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Addison's disease due to adrenal tuberculosis: Contrast-enhanced CT features and clinical duration correlation
European Journal of Radiology 62 (2007) 126–131
Addison’s disease due to adrenal tuberculosis: Contrast-enhanced CT features and clinical duration correlation Ying-Kun Guo a , Zhi-Gang Yang a,b,∗ , Yuan Li a , En-Sen Ma a , Yu-Ping Deng a , Peng-Qiu Min a , Long-Lin Yin a , Jian Hu c , Xiao-Chun Zhang a , Tian-Wu Chen a b
a Department of Radiology, West China Hospital, Sichuan University, 37# Guo Xue Xiang, Chengdu, Sichuan 610041, China National Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 37# Guo Xue Xiang, Chengdu, Sichuan 610041, China c Department of Stomatology, Dental Hospital, Wuhan University, Wuhan, Hubei 502310, China
Received 25 August 2006; received in revised form 14 November 2006; accepted 16 November 2006
Abstract Purpose: To describe CT morphology of untreated adrenal tuberculosis during the different stages of the natural history of the disease and to evaluate the diagnostic implications of CT features. Materials and methods: We retrospectively evaluated CT features in 42 patients with documented adrenal tuberculosis for the location, size, morphology, and enhancement patterns shown on CT images. The clinical duration were correlated with the CT features. Results: Of the 42 patients with untreated adrenal tuberculosis, bilaterally enlarged adrenal glands were revealed in 38 cases (91%), unilaterally enlarged in 3 cases (7%), and normal size in 1 case (2%). Of the 41 cases (98%) with enlargement, mass-like enlargement was seen in 20 cases (49%) and enlargement with preserved contours in 21 cases (51%). Peripheral rim enhancement presented in 22 cases (52%) on contrast-enhanced CT. Non-enhanced CT scan revealed calcification in 21 cases (50%). As the duration of Addison’s disease increased, the presence of calcification and contour preservation increased concomitantly (p < 0.001), whereas peripheral rim enhancement and mass-like enlargement decreased concomitantly on CT images (p < 0.001). Conclusion: CT may be helpful in diagnosing adrenal tuberculosis when clinically suspected, and CT features are correlated to the clinical duration of Addison’s disease. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Addison’s disease; Adrenal tuberculosis; CT
1. Introduction Destruction of 90% of the adrenal cortex is the cause of primary adrenal insufficiency or Addison’s disease. In 1855, Thomas Addison described the autopsy findings of six patients with adrenal tuberculosis, which was once considered the most common cause of primary adrenal insufficiency. Autoimmune adrenalitis is presently the principal cause of Addison’s disease in developed countries [1–4]. Other rare causes include histoplasmosis, blastomycosis, metastatic tumor, adrenal hemorrhage and a variety of opportunistic infections due to the acquired immunodeficiency syndrome (AIDS) [5–7]. In devel-
oping countries, however, adrenal tuberculosis is still the major cause of Addison’s disease. Although some previous reports have described the CT findings of adrenal tuberculosis, most of these studies were case reports with non-enhanced CT scan so the consecutive changes of this disease in each stage were not described accurately [8–14]. In this study, we retrospectively reviewed CT features of 42 cases of Addison’s disease due to adrenal tuberculosis. The purpose of our study was to correlate the initial contrast-enhanced CT features with clinical duration of the Addison’s disease due to adrenal tuberculosis and to evaluate the diagnostic implications of CT features. 2. Materials and methods
∗
Corresponding author at: Department of Radiology, West China Hospital, Sichuan University, 37# Guo Xue Xiang, Chengdu, Sichuan 610041, China, Tel.: +86 28 85423817. E-mail address: [email protected] (Z.-G. Yang). 0720-048X/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2006.11.025
2.1. Subjects This study was approved by our medical school Institutional Review Board (IRB). Informed consent was obtained from each
Y.-K. Guo et al. / European Journal of Radiology 62 (2007) 126–131
of the recruits. No compensation was provided to the subjects for their participation. Forty-two patients with untreated adrenal tuberculosis were enrolled in this study by the Department of Radiology at our Medical School between March 1994 and October 2005. CT scan and laboratory examination were used for diagnoses and follow-ups. Patients with autoimmune endocrine disease, HIV infection, or extra-adrenal neoplastic disease were excluded. The mean (±S.D.) age of the patients was 48 ± 11 years (median, 51 years; range, 29–72 years). Twenty-nine patients (69%) were men (mean age, 48 ± 12 years; median age, 50 years; range, 29–68 years), and 13 (31%) were women (mean age, 49 ± 11years; median age, 50 years; range, 37–72 years). There was no significant difference in age between men and women (independent samples t-test, p = 0.70). All the patients exhibited Addison’s disease symptoms such as fatigue, dizziness, nausea, vomiting and lethargy. Physical examination revealed hyperpigmentation, weight loss, signs of dehydration or hypotension. Further biochemical investigation confirmed the adrenocortical insufficiency in all patients. Extra-adrenal tuberculosis was present in 23 (54%) of the 42 patients including pulmonary, gastrointestinal, vertebral, testicular and nephritic tuberculosis. Thirty-eight of the 42 cases had a definitive diagnosis of tuberculosis confirmed by clinical findings, laboratory findings and follow-up CT or ultrasound over 12 months after antituberculous therapy. The final diagnosis of tuberculosis for the remaining four cases was established by histological examination or percutaneous aspiration biopsy. 2.2. CT protocols Opacification of the bowel was carried out routinely with oral contrast materials (500–800 mL of a 1.5% solution of sodium diatrizoate) before CT scan. CT scan was examined with a 9800 Quick CT scanner (General Electric Medical Systems, Milwaukee, WI), a Somatom Plus 4 helical scanner, a Sensation 4 or 16 multi-detector row scanner (Siemens Medical Systems, Erlangen, Germany). Of the 42 cases, 6 were performed on a GE 9800 scanner with scanning parameters of 140 kVp, 200 mAs and 5 mm collimation, 22 were done on a Somatom Plus 4 scanner, and 14 were done on a Sensation 4 or 16 multi-detector row scanner with scanning parameters of 120 kVp, 200 mAs, 3 mm collimation and reconstruction interval 3 mm. Non-contrast scan was performed for all patients before enhancement, extending from the diaphragm to the iliac crest. A total of 80–100 mL contrast medium containing 300 mg/mL (iopromide, Ultravist 300, Schering) was administrated at a flow rate of 2.5 mL/s (scan delay, 70 s) using a motor injector via a 19-gague venous line into the antecubital vein. 2.3. Image analysis Two experienced abdominal radiologists (20 and 8 years of experiences, respectively) who were unaware of the final diagnosis and clinical duration reviewed independently all contiguous CT scans on hard-copy images and recorded the CT characteristics of the lesions including their location, size, contour,
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calcification, and enhancement patterns. Calcification was evaluated on non-contrast CT scan. The location of the lesion was recorded as unilateral or bilateral. The contour was classified as mass-like enlargement or enlargement with preserved contour. The average of the maximum length and the maximum perpendicular width of the mass were measured on the maximum cross-sectional area of the CT images. The enhancement patterns were categorized as presence or absence of peripheral rim enhancement. Peripheral rim enhancement was considered when thick, thin or irregular enhancement of the rim was present. Based on clinical data, the duration of Addison’s disease was recorded and classified as four categories: 1–6 months, group 1; 7–12 months, group 2; 13–24 months, group 3; and more than 24 months, group 4. With these categories, there were 12 cases (range, 1–6 months; median, 5 months) in group 1, 8 cases (range, 7–11 months; median, 8 months) in group 2, 8 cases (range, 13–21 months; median, 15.5 months) in group 3, and 14 cases (range, 25–62 months; median, 34.5 months) in group 4. The initial CT findings were described in each group and their correlations with duration were assessed. 2.4. Statistical analysis Statistical analysis was performed with commercially available software (SPSS 11.0 Version, Chicago, IL). The size of the adrenal mass was calculated and compared between right and left lateral with an independent samples t-test. Difference of size among groups was tested with a parametric analysis of variance test. The size was correlated with duration of Addison’s disease using the linear correlation analysis. The presence of calcification and peripheral rim enhancement and contour characteristics on CT were correlated with duration using Cochran Armitage trend test. Interobserver agreement on CT findings for the size was tested with linear regression analysis. Agreement on the presence of other findings was tested with kappa statistics. Statistical significance was given when the p-value was less than 0.05. 3. Results 3.1. CT manifestations of the adrenal tuberculosis Of the 42 patients with untreated adrenal tuberculosis, bilateral enlarged adrenals were revealed in 38 cases (91%), unilateral in 3 cases (7%), and normal size in 1 case (2%). Enlargement of the adrenal glands in 41 cases (98%) included mass-like enlargement in 20 cases (49%) and enlargement with the contours preserved in 21 cases (51%) (Fig. 1). Low attenuation in the center with peripheral rim enhancement of the lesions was shown in 22 cases (52%) on contrast-enhanced CT (Fig. 2). Non-enhanced CT scan revealed calcification in 21 cases (50%) (Fig. 3). CT findings of each group are presented in Table 1. The size of the adrenal enlargement was not significantly different between the right (2.0 cm ± 1.0, ranging from 0.9 to 4.5 cm) and the left adrenals (2.1 cm ± 1.2, ranging from 1.0 to 6.2 cm) (p = 0.820).
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Fig. 1. Adrenal tuberculosis in 36-year-old woman with 23 months duration. Contrast-enhanced CT scan reveals the bilaterally enlarged adrenals but the contours are preserved bilaterally.
Fig. 2. Adrenal tuberculosis in 49-year-old man with 2 months duration. Contrast-enhanced CT shows the bilateral mass-like enlargement with peripheral enhancement.
3.2. Correlation between initial CT features and clinical duration As the duration of Addison’s disease increased, the presence of calcification and contour preservation increased concomi-
Fig. 3. Adrenal tuberculosis in 53-year-old woman with 18 months duration. Contrast-enhanced CT scan reveals mass-like enlargement of right adrenal gland with peripheral rim enhancement and calcification in bilateral adrenals.
Fig. 4. Distribution patterns of both peripheral rim enhancement and calcification correlate with clinical duration. As the duration increases, the presence of calcification increases concomitantly (p < 0.001), whereas peripheral rim enhancement decreases concomitantly (p < 0.001).
tantly (p < 0.001), whereas peripheral rim enhancement and mass-like decreased concomitantly on CT images (p < 0.001) (Figs. 4 and 5). However, the size of the adrenal enlargement with different duration of Addison’s disease had no statistic significance among groups 1–3 (p = 0.093). The comparison of
Table 1 Initial CT findings and clinical duration correlation of 42 patients with Addison’s disease Duration
Group 1 (n = 12, 29%) Group 2 (n = 8, 19%) Group 3 (n = 8, 19%) Group 4 (n = 14, 33%) P value
Enlargement
Contour
Size (cm)
B
U
M
Con. P.
R
L
11 8 8 11
1 0 0 2 <0.001
8 5 3 4 <0.001
4 3 5 10 <0.001
2.8 ± 1.1 2.0 ± 0.8 2.0 ± 1.1 1.4 ± 0.4 0.002
3.0 ± 1.5 1.9 ± 1.1 1.9 ± 1.1 1.7 ± 0.6 0.034
Note: B, bilateral; U, unilateral; M, mass; Con. P., contour preserved; R, right; L, left.
Peripheral rim enhancement
Calcification
10 6 4 2 <0.001
1 3 5 12 <0.001
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Fig. 5. Distribution patterns of both mass-like and contour preserved enlargement correlate with clinical duration. As the duration increased, the presence of contour preserved increases concomitantly (p < 0.001), whereas mass-like decreases concomitantly (p < 0.001).
size between groups demonstrated significant difference only between group 1 and group 4 (p = 0.002). As the duration of Addison’s disease increased, the size of enlarged adrenals became smaller, but their correlation was moderate (r = −0.595, p < 0.001). 3.3. Agreement between observers A satisfied agreement was achieved between the two observers in measuring the size of the lesion (p = 0.79), estimating the location of lesions (κ = 0.97) and contour (κ = 0.69), as well as assessing the presence of calcification (κ = 0.81) and peripheral rim enhancement (κ = 0.76). 4. Discussion Tuberculosis in the adrenals can result in progressive destruction of the glands. When 90% of the tissue is destroyed, adrenocortical insufficiency characterized as Addison’s syndrome would appear. Most of the symptoms are insidious and non-specific, such as fatigue, weakness, anorexia, nausea and vomiting. Physical examination may find cutaneous and mucosal pigmentation, weight loss and hypotension. Routine laboratory findings include commonly hyponatremia, hyperkalemia, azotemia, hypoglycemia and hypercalcemia. Specific biochemical tests of patients suspected to Addison’s disease usually include basal levels of cortisol, ACTH in plasma and rapid ACTH stimulation tests, which are used to establish existence of adrenocortical insufficiency. Furthermore, ACTH stimulation test may be useful to differentiate primary and secondary adrenocortical deficiency [2–4]. Extra-adrenal tuberculosis including pulmonary, gastrointestinal, vertebral, testicular or nephritic tuberculosis is commonly present in patients with tuberculous Addison’s disease. Thus, extra-adrenal tuberculosis may be a useful clue to etiology of tuberculous Addison disease, but is non-specific evidence. Acute primary adrenal insufficiency can
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lead to adrenal crisis and become a life-threatening disorder especially in any stressful situation. CT scan may be necessary to determine the cause of Addison’s disease and provide valuable information for making therapeutic decision [1–4,8,14]. Bilateral involvement with enlarged adrenals occurs in tuberculous Addison’s disease. The reason is that hematogenous and lymph routes spread from the primary mycobacterial infection to each adrenal gland with equal chance [15]. Wang et al. [16] reported that all adrenal gland lesions with bilateral involvement were tuberculosis in their study. In our series, the occurrence of bilateral involvement was 91%. In contrast, Yang et al. [17] found primary adrenal tumors rarely involved both adrenals when they differentiated the adrenal tuberculosis from primary adrenal tumor. Pheochromocytoma is the most frequent bilateral primary tumor of the adrenal glands with the incidence of 10% [18]. Lymphoma and metastases as the cause of adrenal insufficiency with bilaterally enlarged adrenals is rare [5]. Differential diagnosis may be difficult without biopsy, but the clinical appearances and the involved patterns may be helpful to discriminate these rare causes from tuberculosis. Thus, bilateral involvement can be used as an important discriminator of tuberculosis from primary tumors in the adrenals. At early stage, pathologic findings of the adrenals revealed caseous necrosis area and tuberculous granuloma because of the destruction of the cortex by tuberculous mycobacteria [14,15]. CT scan frequently demonstrates the mass-like enlargement of the adrenals with tuberculosis. In our series, 75% had mass-like adrenal enlargement with the duration of Addison’s disease no more than 1 year. At the late stage, the enlarged tuberculous adrenals decreased or returned to normal size and configuration because of fibrosis and calcification in the lesions [8,13–15]. In the present study, 73% presented enlarged adrenals but contour preserved with duration of Addison’s disease more than 1 year. Therefore, the configuration of enlarged adrenals shown on CT was correlated to the duration of Addison’s disease. As a result, the configuration of adrenal enlargement could also be used to discriminate tuberculosis from adrenal tumors. The enlarged adrenal with contour preserved contour strongly indicated infectious etiology, while most of tumors commonly present as round or oval intra-adrenal masses [17–20]. Some previous studies considered the size of the involved adrenals as an important feature to determinate the cause and duration of Addison’s disease. Small or atrophic adrenals indicated autoimmune adrenalitis or tuberculosis with long duration, whereas the patients with early stage or active adrenal tuberculosis usually had enlarged adrenals [8–10,14,16]. In our study, as the duration increased, especially in those patients with longstanding adrenal tuberculosis (usually more than 3 years), most of the size of involved glands were smaller than that in the active or early stage cases. These findings were, to some extent, consistent with those previous reports [8–10,14,16]. Peripheral rim enhancement with low attenuation in the center of the adrenals was a striking characteristic of adrenal tuberculosis. Previous studies have shown that this feature represents the pathologic findings of central caseous necrosis surrounded by fibrous tissue and granulomatous inflammatory tissue [8,14–17]. The presence of peripheral rim enhancement
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on CT suggests the possibility of untreated tuberculosis, but a similar pattern may be seen occasionally in primary tumor especially when it contains necrosis in the central area [19]. In our study, peripheral rim enhancement was more commonly seen in untreated tuberculosis less than 1 year duration. As the duration of Addison’s disease increased, the presence of peripheral rim enhancement decreased concomitantly on CT images. This striking tendency indicated the finding may be used to indicate a patient with early and/or active tuberculosis. At this stage, an appropriate therapy as early as possible might be critical to regain the adrenal function [10,22,23]. Calcification in adrenal gland as a common sign of tuberculosis has been reported in the previous studies. At late stage, the encapsulated granuloma becomes quiescent, the inflammatory cells decrease in number, and consequently calcium salts deposit in the caseous material so that calcification could be present on CT images [8,14,15]. Vita et al. [8] reported the prevalence of calcification of adrenal tuberculosis was 53% at the time of diagnosis and indicated long-standing tuberculosis. Wang et al. [16] described CT findings of small calcification dots in the adrenals were seen in 22% patients with active tuberculosis. As shown in our study, calcification could present in each stage of tuberculous adrenalitis, but the occurrence of calcification increased concomitantly on CT images as the duration increased. On the contrary, histological calcification of adrenal primary tumor was infrequent. Other rare diseases with calcification could be detected, such as hemorrhage, histoplasmosis, and blastomycosis. In retrospective review articles, Yang et al. [17] and Kenney et al. [21] found no more than 10% of cases presented calcification in the adrenal tumor, which did not have any significance for its diagnosis. In addition, Vita et al. [8] found that calcification was beneficial to rule out idiopathic adrenal atrophy. So calcification was considered a valuable diagnostic clue and a significant discriminator for the adrenal tuberculosis. As far as Addison’s disease due to tumors involving bilateral adrenal glands are concerned, the bilateral adrenal metastases from other primary tumors should be considered firstly when bilateral adrenal masses are revealed but most cases are easily to be diagnosed because the primary malignancies are known [24]. Secondly, lymphoma cannot be excluded because it is frequently located bilaterally as many as 25% of patients at autopsy. Although imaging characteristic cannot differentiate from lymphoma and tuberculosis, the diagnosis is usually evident in patient with lymphomatous involvement in other areas because primary adrenal lymphoma is extremely rare [25]. As an entity frequently involves bilateral adrenals, hemorrhage must be included in the differential diagnosis, especially in patients with symptoms of Addison’s disease. Bilateral adrenal hemorrhage sometimes mimics tuberculosis on CT images, but history of anticoagulant therapy or injury with subsequent hypoadrenocorticism is a clue to make the diagnosis of hemorrhage. Moreover, MRI is particularly sensitive for detecting intra-adrenal hemorrhage, which shows special signal intensity on T1- and T2-weighted images at different stage of hematoma [26]. About 50% of patients with disseminated histoplasmosis develop Addison’s disease. CT features of adrenal histoplasmosis can mimic tuberculosis so that differential diagnosis may be
difficult on CT imaging, and a CT- or Ultrasound-guided biopsy sometimes need to performed for final diagnosis [27]. There were limitations to our study. First, our series could not reliably evaluation atrophic adrenals resulting from tuberculosis due to selection bias. Based on previous reports, atrophic glands appear most commonly in patients with a more than 10 year duration of tuberculous Addison’s disease [8,9], but our series did not include any patients with over 10 years duration. Second, as a retrospective study, our study materials were collected over 10 years. As a result, some CT scans were performed with 5 mm collimation while others were performed with 3 mm collimation on different CT devices. The different collimation would result in minor difference in the size measurement and the capability of detecting the tiny calcification. In conclusion, contrast-enhanced CT features of Addison’s disease caused by adrenal tuberculosis can provide evidence of etiology for primary adrenal insufficiency. Diagnosis of Addison’s disease with normal-size adrenals based on CT features would be difficult without clinical, laboratory and pathologic findings. A combination of clinical symptoms, laboratory results, pathological findings and CT features could establish a final diagnosis. Furthermore, CT features might be useful to indicate the clinical duration of Addison’s disease, and to provide valuable information for making diagnostic decision. References [1] Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 2002;23:327–64. [2] Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med 2003;139:194–204. [3] Oelkers W. Adrenal insufficiency. N Engl J Med 1996;335:1206–12. [4] Robinet JM. Addison’s disease. RDH 1995;15:20–4. [5] Zar T, Khan F, Petit Jr W, Bernene JR. Primary adrenal lymphoma presenting as adrenal insufficiency: a case report and review of literature. Conn Med 2004;68:7–10. [6] Francque SM, Schwagten VM, Ysebaert DK, Van Marck EA, Beaucourt LA. Bilateral adrenal haemorrhage and acute adrenal insufficiency in a blunt abdominal trauma: a case-report and literature review. Eur J Emerg Med 2004;11:164–7. [7] Rozenblit AM, Kim A, Tuvia J, et al. Adrenal histoplasmosis manifested as Addison’s disease: unusual CT features with magnetic resonance imaging correlation. Clin Radiol 2001;56:682–4. [8] Vita JA, Silverberg SJ, Goland RS, Austin JH, Knowlton AI. Clinical clues to the cause of Addison’s disease. Am J Med 1985;78:461–6. [9] Doppman JL, Gill Jr JR, Nienhuis AW, et al. CT findings in Addison’s disease. J Comput Assist Tomogr 1982;6:757–61. [10] Villabona CM, Sahun M, Ricart W, et al. Tuberculous Addison’s disease Utility of CT in diagnosis and follow-up. Eur J Radiol 1993;17:210–3. [11] Lam KY, Lo CY. A critical examination of adrenal tuberculosis and a 28year autopsy experience of active tuberculosis. Clin Endocrinol (Oxford) 2001;54:633–9. [12] Buxi TB, Vohra RB, Sujatha, Byotra SP, Mukherji S, Daniel M. CT in adrenal enlargement due to tuberculosis: a review of literature with five new cases. Clin Imag 1992;16:102–8. [13] Wilms GE, Baert AL, Kint EJ, Goddeeris PG. Computed tomographic findings in bilateral adrenal tuberculosis. Radiology 1983;146:729– 30. [14] Efremidis SC, Harsoulis F, Douma S, Zafiriadou E, Zamboulis C, Kouri A. Adrenal insufficiency with enlarged adrenals. Abdom Imag 1996;21:168–71.
Y.-K. Guo et al. / European Journal of Radiology 62 (2007) 126–131 [15] Sommers SC. Adrenal glands. In: Kissane JM, editor. Anderson’s pathology. 9th ed. St. Louis: The C.V. Mosby Co.; 1990. pp. 1587. [16] Wang YX, Chen CR, He GX, Tang AR. CT findings of adrenal glands in patients with tuberculous Addison’s disease. J Belge Radiol 1998;81:226–8. [17] Yang ZG, Guo YK, Li Y, Min PQ, Yu JQ, Ma ES. Differentiation between tuberculosis and primary tumors in the adrenal gland: evaluation with contrast-enhanced CT. Eur Radiol 2006;16:2031–6. [18] Lockhart ME, Smith JK, Kenney PJ. Imaging of adrenal masses. Eur J Radiol 2002;41:95–112. [19] Bae KT, Fuangtharnthip P, Prasad SR, Joe BN, Heiken JP. Adrenal masses: CT characterization with histogram analysis method. Radiology 2003;228:735–42. [20] Caoili EM, Korobkin M, Francis IR, et al. Adrenal masses: characterization with combined unenhanced and delayed enhanced CT. Radiology 2002;222:629–33.
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[21] Kenney PJ, Stanley RJ. Calcified adrenal masses. Urol Radiol 1987;9:9–15. [22] Penrice J, Nussey SS. Recovery of adrenocortical function following treatment of tuberculous Addison’s disease. Postgrad Med J 1992;68:204–5. [23] Ammini AC, Gupta R, Mukopadhyay C, et al. Computed tomography morphology of the adrenal glands of patients with Addison’s disease. Austr Radiol 1996;40:38–42. [24] Hauser H, Battikha JG, Wettstein P. Pathology of the adrenal gland: common and uncommon findings in computed tomography. Eur J Radiol 1981;1:215–26. [25] Mantzios G, Tsirigotis P, Veliou F, et al. Primary adrenal lymphoma presenting as Addison’s disease: case report and review of the literature. Ann Hematol 2004;83:460–3. [26] Ling D, Korobkin M, Silverman PM, Dunnick NR. CT demonstration of bilateral adrenal hemorrhage. AJR 1983;141:307–8. [27] Kumar N, Singh S, Govil S. Adrenal histoplasmosis: clinical presentation and imaging features in nine cases. Abdom Imag 2003;28:703–8.
Addison’s disease due to adrenal tuberculosis: Contrast-enhanced CT features and clinical duration correlation Ying-Kun Guo a , Zhi-Gang Yang a,b,∗ , Yuan Li a , En-Sen Ma a , Yu-Ping Deng a , Peng-Qiu Min a , Long-Lin Yin a , Jian Hu c , Xiao-Chun Zhang a , Tian-Wu Chen a b
a Department of Radiology, West China Hospital, Sichuan University, 37# Guo Xue Xiang, Chengdu, Sichuan 610041, China National Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 37# Guo Xue Xiang, Chengdu, Sichuan 610041, China c Department of Stomatology, Dental Hospital, Wuhan University, Wuhan, Hubei 502310, China
Received 25 August 2006; received in revised form 14 November 2006; accepted 16 November 2006
Abstract Purpose: To describe CT morphology of untreated adrenal tuberculosis during the different stages of the natural history of the disease and to evaluate the diagnostic implications of CT features. Materials and methods: We retrospectively evaluated CT features in 42 patients with documented adrenal tuberculosis for the location, size, morphology, and enhancement patterns shown on CT images. The clinical duration were correlated with the CT features. Results: Of the 42 patients with untreated adrenal tuberculosis, bilaterally enlarged adrenal glands were revealed in 38 cases (91%), unilaterally enlarged in 3 cases (7%), and normal size in 1 case (2%). Of the 41 cases (98%) with enlargement, mass-like enlargement was seen in 20 cases (49%) and enlargement with preserved contours in 21 cases (51%). Peripheral rim enhancement presented in 22 cases (52%) on contrast-enhanced CT. Non-enhanced CT scan revealed calcification in 21 cases (50%). As the duration of Addison’s disease increased, the presence of calcification and contour preservation increased concomitantly (p < 0.001), whereas peripheral rim enhancement and mass-like enlargement decreased concomitantly on CT images (p < 0.001). Conclusion: CT may be helpful in diagnosing adrenal tuberculosis when clinically suspected, and CT features are correlated to the clinical duration of Addison’s disease. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Addison’s disease; Adrenal tuberculosis; CT
1. Introduction Destruction of 90% of the adrenal cortex is the cause of primary adrenal insufficiency or Addison’s disease. In 1855, Thomas Addison described the autopsy findings of six patients with adrenal tuberculosis, which was once considered the most common cause of primary adrenal insufficiency. Autoimmune adrenalitis is presently the principal cause of Addison’s disease in developed countries [1–4]. Other rare causes include histoplasmosis, blastomycosis, metastatic tumor, adrenal hemorrhage and a variety of opportunistic infections due to the acquired immunodeficiency syndrome (AIDS) [5–7]. In devel-
oping countries, however, adrenal tuberculosis is still the major cause of Addison’s disease. Although some previous reports have described the CT findings of adrenal tuberculosis, most of these studies were case reports with non-enhanced CT scan so the consecutive changes of this disease in each stage were not described accurately [8–14]. In this study, we retrospectively reviewed CT features of 42 cases of Addison’s disease due to adrenal tuberculosis. The purpose of our study was to correlate the initial contrast-enhanced CT features with clinical duration of the Addison’s disease due to adrenal tuberculosis and to evaluate the diagnostic implications of CT features. 2. Materials and methods
∗
Corresponding author at: Department of Radiology, West China Hospital, Sichuan University, 37# Guo Xue Xiang, Chengdu, Sichuan 610041, China, Tel.: +86 28 85423817. E-mail address: [email protected] (Z.-G. Yang). 0720-048X/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2006.11.025
2.1. Subjects This study was approved by our medical school Institutional Review Board (IRB). Informed consent was obtained from each
Y.-K. Guo et al. / European Journal of Radiology 62 (2007) 126–131
of the recruits. No compensation was provided to the subjects for their participation. Forty-two patients with untreated adrenal tuberculosis were enrolled in this study by the Department of Radiology at our Medical School between March 1994 and October 2005. CT scan and laboratory examination were used for diagnoses and follow-ups. Patients with autoimmune endocrine disease, HIV infection, or extra-adrenal neoplastic disease were excluded. The mean (±S.D.) age of the patients was 48 ± 11 years (median, 51 years; range, 29–72 years). Twenty-nine patients (69%) were men (mean age, 48 ± 12 years; median age, 50 years; range, 29–68 years), and 13 (31%) were women (mean age, 49 ± 11years; median age, 50 years; range, 37–72 years). There was no significant difference in age between men and women (independent samples t-test, p = 0.70). All the patients exhibited Addison’s disease symptoms such as fatigue, dizziness, nausea, vomiting and lethargy. Physical examination revealed hyperpigmentation, weight loss, signs of dehydration or hypotension. Further biochemical investigation confirmed the adrenocortical insufficiency in all patients. Extra-adrenal tuberculosis was present in 23 (54%) of the 42 patients including pulmonary, gastrointestinal, vertebral, testicular and nephritic tuberculosis. Thirty-eight of the 42 cases had a definitive diagnosis of tuberculosis confirmed by clinical findings, laboratory findings and follow-up CT or ultrasound over 12 months after antituberculous therapy. The final diagnosis of tuberculosis for the remaining four cases was established by histological examination or percutaneous aspiration biopsy. 2.2. CT protocols Opacification of the bowel was carried out routinely with oral contrast materials (500–800 mL of a 1.5% solution of sodium diatrizoate) before CT scan. CT scan was examined with a 9800 Quick CT scanner (General Electric Medical Systems, Milwaukee, WI), a Somatom Plus 4 helical scanner, a Sensation 4 or 16 multi-detector row scanner (Siemens Medical Systems, Erlangen, Germany). Of the 42 cases, 6 were performed on a GE 9800 scanner with scanning parameters of 140 kVp, 200 mAs and 5 mm collimation, 22 were done on a Somatom Plus 4 scanner, and 14 were done on a Sensation 4 or 16 multi-detector row scanner with scanning parameters of 120 kVp, 200 mAs, 3 mm collimation and reconstruction interval 3 mm. Non-contrast scan was performed for all patients before enhancement, extending from the diaphragm to the iliac crest. A total of 80–100 mL contrast medium containing 300 mg/mL (iopromide, Ultravist 300, Schering) was administrated at a flow rate of 2.5 mL/s (scan delay, 70 s) using a motor injector via a 19-gague venous line into the antecubital vein. 2.3. Image analysis Two experienced abdominal radiologists (20 and 8 years of experiences, respectively) who were unaware of the final diagnosis and clinical duration reviewed independently all contiguous CT scans on hard-copy images and recorded the CT characteristics of the lesions including their location, size, contour,
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calcification, and enhancement patterns. Calcification was evaluated on non-contrast CT scan. The location of the lesion was recorded as unilateral or bilateral. The contour was classified as mass-like enlargement or enlargement with preserved contour. The average of the maximum length and the maximum perpendicular width of the mass were measured on the maximum cross-sectional area of the CT images. The enhancement patterns were categorized as presence or absence of peripheral rim enhancement. Peripheral rim enhancement was considered when thick, thin or irregular enhancement of the rim was present. Based on clinical data, the duration of Addison’s disease was recorded and classified as four categories: 1–6 months, group 1; 7–12 months, group 2; 13–24 months, group 3; and more than 24 months, group 4. With these categories, there were 12 cases (range, 1–6 months; median, 5 months) in group 1, 8 cases (range, 7–11 months; median, 8 months) in group 2, 8 cases (range, 13–21 months; median, 15.5 months) in group 3, and 14 cases (range, 25–62 months; median, 34.5 months) in group 4. The initial CT findings were described in each group and their correlations with duration were assessed. 2.4. Statistical analysis Statistical analysis was performed with commercially available software (SPSS 11.0 Version, Chicago, IL). The size of the adrenal mass was calculated and compared between right and left lateral with an independent samples t-test. Difference of size among groups was tested with a parametric analysis of variance test. The size was correlated with duration of Addison’s disease using the linear correlation analysis. The presence of calcification and peripheral rim enhancement and contour characteristics on CT were correlated with duration using Cochran Armitage trend test. Interobserver agreement on CT findings for the size was tested with linear regression analysis. Agreement on the presence of other findings was tested with kappa statistics. Statistical significance was given when the p-value was less than 0.05. 3. Results 3.1. CT manifestations of the adrenal tuberculosis Of the 42 patients with untreated adrenal tuberculosis, bilateral enlarged adrenals were revealed in 38 cases (91%), unilateral in 3 cases (7%), and normal size in 1 case (2%). Enlargement of the adrenal glands in 41 cases (98%) included mass-like enlargement in 20 cases (49%) and enlargement with the contours preserved in 21 cases (51%) (Fig. 1). Low attenuation in the center with peripheral rim enhancement of the lesions was shown in 22 cases (52%) on contrast-enhanced CT (Fig. 2). Non-enhanced CT scan revealed calcification in 21 cases (50%) (Fig. 3). CT findings of each group are presented in Table 1. The size of the adrenal enlargement was not significantly different between the right (2.0 cm ± 1.0, ranging from 0.9 to 4.5 cm) and the left adrenals (2.1 cm ± 1.2, ranging from 1.0 to 6.2 cm) (p = 0.820).
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Fig. 1. Adrenal tuberculosis in 36-year-old woman with 23 months duration. Contrast-enhanced CT scan reveals the bilaterally enlarged adrenals but the contours are preserved bilaterally.
Fig. 2. Adrenal tuberculosis in 49-year-old man with 2 months duration. Contrast-enhanced CT shows the bilateral mass-like enlargement with peripheral enhancement.
3.2. Correlation between initial CT features and clinical duration As the duration of Addison’s disease increased, the presence of calcification and contour preservation increased concomi-
Fig. 3. Adrenal tuberculosis in 53-year-old woman with 18 months duration. Contrast-enhanced CT scan reveals mass-like enlargement of right adrenal gland with peripheral rim enhancement and calcification in bilateral adrenals.
Fig. 4. Distribution patterns of both peripheral rim enhancement and calcification correlate with clinical duration. As the duration increases, the presence of calcification increases concomitantly (p < 0.001), whereas peripheral rim enhancement decreases concomitantly (p < 0.001).
tantly (p < 0.001), whereas peripheral rim enhancement and mass-like decreased concomitantly on CT images (p < 0.001) (Figs. 4 and 5). However, the size of the adrenal enlargement with different duration of Addison’s disease had no statistic significance among groups 1–3 (p = 0.093). The comparison of
Table 1 Initial CT findings and clinical duration correlation of 42 patients with Addison’s disease Duration
Group 1 (n = 12, 29%) Group 2 (n = 8, 19%) Group 3 (n = 8, 19%) Group 4 (n = 14, 33%) P value
Enlargement
Contour
Size (cm)
B
U
M
Con. P.
R
L
11 8 8 11
1 0 0 2 <0.001
8 5 3 4 <0.001
4 3 5 10 <0.001
2.8 ± 1.1 2.0 ± 0.8 2.0 ± 1.1 1.4 ± 0.4 0.002
3.0 ± 1.5 1.9 ± 1.1 1.9 ± 1.1 1.7 ± 0.6 0.034
Note: B, bilateral; U, unilateral; M, mass; Con. P., contour preserved; R, right; L, left.
Peripheral rim enhancement
Calcification
10 6 4 2 <0.001
1 3 5 12 <0.001
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Fig. 5. Distribution patterns of both mass-like and contour preserved enlargement correlate with clinical duration. As the duration increased, the presence of contour preserved increases concomitantly (p < 0.001), whereas mass-like decreases concomitantly (p < 0.001).
size between groups demonstrated significant difference only between group 1 and group 4 (p = 0.002). As the duration of Addison’s disease increased, the size of enlarged adrenals became smaller, but their correlation was moderate (r = −0.595, p < 0.001). 3.3. Agreement between observers A satisfied agreement was achieved between the two observers in measuring the size of the lesion (p = 0.79), estimating the location of lesions (κ = 0.97) and contour (κ = 0.69), as well as assessing the presence of calcification (κ = 0.81) and peripheral rim enhancement (κ = 0.76). 4. Discussion Tuberculosis in the adrenals can result in progressive destruction of the glands. When 90% of the tissue is destroyed, adrenocortical insufficiency characterized as Addison’s syndrome would appear. Most of the symptoms are insidious and non-specific, such as fatigue, weakness, anorexia, nausea and vomiting. Physical examination may find cutaneous and mucosal pigmentation, weight loss and hypotension. Routine laboratory findings include commonly hyponatremia, hyperkalemia, azotemia, hypoglycemia and hypercalcemia. Specific biochemical tests of patients suspected to Addison’s disease usually include basal levels of cortisol, ACTH in plasma and rapid ACTH stimulation tests, which are used to establish existence of adrenocortical insufficiency. Furthermore, ACTH stimulation test may be useful to differentiate primary and secondary adrenocortical deficiency [2–4]. Extra-adrenal tuberculosis including pulmonary, gastrointestinal, vertebral, testicular or nephritic tuberculosis is commonly present in patients with tuberculous Addison’s disease. Thus, extra-adrenal tuberculosis may be a useful clue to etiology of tuberculous Addison disease, but is non-specific evidence. Acute primary adrenal insufficiency can
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lead to adrenal crisis and become a life-threatening disorder especially in any stressful situation. CT scan may be necessary to determine the cause of Addison’s disease and provide valuable information for making therapeutic decision [1–4,8,14]. Bilateral involvement with enlarged adrenals occurs in tuberculous Addison’s disease. The reason is that hematogenous and lymph routes spread from the primary mycobacterial infection to each adrenal gland with equal chance [15]. Wang et al. [16] reported that all adrenal gland lesions with bilateral involvement were tuberculosis in their study. In our series, the occurrence of bilateral involvement was 91%. In contrast, Yang et al. [17] found primary adrenal tumors rarely involved both adrenals when they differentiated the adrenal tuberculosis from primary adrenal tumor. Pheochromocytoma is the most frequent bilateral primary tumor of the adrenal glands with the incidence of 10% [18]. Lymphoma and metastases as the cause of adrenal insufficiency with bilaterally enlarged adrenals is rare [5]. Differential diagnosis may be difficult without biopsy, but the clinical appearances and the involved patterns may be helpful to discriminate these rare causes from tuberculosis. Thus, bilateral involvement can be used as an important discriminator of tuberculosis from primary tumors in the adrenals. At early stage, pathologic findings of the adrenals revealed caseous necrosis area and tuberculous granuloma because of the destruction of the cortex by tuberculous mycobacteria [14,15]. CT scan frequently demonstrates the mass-like enlargement of the adrenals with tuberculosis. In our series, 75% had mass-like adrenal enlargement with the duration of Addison’s disease no more than 1 year. At the late stage, the enlarged tuberculous adrenals decreased or returned to normal size and configuration because of fibrosis and calcification in the lesions [8,13–15]. In the present study, 73% presented enlarged adrenals but contour preserved with duration of Addison’s disease more than 1 year. Therefore, the configuration of enlarged adrenals shown on CT was correlated to the duration of Addison’s disease. As a result, the configuration of adrenal enlargement could also be used to discriminate tuberculosis from adrenal tumors. The enlarged adrenal with contour preserved contour strongly indicated infectious etiology, while most of tumors commonly present as round or oval intra-adrenal masses [17–20]. Some previous studies considered the size of the involved adrenals as an important feature to determinate the cause and duration of Addison’s disease. Small or atrophic adrenals indicated autoimmune adrenalitis or tuberculosis with long duration, whereas the patients with early stage or active adrenal tuberculosis usually had enlarged adrenals [8–10,14,16]. In our study, as the duration increased, especially in those patients with longstanding adrenal tuberculosis (usually more than 3 years), most of the size of involved glands were smaller than that in the active or early stage cases. These findings were, to some extent, consistent with those previous reports [8–10,14,16]. Peripheral rim enhancement with low attenuation in the center of the adrenals was a striking characteristic of adrenal tuberculosis. Previous studies have shown that this feature represents the pathologic findings of central caseous necrosis surrounded by fibrous tissue and granulomatous inflammatory tissue [8,14–17]. The presence of peripheral rim enhancement
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on CT suggests the possibility of untreated tuberculosis, but a similar pattern may be seen occasionally in primary tumor especially when it contains necrosis in the central area [19]. In our study, peripheral rim enhancement was more commonly seen in untreated tuberculosis less than 1 year duration. As the duration of Addison’s disease increased, the presence of peripheral rim enhancement decreased concomitantly on CT images. This striking tendency indicated the finding may be used to indicate a patient with early and/or active tuberculosis. At this stage, an appropriate therapy as early as possible might be critical to regain the adrenal function [10,22,23]. Calcification in adrenal gland as a common sign of tuberculosis has been reported in the previous studies. At late stage, the encapsulated granuloma becomes quiescent, the inflammatory cells decrease in number, and consequently calcium salts deposit in the caseous material so that calcification could be present on CT images [8,14,15]. Vita et al. [8] reported the prevalence of calcification of adrenal tuberculosis was 53% at the time of diagnosis and indicated long-standing tuberculosis. Wang et al. [16] described CT findings of small calcification dots in the adrenals were seen in 22% patients with active tuberculosis. As shown in our study, calcification could present in each stage of tuberculous adrenalitis, but the occurrence of calcification increased concomitantly on CT images as the duration increased. On the contrary, histological calcification of adrenal primary tumor was infrequent. Other rare diseases with calcification could be detected, such as hemorrhage, histoplasmosis, and blastomycosis. In retrospective review articles, Yang et al. [17] and Kenney et al. [21] found no more than 10% of cases presented calcification in the adrenal tumor, which did not have any significance for its diagnosis. In addition, Vita et al. [8] found that calcification was beneficial to rule out idiopathic adrenal atrophy. So calcification was considered a valuable diagnostic clue and a significant discriminator for the adrenal tuberculosis. As far as Addison’s disease due to tumors involving bilateral adrenal glands are concerned, the bilateral adrenal metastases from other primary tumors should be considered firstly when bilateral adrenal masses are revealed but most cases are easily to be diagnosed because the primary malignancies are known [24]. Secondly, lymphoma cannot be excluded because it is frequently located bilaterally as many as 25% of patients at autopsy. Although imaging characteristic cannot differentiate from lymphoma and tuberculosis, the diagnosis is usually evident in patient with lymphomatous involvement in other areas because primary adrenal lymphoma is extremely rare [25]. As an entity frequently involves bilateral adrenals, hemorrhage must be included in the differential diagnosis, especially in patients with symptoms of Addison’s disease. Bilateral adrenal hemorrhage sometimes mimics tuberculosis on CT images, but history of anticoagulant therapy or injury with subsequent hypoadrenocorticism is a clue to make the diagnosis of hemorrhage. Moreover, MRI is particularly sensitive for detecting intra-adrenal hemorrhage, which shows special signal intensity on T1- and T2-weighted images at different stage of hematoma [26]. About 50% of patients with disseminated histoplasmosis develop Addison’s disease. CT features of adrenal histoplasmosis can mimic tuberculosis so that differential diagnosis may be
difficult on CT imaging, and a CT- or Ultrasound-guided biopsy sometimes need to performed for final diagnosis [27]. There were limitations to our study. First, our series could not reliably evaluation atrophic adrenals resulting from tuberculosis due to selection bias. Based on previous reports, atrophic glands appear most commonly in patients with a more than 10 year duration of tuberculous Addison’s disease [8,9], but our series did not include any patients with over 10 years duration. Second, as a retrospective study, our study materials were collected over 10 years. As a result, some CT scans were performed with 5 mm collimation while others were performed with 3 mm collimation on different CT devices. The different collimation would result in minor difference in the size measurement and the capability of detecting the tiny calcification. In conclusion, contrast-enhanced CT features of Addison’s disease caused by adrenal tuberculosis can provide evidence of etiology for primary adrenal insufficiency. Diagnosis of Addison’s disease with normal-size adrenals based on CT features would be difficult without clinical, laboratory and pathologic findings. A combination of clinical symptoms, laboratory results, pathological findings and CT features could establish a final diagnosis. Furthermore, CT features might be useful to indicate the clinical duration of Addison’s disease, and to provide valuable information for making diagnostic decision. References [1] Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 2002;23:327–64. [2] Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med 2003;139:194–204. [3] Oelkers W. Adrenal insufficiency. N Engl J Med 1996;335:1206–12. [4] Robinet JM. Addison’s disease. RDH 1995;15:20–4. [5] Zar T, Khan F, Petit Jr W, Bernene JR. Primary adrenal lymphoma presenting as adrenal insufficiency: a case report and review of literature. Conn Med 2004;68:7–10. [6] Francque SM, Schwagten VM, Ysebaert DK, Van Marck EA, Beaucourt LA. Bilateral adrenal haemorrhage and acute adrenal insufficiency in a blunt abdominal trauma: a case-report and literature review. Eur J Emerg Med 2004;11:164–7. [7] Rozenblit AM, Kim A, Tuvia J, et al. Adrenal histoplasmosis manifested as Addison’s disease: unusual CT features with magnetic resonance imaging correlation. Clin Radiol 2001;56:682–4. [8] Vita JA, Silverberg SJ, Goland RS, Austin JH, Knowlton AI. Clinical clues to the cause of Addison’s disease. Am J Med 1985;78:461–6. [9] Doppman JL, Gill Jr JR, Nienhuis AW, et al. CT findings in Addison’s disease. J Comput Assist Tomogr 1982;6:757–61. [10] Villabona CM, Sahun M, Ricart W, et al. Tuberculous Addison’s disease Utility of CT in diagnosis and follow-up. Eur J Radiol 1993;17:210–3. [11] Lam KY, Lo CY. A critical examination of adrenal tuberculosis and a 28year autopsy experience of active tuberculosis. Clin Endocrinol (Oxford) 2001;54:633–9. [12] Buxi TB, Vohra RB, Sujatha, Byotra SP, Mukherji S, Daniel M. CT in adrenal enlargement due to tuberculosis: a review of literature with five new cases. Clin Imag 1992;16:102–8. [13] Wilms GE, Baert AL, Kint EJ, Goddeeris PG. Computed tomographic findings in bilateral adrenal tuberculosis. Radiology 1983;146:729– 30. [14] Efremidis SC, Harsoulis F, Douma S, Zafiriadou E, Zamboulis C, Kouri A. Adrenal insufficiency with enlarged adrenals. Abdom Imag 1996;21:168–71.
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