Case Report ABSTRACT CASE STUDY

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1 Case Report Raquel G. Martins, MD, MSc 1 ; Reshma Agrawal, MBBS, BDS, MFDS, RCS (Eng) 2 ; Daniel M. Berney, MA, MBBChir, FRCPath 2 ; Rodney Reznek, FRCP, FRCR 3 ; Matthew Matson, MBBS, MRCP, FRCR 3 ; Ashley B. Grossman, BA, BSc, MD, FRCP, FMedSci 1,4 ; Maralyn R. Druce, MA, MRCP, PhD 1,4 ABSTRACT Objective: To outline the potential role for adrenal venous sampling in the diagnosis and management of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS). Methods: We present a case description and discuss the management of a 59-year-old woman with an 8-year history of weight gain, centripetal obesity, a round plethoric face, skin thinning, easy bruising, hirsutism, and progressive muscle weakness. Results: The patient reported a prior personal history of asthma, type 2 diabetes mellitus, hypertension, dyslipidemia, and bilateral leg ulcers, but she denied having any personal or family history of endocrinopathy and was not taking any corticosteroid medication. Elevated midnight serum cortisol, failure to suppress cortisol levels with a low-dose dexamethasone suppression test, and undetectable plasma ACTH all indicated ACTH-independent CS. Additional investigations including dynamic tests and adrenal imaging were supported by adrenal venous sampling in order to make a diagnosis and formulate a management plan. She was ultimately noted to have bilateral functioning adrenal nodules (adenoma and adenolipoma) and underwent successful bilateral laparoscopic adrenalectomy, with postoperative glucocorticoid and mineralocorticoid replacement. Conclusion: Adrenal venous sampling may be an important step in the differential diagnosis of CS and localization of the source of cortisol excess. It may distinguish pheochromocytoma or benign nonfunctioning adrenal nodules from cortisol-secreting adenomas and may avoid unnecessary bilateral adrenalectomy. It can also ensure that the correct operation is completed, if required, and thus avoid the increased morbidity and mortality associated with repeated surgical interventions. (Endocr Pract. 2012;18:e153-e157) Abbreviations: ACTH = adrenocorticotropic hormone; AIMAH = ACTH-independent macronodular adrenal hyperplasia; AV:PV = adrenal vein:peripheral vein; AVS = adrenal venous sampling; CS = Cushing syndrome; HU = Hounsfield units; MAH = macronodular adrenal hyperplasia; MRI = magnetic resonance imaging; PPNAD = primary pigmented nodular adrenal disease CASE STUDY Submitted for publication May 18, 2012 Accepted for publication July 11, 2012 From the Departments of 1 Endocrinology, 2 Cellular Pathology, and 3 Radiology, St. Bartholomew s Hospital and the London National Health Service Trust, and 4 St. Bartholomew s Hospital and the London School of Medicine, London, United Kingdom. Address correspondence to Dr. Maralyn R. Druce, Department of Endocrinology, St. Bartholomew s Hospital, London EC1A 7BE, United Kingdom. m.r.druce@qmul.ac.uk. Published as a Rapid Electronic Article in Press at practice.org on September 14, DOI: /EP12136.CR To purchase reprints of this article, please visit: Copyright 2012 AACE. A 59-year-old English woman was referred to a specialist center for evaluation of Cushing syndrome (CS). The patient reported an 8-year history of cushingoid features, including weight gain, centripetal obesity, a round plethoric face, skin thinning, easy bruising, and a decrease in mobility resulting in progressive difficulty rising from a chair or climbing stairs. She also had severe, long-standing hirsutism, which she managed by shaving, and complained of chronic diarrhea and a productive cough with yellow sputum. The patient reported a prior personal history of asthma (with previous intermittent use of corticosteroid inhalers, as needed), type 2 diabetes mellitus (diagnosed 10 years previously), hypertension, dyslipidemia, and e153

2 e154 bilateral leg ulcers (3 years before) necessitating a lower limb skin graft. Her menopause had occurred at age 49 years. She was taking valsartan (160 mg daily), doxazosin MR (4 mg twice a day), bumetanide (1 mg daily), spironolactone (25 mg daily), metformin (1 g twice a day), pioglitazone (30 mg daily), atorvastatin (10 mg daily), ezetimibe (10 mg daily), and salbutamol (as needed). She reported a family history of osteoarthritis and hypertension but not of endocrinopathy. On physical examination, the patient was obese (body mass index, 34.8 kg/m 2 ), overtly cushingoid, grossly hirsute, and plethoric, with an interscapular fat pad, prominent abdominal livid striae, and proximal muscle wasting in the lower limbs. Blood pressure (with the patient taking medication) was 127/87 mm Hg. Other aspects of the physical examination were unremarkable. Results of investigations from the referring hospital included grossly elevated urinary free cortisol of 566 µg/24 h (reference range, 0 to 100), an absence of suppression on low-dose dexamethasone suppression testing and highdose dexamethasone suppression testing, a suppressed plasma adrenocorticotropic hormone (ACTH) concentration, no response of ACTH or cortisol to a corticotropinreleasing hormone test (all ACTH levels <10 ng/l), and normal basal pituitary function. Pituitary magnetic resonance imaging (MRI) at the referring hospital showed normal findings, whereas adrenal MRI was suggestive of bilateral adrenal masses. Therefore, the patient was referred to our department for further evaluation and management. A complete blood cell count and general biochemistry findings were unremarkable; hemoglobin A 1c was 10.0%. All diarrhea investigations (including stool culture and 5-hydroxyindoleacetic acid and gut peptide levels) were negative. Basal pituitary function was normal, as were 17-hydroxyprogesterone, androstenedione, and testosterone levels; serum dehydroepiandrosterone sulfate was low, and sex hormone-binding globulin was slightly low. Serum aldosterone levels were normal, and renin activity was not suppressed (Table 1). Midnight cortisol levels determined while the patient was asleep were elevated (596 nmol/l), and the low-dose dexamethasone suppression testing demonstrated lack of suppression (615 to 746 nmol/l), consistent with a diagnosis of CS. Plasma ACTH was undetectable (<10 ng/l), and the serum cortisol value did not change on high-dose dexamethasone suppression testing (644 to 676 nmol/l). Thus, it was confirmed that she had ACTH-independent CS. The patient was submitted to a mixed-meal test in view of reported literature on food-induced hypercortisolemia, particularly in patients with bilateral nodular adrenal lesions (1,2), but this study was negative that is, there was no significant change in serum cortisol. Dual-energy x-ray absorptiometry bone scanning showed osteopenia. Adrenal computed tomography with contrast enhancement showed a mass measuring 2.8 cm in the right adrenal gland. This lesion had the radiologic appearance of multiple small pockets of fat consistent with a lipomatous element coexistent with elements that could represent benign cortical adenoma. There was an additional mass measuring 2.6 cm in the left adrenal gland. Before administration of contrast medium, the attenuation value of the mass measured 23 Hounsfield units (HU), 72 HU at 1 minute, and 41 HU at 10 minutes an appearance consistent with a benign cortical adenoma. The results of these tests showed that the patient had ACTH-independent CS associated with bilateral adrenal masses. Either or both of these lesions could potentially have been the source of excess cortisol secretion, production of cortisol from both adenomas and adenolipomas being well described (3) (Fig. 1). The persistently undetectable ACTH (including during the corticotropin-releasing hormone test) suggested that secondary adrenal hyperplasia due to ACTH stimulation, as in Cushing disease or the ectopic ACTH syndrome, was extremely improbable. In order to distinguish between unilateral and bilateral cortisol hypersecretion, the patient was submitted to adrenal venous sampling (AVS). Adrenaline and noradrenaline were measured to confirm that the adrenal vein catheterization was successful; this result was indeed confirmed, with the right adrenal vein adrenaline nmol/l and the left adrenal vein adrenaline 75 nmol/l (peripheral vein <4 nmol/l). The adrenal vein:peripheral vein (AV:PV) cortisol ratio was on the left side and 8.76 on the right side (Table 2). Aldosterone was also measured during catheterization, with levels of 2,087 nmol/l in the left adrenal vein and 4,220 nmol/l in the right adrenal vein (the value from the peripheral vein being <78 nmol/l). Thus, the cortisol/aldosterone ratio was 1.38 on the left and 5.3 on the right, with a left to right lateralization ratio of 3.8. After the adrenal vein study, the patient commenced treatment with metyrapone (500 mg three times a day), with adequate control of cortisol secretion as demonstrated by a mean cortisol level of 280 nmol/l on a 5-point Cushing day-curve (therapeutic range, 15 to 300 nmol/l) (4). The results of AVS showed that the patient had CS with undetectable ACTH and bilateral adrenal cortisol hypersecretion. Therefore, the patient was referred for bilateral adrenalectomy, which was successfully completed laparoscopically and was uncomplicated. The histologic examination of the left adrenal mass revealed a well-circumscribed single nodule composed of an admixture of zona reticularis and zona fasciculata type cells, with normal adjacent adrenal tissue and no other nodular areas. No malignant features were seen, and this lesion was interpreted as an adrenocortical adenoma. The right adrenal mass was a similar well-circumscribed lesion; however, the adenomatous areas were interspersed with lipomatous regions. No myeloid areas were seen. This mass was interpreted as an adenolipoma, again with normal adjacent adrenal tissue.

3 e155 Table 1 Results of Endocrine-Related Tests at Baseline Patient Reference Test value range Complete blood cell count Hemoglobin (g/dl) Leukocytes ( 10 9 /L) Platelets ( 10 9 /L) Renal function Sodium (mmol/l) Potassium (mmol/l) Urea nitrogen (mmol/l) Creatinine (µmol/l) Hemoglobin A 1c (%) Fasting plasma glucose (mmol/l) Luteinizing hormone (IU/L) 7.0 Follicle-stimulating hormone (IU/L) 51 Estradiol (pmol/l) 47 Sex hormone-binding globulin (mmol/l) Prolactin (miu/l) Thyroid-stimulating hormone (miu/l) Thyroxine (pmol/l) am cortisol (nmol/l) 615 Androstenedione (nmol/l) Dehydroepiandrosterone sulfate (µg/l) Testosterone (nmol/l) Hydroxyprogesterone (nmol/l) Aldosterone (nmol/l) Plasma renin activity Fasting gut hormones a Chromogranin A (pmol/l) a All within reference range. Postoperatively, the glycemic and blood pressure control of the patient improved, and she was discharged with a regimen consisting of hydrocortisone (10 mg + 5 mg + 5 mg), fludrocortisone (0.1 mg daily), valsartan (160 mg daily), atorvastatin (20 mg daily), and metformin (500 mg twice a day), together with a Steroid Card, a medical bracelet information pack, a hydrocortisone emergency kit, and advice regarding increasing her hydrocortisone in the event of intercurrent illness. The patient remains well on regularly scheduled endocrine follow-up. DISCUSSION The management of patients with ACTH-independent CS and bilateral adrenal masses is challenging. The imaging features on computed tomography or MRI cannot distinguish between a functioning and a nonfunctioning adrenocortical mass. The adrenal uptake of iodine 131 ( 131 I)-6b-iodomethylnorcholesterol ([ 131 I]-NP-59) has been used for this purpose (5), but it is not available in all countries and it requires a cumbersome protocol (6). AVS can be helpful in this setting, although its use for this indication is still limited, accounting for differences in the protocol and doubts in the interpretation of the results. In the literature, there is only a single report (from the Mayo Clinic) in which AVS was used in this setting, which determined cutoff values to distinguish unilateral from bilateral cortisol hypersecretion in 10 patients (6). The Mayo Clinic investigators, who used AVS in the assessment of patients with bilateral adrenal masses and

4 e156 Fig. 1. Computed tomographic scan of the abdomen of the study patient, showing a mass measuring 2.8 cm (with a lipomatous element) in the right adrenal gland and a mass measuring 2.6 cm in the left adrenal gland (red arrows). ACTH-independent CS, found that an AV:PV gradient greater than 6.5 was consistent with a cortisol-secreting adenoma (6). They determined the laterality of secretion by the side-to-side (high-side to low-side) adrenal vein cortisol gradient and found a cortisol lateralization ratio of 2.0 or less in all patients with clinically important bilateral cortisol hypersecretion. In our patient, the cortisol lateralization ratio was 1.9, but both AV:PV ratios were greater than 6.5. The only difference in their protocol in comparison with ours is that they performed AVS during dexamethasone suppression testing to exclude ACTH stimulation, but in our patient, ACTH was fully suppressed. The Mayo Clinic authors used an AV:PV plasma adrenaline ratio to confirm the success of adrenal vein catheterization, although they warned that it cannot be used to correct for blood sample dilution between the 2 adrenal veins. There is also a single case report in which aldosterone was used to correct for side-to-side dilution differences (7); however, whether it can be used for this purpose remains to be determined (6). In our case, we found that correcting for aldosterone produced a lateralization ratio of 3.8 favoring the left. Our conclusion from our study was that there was bilateral secretion of cortisol, although predominantly on the left, and this was borne out by the histopathologic findings, which showed bilateral adenomas with different morphologic features and cell composition. In general, this investigation appears to be a helpful adjunct in the diagnosis and management of ACTHindependent CS in selected cases. A limiting factor may be local expertise in venous cannulation, although experience is growing because of its value in other circumstances, such as the investigation of Conn syndrome. Expertise may be concentrated in regional centers for this purpose. The limited experience with AVS in the management of CS and bilateral adrenal masses may be partially explained by the rarity of this situation. Its differential diagnosis includes bilateral cortisol-secreting adenomas (or carcinoma), primary pigmented nodular adrenal disease (PPNAD), bilateral ACTH-independent macronodular adrenal hyperplasia (AIMAH), and Cushing diseaseassociated macronodular adrenal hyperplasia (MAH). PPNAD manifests in children and young adults with multiple, small (2 to 4 mm), pigmented (black or brown) nodules (8). AIMAH has a bimodal age distribution, with a rare subset of patients presenting during the first years of life (particularly with the McCune-Albright syndrome) and the majority during the fifth and sixth decades of life. AIMAH usually manifests with numerous nonpigmented nodules, larger than 5 mm in diameter, and most cases are related to adrenal aberrant receptor expression for gastric inhibitory polypeptide, vasopressin, catecholamine, luteinizing hormone, human chorionic gonadotropin, serotonin, or angiotensin (1). Investigation for the possibility of aberrant receptors (for example, by evaluation of cortisol levels after a mixed meal) may provide supportive evidence for the underlying diagnosis, and there was hope that this might indicate the possibility of a trial of relevant medical Table 2 Biochemical Results of Adrenal Venous Sampling Adrenal Cortisol vein to lateralization Cortisol peripheral Adrenaline Noradrenaline Aldosterone ratio Site (nmol/l) vein ratio (nmol/l) (nmol/l) (nmol/l) (left:right) Left adrenal vein 11, , Right adrenal vein 5, ,220 Peripheral vein (low IVC) 664 <4 a Mean of 2.7 <78 Abbreviation: IVC = inferior vena cava. a Confirming adequacy of cannulation. and 3.0 = 2.85

5 e157 therapy. To date, however, this has not been borne out in the literature or in practice. MAH occurs in 10% to 40% of patients with CS, and it is thought to result from longstanding ACTH stimulation, provoking autonomous adrenal adenoma formation and, ultimately, ACTH suppression (9). Typically, MAH manifests with one or more nodules (which may be up to several centimeters in diameter) surrounded by tissue hyperplasia (9). Although adrenal adenomas and carcinomas are responsible for about 60% and 40% of cases of ACTHindependent CS, respectively (10), bilateral functioning adenomas are exceedingly rare, with few cases described (6,11-15). One of the characteristic morphologic features of Cushing adenomas is the pronounced atrophy of adjacent adrenal glands (16). In our described case, the patient presented with only one large nodule (2.6 cm and 2.8 cm, respectively) in each gland. Although these nodules were surrounded by normal adrenal tissue, the histologic features were suggestive of bilateral adenomas (one with some fatty components within it). TREATMENT AND MANAGEMENT The importance of establishing a correct diagnosis is underscored by the consequences on the selection of treatment. AIMAH and PPNAD are treated with bilateral adrenalectomy, but in MAH (because this is an ACTHdependent form of CS), it can lead to Nelson syndrome. The ideal treatment for patients with ACTH-independent CS and bilateral functioning adrenal adenomas is less clear. Bilateral adrenalectomy solves the problem but results in postoperative adrenal insufficiency, necessitating lifelong glucocorticoid and mineralocorticoid replacement. For this reason, some recent reports have described the use of bilateral partial adrenalectomy, removing only the tumors (14,17). In the presented case, our patient was submitted to laparoscopic bilateral adrenalectomy, without complications, resulting in cure of the disease and improvement of its sequelae. CONCLUSION We have described a rare case in which a patient presented with ACTH-independent CS and bilateral functioning adrenal adenomas. The radiologic features of such adrenal masses are helpful in making the diagnosis, but they cannot distinguish between functioning and nonfunctioning lesions. AVS is an extremely helpful investigation for this indication, but it is still necessary to validate the protocol and the cutoff values for interpretation of its results. Finally, to prevent the subsequent appearance of Nelson syndrome, the clinician must distinguish this situation from MAH caused by Cushing disease. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Lacroix A. ACTH-independent macronodular adrenal hyperplasia. 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