the patient showed basal plasma cortisols to be 6.4 and 4.2 μg/dl during dexamethasone therapy. Infusions of 250 μg of cosyntropin daily for 5 consecutive days failed to stimulate the plasma cortisol higher than 6.9 μg/dl. Urinary 17-ketosteroids and ketogenic steroids did not increase. At dismissal, a regimen of cortisone acetate (37.5 mg/day) and dipyridamole was being administered. Subsequently, a prolonged activated partial thromboplastin time was noted. A coagulation screen revealed a first-state inhibitor that caused inhibition of the plasma clot and the activated partial thromboplastin time. This first-state inhibitor was consistent with a lupus anticoagulant. Review of a sequence of follow-up CT examinations at 1.5, 8, and 9 months after the first scan revealed a progressive decrease in size and density of the bilateral adrenal masses. A 53-year-old woman was examined at our institution in 1985 because of vasculitis. She had been found to have a prolonged prothrombin time and activated partial thromboplastin time 10 years previously. Investigations 5 years later disclosed an increased activated partial thromboplastin time, a false-positive serology for syphilis, and a positive antinuclear antibody test. Between 1980 and 1985, she had undergone uterine dilation and curettage three times for menorrhagia without complications. In October 1985, a fourth uterine dilation and curettage had been performed as an outpatient procedure. Several days later, acute abdominal pain developed and then became progressively worse. She was admitted to her local hospital and became febrile and hypotensive on the subsequent day. A CT scan of the abdomen revealed bilateral adrenal enlargement, consistent with adrenal hemorrhage. The activated partial thromboplastin time and prothrombin time were prolonged. Treatment with prednisolone and, subsequently, cortisone acetate resulted in resolution of her pain, fever, and hypotension. After dismissal of the patient from the hospital, an acute palsy of the left fourth cranial nerve developed, and she was referred to our institution for assessment. Findings on physical examination were within normal limits except for the nerve palsy. On laboratory testing, the activated partial thromboplastin time and the anti-double-stranded DNA (anti-dsDNA) titer were elevated. The total, C3, and C4 components of complement were decreased. Plasma cortisol levels remained undetectable during a cosyntropin stimulation test performed while the patient was receiving dexamethasone. CT of the abdomen showed persistent bilateral adrenal masses but with decreased size and density in comparison with the scan done 37 days before, the sequence being consistent with resolving adrenal hemorrhage. The coagulation screen was positive for a lupus anticoagulant. She was treated with prednisone (40 mg/day) for presumed vasculitis. At the time of 6-month follow-up examination, the activated partial thromboplastin time and anti-dsDNA titer were within normal limits, and a decrease in the potency of the lupus anticoagulant was noted. The patient continued to require adrenal steroid replacement 18 months after this therapy was initiated. A 71-year-old man was admitted to his local hospital because of fatigue, anemia, weight loss, fever, and hypotension. The activated partial thromboplastin time was elevated. His hypotension responded to intravenous administration of fluids. A CT scan of the chest and abdomen revealed mediastinal lymphade-nopathy and bilateral adrenal masses of high density (Fig. 2 A). A pulmonary malignant tumor and mediastinal and adrenal metastatic lesions were suspected. Biopsy samples of a mediastinal lymph node revealed multiple granulomas. Special stains and cultures for mycobacteria and fungi were negative. The patient was dismissed in February 1986, after a 3-week hospital stay during which no diagnosis was made. Before dismissal, a follow-up CT scan showed persistence of adrenal masses of high density (Fig. 2 B). At the time of initial examination at our medical center in April 1986, the patient was weak and cachectic. His blood pressure and serum electrolytes were within normal limits. He had mild pancytopenia, and a bone marrow study was nondiagnostic. The corticotropin level was elevated at 950 pg/ml (normal, 0 to 60 pg/ ml). The baseline serum Cortisol and aldosterone levels were 3.1 μg/dl and less than 1 ng/dl, respectively, and neither value increased with cosyntropin stimulation. A CT scan of the abdomen revealed small adrenal masses that were diminished in size and density (Fig. 2 C and D) in comparison with the original CT examination several months before. The activated partial thromboplastin time, the bleeding time, and the prothrombin time were prolonged. A coagulation screen identified the presence of a lupus anticoagulant. IgG anticardiolipin antibody was present at a titer of 1:128. Within hours after daily prednisone therapy was initiated, his constitutional symptoms began to resolve. He had resumed vigorous activity after 2 weeks of therapy and was doing well after 6 months. A 42-year-old woman was transferred to the Mayo Clinic for evaluation of intracranial mass lesions and weakness of the lower extremities. In May 1984, she had been admitted to a hospital elsewhere with a 3-week history of nausea, vomiting, myalgia, lethargy, and pain in the left upper quadrant. Thrombocytopenia was noted. CT of the abdomen showed large bilateral adrenal masses that did not change in density after administration of contrast medium. The baseline corticotropin level was elevated at 194 pg/ml. A corticotropin stimulation test showed no increase in plasma cortisols above the baseline of 20 μg/dl. Decreased adrenocortical reserve was diagnosed. Prednisone therapy (80 mg/day) was started for a presumptive diagnosis of idiopathic thrombocytopenic purpura. Repeat CT of the abdomen 1 month later showed that the bilateral adrenal masses had decreased in size. The thrombocytopenia responded minimally to prednisone and vincristine. Splenectomy was subsequently performed without further benefit. The pathologic changes were nonspecific. In October 1984, the patient became lethargic and had flaccidity and weakness of the lower extremities. The findings on CT scan of the head were suggestive of two cerebral masses with surrounding edema. Dexamethasone and man-nitol were given. She had gradual loss of bowel and bladder function, and a T-12 sensory level developed. She was transferred to a Mayo-affiliated hospital for further evaluation, where a CT scan of the head confirmed the mass lesions in the left basal ganglia. A CT scan of the abdomen showed bilateral enlargement of the adrenal glands, the right being larger than the left. The size of both adrenal glands had decreased in comparison with the examinations conducted elsewhere 1,4, and 5 months earlier. A lymphoma of the central nervous system, a spinal cord metastatic lesion, and secondary immune thrombocytopenia were diagnosed. She was given dexamethasone, was dismissed from the hospital, and died shortly thereafter. No postmortem examination was performed. In the five cases reported herein, no definite histologic proof of adrenal hemorrhage was available. Rather, the diagnosis was based on the initial CT appearance of high-density adrenal gland masses and their decreasing size and density on follow-up scans. Definite biochemical evidence of primary adrenal insufficiency was noted in four of the five cases. In one patient (case 5), the plasma corticotropin level was elevated and results of a corticotropin stimulation test were abnormal, findings consistent with absent adrenocortical reserve. The adrenal masses in this case cannot be excluded as being lymphomatous in origin, but their appearance on CT scan was characteristic of hemorrhage. If these masses were lymphoma, the observed decrease in size could have been an effect of the large doses of prednisone. Adrenal insufficiency from adrenal hemorrhage was first reported in 1857.11Gooiden RH Disease of the supra-renal capsules with the absence of bronze skin.Lancet. 1857; 2: 266-267Abstract Scopus (7) Google Scholar Unfortunately, antemortem diagnoses of this condition have been rare. The first case of successful diagnosis and treatment with adrenal corticosteroids was reported in 1956.12Thorn GW Goldfien A Nelson DH The treatment of adrenal dysfunction.Med Clin North Am. September 1956; : 1261-1279PubMed Google Scholar Before 1981, only 11 patients with adrenal hemorrhage and adrenal insufficiency, in whom corticosteroid therapy led to survival, had been described in published reports.10Wolverson MK Kannegiesser H CT of bilateral adrenal hemorrhage with acute adrenal insufficiency in the adult.AJR. 1984; 142: 311-314Crossref PubMed Scopus (62) Google Scholar, 13Clark OH Hall AD Schambelan M Clinical manifestations of adrenal hemorrhage.Am J Surg. 1974; 128: 219-224Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 14Klassen J Murphy BEP Survival after bilateral adrenal hemorrhage during heparin therapy.Can Med Assoc J. 1967; 97: 1162-1165PubMed Google Scholar, 15Shapiro M Zalewski S Steiner Z Bernheim J Na-briski D Taragan R Bruderman I Shenkman L Adrenal insufficiency in a general hospital over a 14-year period.Isr J Med Sci. 1984; 20: 381-387PubMed Google Scholar Since 1981, 18 additional cases of adrenal hemorrhage, in which adrenal insufficiency was diagnosed and treated successfully, have been reported. In 16 of the 18 cases, the diagnosis was made possible by the use of CT of the abdomen.2Anderson KC Kuhajda FP Bell WR Diagnosis and treatment of anticoagulant-related adrenal hemorrhage.AmJHematol. 1981; 11: 379-385PubMed Google Scholar, 4Ling D Korobkin M Silverman PM Dunnick NR CT demonstration of bilateral adrenal hemorrhage.AJR. 1983; 141: 307-308Crossref PubMed Scopus (50) Google Scholar, 5Liu L Haskin ME Rose LI Bemis CE Diagnosis of bilateral adrenocortical hemorrhage by computed tomography.Ann Intern Med. 1982; 97: 720-721Crossref PubMed Scopus (30) Google Scholar, 6Lundstrom GK Chen PS Bilateral adrenal hemorrhage associated with prior steroid use: CT diagnosis.J Can Assoc Radiol. 1985; 36: 58-60PubMed Google Scholar, 7Marcus AO Duick DS Little D Waldmann EB Bilateral adrenal hemorrhage during anticoagulant therapy.Ariz Med. 1982; 39: 575-577PubMed Google Scholar, 8Scott Jr, WW Fishman EK Siegelman SS Anticoagulants and abdominal pain: the role of computed tomography.JAMA. 1984; 252: 2053-2056Crossref PubMed Scopus (40) Google Scholar, 9Swift DE Overholt EL Travelli R Methods of diagnosis of acute adrenal hemorrhage complicating anticoagulant therapy—abdominal CAT scanning.Wis Med J. November 1981; 80: 25-28PubMed Google Scholar, 10Wolverson MK Kannegiesser H CT of bilateral adrenal hemorrhage with acute adrenal insufficiency in the adult.AJR. 1984; 142: 311-314Crossref PubMed Scopus (62) Google Scholar, 16Rao RH Vagnucci AH Amico JA Bilateral massive adrenal hemorrhage: early recognition and treatment.Ann Intern Med. 1989; 110: 227-235Crossref PubMed Scopus (204) Google Scholar The adrenal hemorrhage was distinguished from all other causes of bilateral adrenal masses by the CT examination. Other causes of bilateral adrenal masses include primary and secondary tumor, granulomatous disease, and hyperplasia. Adrenal hemorrhage manifests as round or oval adrenal masses of high density (relative to the adjacent liver or spleen) that decrease in both size and density with time. On the basis of our cases and a review of the literature, several clinical and pathologic conditions seem to be associated with adrenal hemorrhage in adults. One commonly associated condition is high-level corticotropin stimulation of the adrenal glands,3Xarli VP Steele AA Davis PJ Buescher ES Rios CN Garcia-Bunuel R Adrenal hemorrhage in the adult.Medicine (Baltimore). 1978; 57: 211-221Crossref PubMed Scopus (173) Google Scholar, 17Wilson DAW Roth D Adrenal apoplexy occurring during corticotropin therapy of ulcerative colitis.JAMA. 1953; 152: 230-231Crossref PubMed Scopus (11) Google Scholar which might occur during the course of myocardial infarction, sepsis, pulmonary embolus, surgical stress, postoperative complications, shock, and other such illnesses. Adrenal hemorrhage usually occurs within the first 3 weeks of a medical illness or the postoperative period.3Xarli VP Steele AA Davis PJ Buescher ES Rios CN Garcia-Bunuel R Adrenal hemorrhage in the adult.Medicine (Baltimore). 1978; 57: 211-221Crossref PubMed Scopus (173) Google Scholar, 18Clark OH Postoperative adrenal hemorrhage.Ann Surg. 1975; 182: 124-129Crossref PubMed Scopus (31) Google Scholar All of our cases occurred in the context of a systemic medical illness or during the postoperative period. Anticoagulation and coagulopathies are also common predisposing risk factors for adrenal hemorrhage. About a third (48 of 150) of the patients described in reports in the 20 years before 1981 were on anticoagulation therapy.2Anderson KC Kuhajda FP Bell WR Diagnosis and treatment of anticoagulant-related adrenal hemorrhage.AmJHematol. 1981; 11: 379-385PubMed Google Scholar In some cases, the activated partial thromboplastin time did not exceed the therapeutic range, and there was no evidence of other bleeding diatheses.1Amador E Adrenal hemorrhage during anticoagulation therapy: a clinical and pathological study often cases.Ann Intern Med. 1965; 63: 559-571Crossref PubMed Scopus (47) Google Scholar, 3Xarli VP Steele AA Davis PJ Buescher ES Rios CN Garcia-Bunuel R Adrenal hemorrhage in the adult.Medicine (Baltimore). 1978; 57: 211-221Crossref PubMed Scopus (173) Google Scholar Three of our patients had a circulating lupus anticoagulant. Schafer19Schafer AI The hypercoagulable states.Ann Intern Med. 1985; 102: 814-828Crossref PubMed Scopus (392) Google Scholar suggested that despite prolongation of the activated partial thromboplastin time, the presence of a lupus anticoagulant denotes a hypercoagu-lable state. One could speculate that a lupus anticoagulant could induce adrenal venous thrombosis and thus lead to adrenal hemorrhagic infarction. An acute medical or surgical illness, the postoperative state, and the presence of a coagulopathy are the major risk factors for bilateral adrenal hemorrhage. A recent review identified thromboembolic disease as an additional risk factor. The presence of more than one of the aforementioned factors increases the risk substantially.16Rao RH Vagnucci AH Amico JA Bilateral massive adrenal hemorrhage: early recognition and treatment.Ann Intern Med. 1989; 110: 227-235Crossref PubMed Scopus (204) Google Scholar The symptoms and signs of bilateral adrenal hemorrhage are nonspecific. Chest, back, flank, or abdominal pain, usually associated with fever, is common. Hypotension is frequently a preterminal finding. Biochemical evidence of adrenal insufficiency (such as hyponatremia, leukocytosis, acidosis, hyperkalemia, and azotemia) can be absent or, if present, attributed to the concomitant illness. A sudden decrease in hemoglobin concentration and hematocrit has also been described.16Rao RH Vagnucci AH Amico JA Bilateral massive adrenal hemorrhage: early recognition and treatment.Ann Intern Med. 1989; 110: 227-235Crossref PubMed Scopus (204) Google Scholar For the early diagnosis of bilateral adrenal hemorrhage, the clinician must identify those patients at high risk and recognize the nonspecific manifestations of adrenal insufficiency. Once the diagnosis is suspected, prompt steroid replacement should be instituted. The anatomic diagnosis can then be established by CT of the abdomen, after which hormonal function can be evaluated with a rapid corticotropin stimulation test.16Rao RH Vagnucci AH Amico JA Bilateral massive adrenal hemorrhage: early recognition and treatment.Ann Intern Med. 1989; 110: 227-235Crossref PubMed Scopus (204) Google Scholar Concomitant single baseline plasma samples showing low cortisol and high corticotropin levels can be obtained as an alternative to the rapid corticotropin test as long as steroid replacement is not inordinately delayed and the patient is hemodynamically stable.16Rao RH Vagnucci AH Amico JA Bilateral massive adrenal hemorrhage: early recognition and treatment.Ann Intern Med. 1989; 110: 227-235Crossref PubMed Scopus (204) Google Scholar Bilateral adrenal hemorrhage is a rare cause of adrenal insufficiency. The nonspecific clinical manifestations of adrenal insufficiency are frequently inseparable from those of the concurrent major illness. The diagnosis necessitates a high index of suspicion and can be confirmed by the use of CT of the abdomen. Once the diagnosis is suspected, lifesaving steroid replacement should be initiated without delay. Biochemical confirmation of adrenal insufficiency can then be performed with appropriate endocrine testing. An acute medical or surgical stress, a coagulopathy (spontaneous or drug induced), and the postoperative state are risk factors for bilateral adrenal hemorrhage. The presence of a circulating lupus anticoagulant is probably an additional contributing factor to the pathogenesis of bilateral adrenal hemorrhage.