Application of parametric ultrasound contrast agent perfusion studies for differentiation of hyperplastic adrenal nodules from adenomas-Initial study.

OBJECTIVES: To evaluate the possibilities of differentiation of non-malignant adrenal masses with the application of the new technique for the evaluation of enhancement after administration of an ultrasound contrast agent: parametric imaging. PATIENTS AND METHODS: 34 non-malignant adrenal masses in 29 patients were evaluated in a dynamic examination after the administration of ultrasound contrast agent with parametric imaging. Patterns on parametric imaging of arrival time were evaluated. The final diagnosis was based on CT, MRI, biochemical studies, follow up and/or histopathology examination. RESULTS: The study included: 12 adenomas, 10 hyperplastic nodules, 7 myelolipomas, 3 pheochromocytomas, hemangioma with hemorrhage and cyst. The pattern of peripheral laminar inflow of Sonovue on parametric images of arrival time of was 100% sensitive for hyperplastic nodules and 83% specific in regard to adenomas. CONCLUSIONS: Parametric contrast enhanced ultrasound may accurately differentiate hyperplastic adrenal nodules from adenomas and could be complementary to CT or MRI. Incorporation of perfusion studies to CT or MRI could possibly enable one-shop complete characterization of adrenal masses. This could deliver additional information in diagnostics of patients with Conn Syndrome and warrants further studies in this cohort of patients.

Standards of ultrasound imaging of the adrenal glands.

Adrenal glands are paired endocrine glands located over the upper renal poles. Adrenal pathologies have various clinical presentations. They can coexist with the hyperfunction of individual cortical zones or the medulla, insufficiency of the adrenal cortex or retained normal hormonal function. The most common adrenal masses are tumors incidentally detected in imaging examinations (ultrasound, tomography, magnetic resonance imaging), referred to as incidentalomas. They include a range of histopathological entities but cortical adenomas without hormonal hyperfunction are the most common. Each abdominal ultrasound scan of a child or adult should include the assessment of the suprarenal areas. If a previously non-reported, incidental solid focal lesion exceeding 1 cm (incidentaloma) is detected in the suprarenal area, computed tomography or magnetic resonance imaging should be conducted to confirm its presence and for differentiation and the tumor functional status should be determined. Ultrasound imaging is also used to monitor adrenal incidentaloma that is not eligible for a surgery. The paper presents recommendations concerning the performance and assessment of ultrasound examinations of the adrenal glands and their pathological lesions. The article includes new ultrasound techniques, such as tissue harmonic imaging, spatial compound imaging, three-dimensional ultrasound, elastography, contrast-enhanced ultrasound and parametric imaging. The guidelines presented above are consistent with the recommendations of the Polish Ultrasound Society.

Echogenicity of benign adrenal focal lesions on imaging with new ultrasound techniques - report with pictorial presentation.

AIM: The aim of the research was to assess the echogenicity of benign adrenal focal lesions using new ultrasound techniques. MATERIAL AND METHOD: 34 benign adrenal masses in 29 patients were analyzed retrospectively. The examinations were conducted using Aplio XG (Toshiba, Japan) ultrasound scanner with a convex probe 1-6 MHz in the B-mode presentation with the combined use of new ultrasound techniques: harmonic imaging and spatial compound sonography. The size of the adrenal tumors, their echogenicity and homogeneity were analyzed. Statistical analysis was conducted using the STATISTICA 10 software. RESULTS: The following adrenal masses were assessed: 12 adenomas, 10 nodular hyperplasias of adrenal cortex, 7 myelolipomas, 3 pheochromocytomas, a hemangioma with hemorrhage and a cyst. The mean diameter of nodular hyperplasia of adrenal cortex was not statistically different from that of adenomas (p = 0.075). The possibility of differentiating between nodular hyperplasia and adenoma using the parameter of hypoechogenicity or homogeneity of the lesion was demonstrated with the sensitivity and specificity of 100% and 41.7%, respectively. The larger the benign adrenal tumor was, the more frequently did it turn out to have a mixed and inhomogenous echogenicity (p < 0.05; ROC areas under the curve: 0.832 and 0.805, respectively). CONCLUSIONS: A variety of echogenicity patterns of benign adrenal focal lesions was demonstrated. The image of an adrenal tumor correlates with its size. The ultrasound examination, apart from its indisputable usefulness in detecting and monitoring adrenal tumors, may also allow for the differentiation between benign lesions. However, for lesions found incidentally an algorithm for the assessment of adrenal incidentalomas is applicable, which includes computed tomography and magnetic resonance imaging.

Shear wave elastography of adrenal masses is feasible and may help to differentiate between solid and cystic lesions - an initial report.

INTRODUCTION: The aim of this study was to evaluate the feasibility and usefulness of supersonic shear wave elastography (SSWE) in the diagnosis of nonmalignant adrenal masses. MATERIAL AND METHODS: 13 patients with a total number of 16 adrenal masses were enrolled in the study. In each case, both conventional ultrasound imaging and SSWE for stiffness assessment were performed. The final diagnosis was based on CT, MRI, biochemical studies, surgery or more than one year of follow up. RESULTS: The final diagnosis: nodular hyperplasia in six masses, six adenomas, three cysts, and one myelolipoma. All solid adrenal masses presented the elastography signal in contrast to cystic lesions that were devoid of it, as shear waves do not propagate through fluids. CONCLUSIONS: SSWE is a feasible technique that can be applied during ultrasound of the abdomen and retroperitoneum. SSWE presents potential for the differentiation of solid and cystic adrenal lesions. Further large scale studies evaluating the possibility of differentiation of adrenal and other retroperitoneal masses with SSWE are warranted.

Quality of life in European patients with Addison's disease: validity of the disease-specific questionnaire AddiQoL.

CONTEXT: Patients with Addison's disease (AD) self-report impairment in specific dimensions on well-being questionnaires. An AD-specific quality-of-life questionnaire (AddiQoL) was developed to aid evaluation of patients. OBJECTIVE: We aimed to translate and determine construct validity, reliability, and concurrent validity of the AddiQoL questionnaire. METHODS: After translation, the final versions were tested in AD patients from Norway (n = 107), Sweden (n = 101), Italy (n = 165), Germany (n = 200), and Poland (n = 50). Construct validity was examined by exploratory factor analysis and Rasch analysis, aiming at unidimensionality and fit to the Rasch model. Reliability was determined by Cronbach's coefficient-α and Person separation index. Longitudinal reliability was tested by differential item functioning in stable patient subgroups. Concurrent validity was examined in Norwegian (n = 101) and Swedish (n = 107) patients. RESULTS: Exploratory factor analysis and Rasch analysis identified six items with poor psychometric properties. The 30 remaining items fitted the Rasch model and proved unidimensional, supported by appropriate item and person fit residuals and a nonsignificant χ(2) probability. Crohnbach's α-coefficient 0.93 and Person separation index 0.86 indicate high reliability. Longitudinal reliability was excellent. Correlation with Short Form-36 and Psychological General Well-Being Index scores was high. A shorter subscale comprising eight items also proved valid and reliable. Testing of AddiQoL-30 in this large patient cohort showed significantly worse scores with increasing age and in women compared with men but no difference between patients with isolated AD and those with concomitant diseases. CONCLUSION: The validation process resulted in a revised 30-item AddiQoL questionnaire and an eight-item AddiQoL short version with good psychometric properties and high reliability.

Identification of TPIT and other novel autoantigens in lymphocytic hypophysitis: immunoscreening of a pituitary cDNA library and development of immunoprecipitation assays.

BACKGROUND: Lymphocytic hypophysitis is an organ-specific autoimmune disease of the pituitary gland. A specific and sensitive serological test currently does not exist to aid in the diagnosis. OBJECTIVE: To identify target autoantigens in lymphocytic hypophysitis and develop a diagnostic assay for these proteins. DESIGN/METHODS: A pituitary cDNA expression library was immunoscreened using sera from four patients with lymphocytic hypophysitis. Relevant cDNA clones from screening, along with previously identified autoantigens pituitary gland-specific factor 1a and 2 (PGSF1a and PGSF2) and neuron-specific enolase (NSE) were tested in an in vitro transcription and translation immunoprecipitation assay. The corticotroph-specific transcription factor, TPIT, was investigated separately as a candidate autoantigen. RESULTS: Significantly positive autoantibody reactivity against TPIT was found in 9/86 hypophysitis patients vs 1/90 controls (P = 0.018). The reactivity against TPIT was not specific for lymphocytic hypophysitis with autoantibodies detectable in the sera from patients with other autoimmune endocrine diseases. Autoantibodies were also detected against chromodomain-helicase-DNA binding protein 8, presynaptic cytomatrix protein (piccolo), Ca(2+)-dependent secretion activator, PGSF2 and NSE in serum samples from patients with lymphocytic hypophysitis, but at a frequency that did not differ from healthy controls. Importantly, 8/86 patients with lymphocytic hypophysitis had autoantibodies against any two autoantigens in comparison with 0/90 controls (P = 0.0093). CONCLUSIONS: TPIT, a corticotroph-specific transcription factor, was identified as a target autoantigen in 10.5% of patients with lymphocytic hypophysitis. Further autoantigens related to vesicle processing were also identified as potential autoantigens with different immunoreactivity patterns in patients and controls.

Addison's Disease Revisited in Poland: Year 2008 versus Year 1990.

This study aimed at comparing two groups of patients with Addison's disease: A, including 180 patients described in 1991 and B, consisting of 138 patients registered since 1991. The incidence of coexisting autoimmune disorders was evaluated and etiological factors were analyzed. Immunological and imaging studies (computed tomography in group B) were performed. Adrenal autoantibodies were examined by an indirect immunofluorescence technique in group A, and by the assay measuring autoantibodies against steroid 21-hydroxylase in group B. Adrenal autoantibodies were revealed in 37% of patients examined by the immunofluorescence method and in 63% investigated by the modern technique. Tuberculosis was found in 52 patients in the group A and in two patients in the group B; metastatic infiltrations of the adrenals in CT were detected in 16 patients. Probable autoimmune Addison's disease was diagnosed in 125/180 patients (69%) in the group A and in 116/138 patients (84%) in the group B.

Bilateral, incidentally found adrenal tumours - results of observation of 1790 patients registered at a single endocrinological centre.

INTRODUCTION: During the last 22 years we registered 1790 patients with incidentally found adrenal tumours (AI, adrenal incidentalomas). In 351 of them, bilateral tumours were detected. The aim of our study was to analyze the character of bilateral tumours and summarize the methods of their management. MATERIAL AND METHODS: In the whole group of 1790 patients, there were 1311 women and 479 men, aged 11-87 years. The group of patients with bilateral adrenal tumours included 258 women and 93 men, 25-83 years old. Hormonal investigations and imaging examinations were performed to search for subclinical adrenal hyperfunction and to define the malignant potential of the tumours. RESULTS: Sixty-nine patients were treated by surgery for oncological or endocrinological purposes (mainly pre-Cushing's syndrome). Histological findings included malignant tumours: metastases - 9, adrenal cancer - 7, and lymphomas - 5; and non-malignant tumours: adenomas - 24, nodular hyperplasia - 14, myelolipomas - 4, and pheochromocytomas - 4. Subclinical Cushing's syndrome was relatively more frequent in nodular hyperplasia (40%) than in adenomas (30%). CONCLUSIONS: Indications for surgery were recommended in 20% of patients with bilateral AI, most frequently for adenomas, nodular hyperplasia, and oncological pathologies, with a good prognosis in the non-malignant group. (Pol J Endocrinol 2010; 61 (1): 69-73).

Nelson's syndrome: physiopathology, management and prognosis.

A classical description of a postadrenalectomy syndrome in Cushing's disease, described in 1958 by Don Nelson, included a deep skin hyperpigmentation, presence of a large pituitary tumor, high plasma adrenocorticotropic hormone levels and visual field deficits. The main pathophysiological mechanism of Nelson's syndrome development is a loss of feedback control of hypercortisolemia on corticotroph as a consequence of the removal of hyperactive adrenal glands. Modern techniques of imaging, computed tomography and MRI, made early detection of pituitary tumor at the stage of microadenoma possible. Determinations of plasma adrenocorticotropic hormone concentration during replacement therapy are the next essential diagnostic element. Absolute temporal scotomas in visual field examination are an early sign of Nelson's syndrome. Sufficient hydrocortisone therapy is very important to avoid hypocortisolemia, which stimulates corticotroph cells. Methods of treatment include neurosurgery, radiation therapy and pharmacotherapy. Prognosis in Nelson's syndrome depends on the stage of the disease; it may be poor in invasive pituitary tumors.

Pheochromocytoma crisis induced by glucocorticoids: a report of four cases and review of the literature.

CONTEXT: Pheochromocytoma crisis (PC) is a rare life-threatening endocrine emergency that may present spontaneously or can be unmasked by 'triggers', including certain medications that provoke the release of catecholamines by tumors. Several isolated cases of PC have been reported after administration of exogenous glucocorticoids; evidence that these drugs cause adverse events in patients with pheochromocytoma is mainly anecdotal. PATIENTS: We report four cases of PC most likely induced by glucocorticoids and review seven previous reports in the literature linking steroid administration to the development of PC. RESULTS: In four new cases reported here, glucocorticoid administration was associated with a fatal outcome in one case, a pheochromocytoma multisystem crisis in another, and serious hypertensive crises in two others. Two patients had incidental adrenal masses and were undergoing high-dose dexamethasone suppression tests (DST). CONCLUSIONS: Exogenous glucocorticoids may unpredictably trigger PC. Pheochromocytoma should be included in the differential diagnosis of any patient who develops a hypertensive crisis, cardiac failure, tachycardia, headache, and abdominal or chest pain after receiving exogenous glucocorticoids. Glucocorticoid induced PC is frequently associated with hemorrhagic pheochromocytoma. Although exogenous glucocorticoids cause serious complications unpredictably, they should be avoided or administered only if necessary and with caution in patients with known or suspected pheochromocytoma. During the investigation of incidental adrenal masses, pheochromocytoma should ideally be ruled out before administering glucocorticoids. However, no cases have been reported with 1 mg of dexamethasone when given as a DST in patients with pheochromocytoma; larger doses, as low as 2 mg of dexamethasone, may trigger a PC. A patient with pheochromocytoma presenting as an adrenal incidentaloma may also be at risk if exposed to glucocorticoids given as pre-treatment in case of allergy to contrast media.

Retroperitoneal hemorrhage from adrenocortical carcinoma as a poor prognostic factor.

In most patients, adrenocortical carcinoma is diagnosed at an advanced stage of the disease. A sudden retroperitoneal hemorrhage may sometimes be the first symptom of the adrenal cancer. We describe four patients with adrenocortical carcinoma diagnosed during a retroperitoneal hemorrhage. A clinical analysis suggests that such a complication is a poor prognostic factor.

1,111 patients with adrenal incidentalomas observed at a single endocrinological center: incidence of chromaffin tumors.

A majority of incidentally found adrenal tumors derive from the adrenal cortex. The aim of our study was evaluation of the incidence of chromaffin tumors in a group of 1,111 patients with adrenal incidentalomas. In this group there were 803 women and 308 men, aged 10-87 years. Clinical examination, imaging studies (ultrasound scans, CT, and MRI if necessary), and hormonal determinations (cortisol, ACTH and androgens in the blood, dexamethasone suppression test, urinary excretion of 17-OHCS, aldosterone and 17-KS, as well as PRA/aldosterone stimulation test and metanephrines in hypertensive patients and those with density in CT over 20 HU) were used. In 380 patients treated by surgery (mainly by laparoscopic approach), histological and immunocytochemical examinations were performed. Clinical examination revealed hypertension in 25% of the patients under study. Chromaffin tumors were detected in 43 patients, 33 women, and 10 men aged 20-75 years: pheochromocytoma in 36 (malignant in 3); chromaffin cells hyperplasia in 2; paraganglioma in 3; ganglioneuroblastoma in 1; ganglioneuroma in 1; and schwannoma in 2. The tumors' diameter ranged between 1.1 and 20.0 cm, density=25 Hounsfield units (HU) or more before contrast medium injection. Hypertension was present in 53% of these patients. The urinary metanephrines excretion was elevated in 31 of 38 patients, in whom the determinations were done. Chromaffin tumors were detected in 4% (pheochromocytomas in 3%) of 1,111 patients with adrenal incidentalomas. Malignancy was present in 9% of 43 patients with chromaffin tumors. High density in CT was a very important diagnostic finding in the incidentally found medullary tumors.

ACTH responses to somatostatin, valproic acid and dexamethasone in Nelson's syndrome.

OBJECTIVE: Pituitary tumours occurring in patients bilaterally adrenalectomized because of Cushing's disease (Nelson's syndrome) are frequently invasive and a complete their resection is not possible in most of them. Administration of the drugs decreasing ACTH secretion could be helpful in such unresectable tumours. We tried to evaluate the influence of somatostatin and valproic acid, compared to dexamethasone, in short-term studies, on plasma ACTH levels in Nelson's syndrome (NS). MATERIAL AND METHODS: Basal ACTH levels were determined within 18 h after last dose of hydrocortisone and next, 1 and 2 hours following oral administration of 20 mg of hydrocortisone. Somatostatin was injected s.c. in two patients with NS while sodium valproate and dexamethasone were administered orally for three days in three patients with NS (two with an invasive pituitary tumour and one with a localized, intrasellar adenoma). The blood for ACTH and cortisol determination was drawn before the tests (two hours after 20 mg of hydrocortisone ingestion) as well as 1 and 2 hours following somatostatin injection and after 3 days of valproic acid or dexamethasone administration. RESULTS: High plasma ACTH levels were found before the tests. Somatostatin lowered ACTH levels in both patients, more effectively in the patient with non-invasive pituitary adenoma. Valproic acid decreased moderately ACTH concentration in two patients, while following dexamethasone administration a fall in ACTH levels was observed in all three patients, the most evident in the patient with a non-invasive Nelson's adenoma. CONCLUSION: Somatostatin seemed to be more effective in its inhibitory action on ACTH secretion than valproic acid, thus its administration in invasive cases of NS could be tried as a supplementary method to neurosurgery. The response to dexamethasone administration indicates that a feed-back regulation, although impaired, exists in these cases.

Clinical role of determination of plasma mitotane and its metabolites levels in patients with adrenal cancer: results of a long-term follow-up.

Our study aimed at evaluation of the relations between the plasma levels of mitotane (o,p'-DDD) and its metabolites, o,p'-DDA and o,p'-DDE, and the efficacy of Mitotane therapy during a long-term follow-up. Eighteen patients, aged 11 to 70 years, were included to the study. Metastatic or regional stage was diagnosed in 15 patients, while localized disease in three patients. Mitotane has been administered in daily doses of 3.0 to 10.0 g in metastatic and regional stages, and 1.5 to 4.0 g in the localized disease, simultaneously with hydrocortisone, prednisolone and fludrocortisone. Mitotane and its metabolites were determined by a high-pressure liquid chromatographic method. The plasma o,p'-DDD level exceeding 44 _M/L, considered as curative one, was reached in nine cases. The o,p'-DDA/o,p'-DDD ratio rose significantly mainly in the first 1-3 months of therapy. The o,p'-DDE levels rose slowly, reaching higher values in long-term therapy, over 12 months of mitotane administration. In the group of patients with regional or metastatic stage, both the o,p'-DDE levels and the o,p'-DDE/o,p'-DDD ratios were higher in the survivors than in non-survivors. The results of our study suggest that the plasma concentrations of o,p'-DDE were more closely related to clinical improvement or remission than the o,p'-DDD levels.

Autoimmunity as the most frequent cause of idiopathic secondary adrenal insufficiency: report of 111 cases.

The origin of the isolated secondary adrenal insufficiency is unknown in most cases. An observation of a group of over 100 patients with secondary adrenal insufficiency and coexisting autoimmune abnormalities suggests that autoimmunity could be a frequent cause of idiopathic secondary failure, similarly as in Addison's disease. We studied 176 patients with idiopathic isolated secondary adrenal insufficiency. The methods included clinical examination and measurements of pituitary, adrenal, thyroid and gonadal hormones in all the cases. Since thyroid autoimmunity has been the most frequent finding in Addison's disease we have also chosen thyroid autoantibodies as markers of an autoimmune process in our material. Anti-peroxidase, anti-microsomal and anti-thyroglobulin autoantibodies were determined in 151 patients. In 111 out of 151 patients (73%) coexisting autoimmune diseases and/or presence of thyroid autoantibodies were detected. The most frequent autoimmune diseases associated with secondary adrenal insufficiency were primary hypothyroidism, hyperthyroidism (mainly in the past) and premature ovarian failure. Thyroid autoantibodies, especially antiperoxidase autoantibodies, were present in 106 patients. Thus, coexistence of isolated secondary adrenal insufficiency with some autoimmune disorders in 73% of the patients under study suggests that autoimmunity is the most frequent cause of the idiopathic form of this disease.