Adrenal morphology and associated comorbidities in congenital adrenal hyperplasia.

OBJECTIVE: Adrenonodular hyperplasia and tumour formation are potential long-term complications of congenital adrenal hyperplasia (CAH) with little known regarding the clinical implications. Our aim was to describe volumetric adrenal morphology and determine the association between radiological findings and comorbidities in adults with classic CAH. DESIGN: This was a cross-sectional study of 88 patients (mean age 29.2 ± 13 years, 47 females) with classic CAH seen in a tertiary referral centre. METHODS: CT imaging, performed at study entry or when reaching adulthood, was used to create 3-dimensional volumetric models. Clinical, genetic and hormonal evaluations were collected and correlated with adrenal morphology and tumour formation. RESULTS: Over one-third of the cohort was obese. 53% had elevated 17-OH-progesterone or androstenedione; and 60% had adrenal hyperplasia. Tumours included 11 myelolipomas, 8 benign adrenocortical adenomas, 1 pheochromocytoma and 50% of men had testicular adrenal rest tissue. CAH patients with adrenal hyperplasia had significantly higher number of comorbidities than those with morphologically normal adrenals (P = 0.03). Variables that positively correlated with adrenal volume included hypogonadal/oligomenorrhoeic status, hypertension, androstenedione, aldosterone, and triglyceride levels, and in women, low HDL and insulin resistance. Elevated aldosterone was observed in a subset of patients with simple virilizing CAH. CONCLUSIONS: Adrenocortical hyperplasia is associated with a number of comorbidities, especially hypogonadism. Aldosterone production associated with adrenal enlargement may play a role in the development of metabolic risk factors. Further studies are needed to assess the long-term impact of the excess adrenal steroid milieu associated with adrenal enlargement to develop improved management strategies for CAH.

Active Surveillance of Nonfatty Renal Masses in Patients With Lymphangioleiomyomatosis: Use of CT Features and Patterns of Growth to Differentiate Angiomyolipoma From Renal Cancer.

OBJECTIVE: The objective of this study was to report our experience with active surveillance of nonfatty renal masses in a large cohort of patients with lymphangioleiomyomatosis (LAM), correlate their CT features and patterns of growth with histopathology results, and provide guidelines for management. SUBJECTS AND METHODS: Yearly CT examinations were performed of 367 women (age range, 21-75 years; mean age, 47 years). For the 31 patients with 37 nonfatty renal masses that were biopsied, excised, or followed for ≥ 5 years, CT enhancement characteristics and patterns of growth were compared with the histopathology results. RESULTS: Four of 37 nonfatty renal masses were biopsied without follow-up CT examinations: Two were heterogeneous renal cell carcinomas (RCCs), one was a heterogeneous nonfatty angiomyolipoma (AML), and one was homogeneous nonfatty AML. In the remaining 33 nonfatty renal masses with multiple follow-up CT examinations, two growth patterns were identified. Four showed a continuous increase in size of > 0.5 cm/y in some years, and all four in this first group were heterogeneous and were biopsy-proven RCC. The second group was composed of the remaining 29 masses. These 29 masses showed yearly no change, increase, or decrease in diameter. Eight were heterogeneous, and 21 were homogeneous. Of the masses showing a yearly increase, the increase was < 0.5 cm/y in all except one. In the one exception, the increase followed a decrease. Nine of the 29 masses were biopsied, and all nine were nonfatty renal masses (five homogeneous, four heterogeneous). CONCLUSION: Our data provide further evidence in a large prospective study with longterm follow-up that active surveillance is an appropriate strategy in the management of nonfatty renal masses in patients with LAM. Our analysis of the growth patterns reveals duration of growth in addition to growth rate as criteria for biopsy or excision. Biopsy should be reserved for nonfatty renal masses that show sustained growth or growth > 0.5 cm/y during follow-up.

Imaging features of lymphangioleiomyomatosis: diagnostic pitfalls.

OBJECTIVE: The objective of this article is to illustrate CT findings that may be misinterpreted and lead to unnecessary biopsy or surgical procedures in patients with lymphangioleiomyomatosis. CONCLUSION: Sequelae of pleurodesis, acutely hemorrhagic renal angiomyolipomas, and lymphatic involvement with lymphangioleiomyomatosis including enlarged lymph nodes and lymphangioleiomyomas are common benign conditions seen in patients with lymphangioleiomyomatosis that may be misdiagnosed on CT for malignancy and may prompt unnecessary biopsy and surgery. Ruptured abdominal pelvic lymphangioleiomyomas may be mistaken for appendicitis and other acute abdominal pelvic events.

CT of sclerotic bone lesions: imaging features differentiating tuberous sclerosis complex with lymphangioleiomyomatosis from sporadic lymphangioleiomymatosis.

PURPOSE: To determine if sclerotic bone lesions evident at body computed tomography (CT) are of value as a diagnostic criterion of tuberous sclerosis complex (TSC) and in the differentiation of TSC with lymphangioleiomyomatosis (LAM) from sporadic LAM. MATERIALS AND METHODS: Informed consent was signed by all patients in this HIPAA-compliant study approved by the institutional review board. Retrospective analysis was performed of the body CT studies of 472 patients: 365 with sporadic LAM, 82 with TSC/LAM, and 25 with TSC. The images were reviewed by using a picture archiving and communication system workstation with bone settings (window width, 1500 HU; window level, 300 HU) and fit-to-screen option. CT image characteristics assessed included shape, size, and distribution of sclerotic bone lesions with subsequent calculation of differences in the frequency of these lesions. RESULTS: Most commonly the sclerotic bone lesions were round, measured 0.3 cm (range, 0.2-3.2), and were distributed throughout the spine. The frequencies differed among the three patient groups Four or more sclerotic bone lesions were detected in all 25 (100%) of those with TSC, with a sensitivity of .89 (72 of 82) and specificity of .97 (355 of 367) in the differentiation of sporadic LAM from TSC/LAM (P < .01). CONCLUSION: The number of sclerotic bone lesions at body CT is of potential value in the diagnosis of TSC and in the differentiation of patients with sporadic LAM from those with TSC/LAM. (c) RSNA, 2010.

Combination therapy in treatment of experimental pulmonary aspergillosis: in vitro and in vivo correlations of the concentration- and dose- dependent interactions between anidulafungin and voriconazole by Bliss independence drug interaction analysis.

We studied the antifungal activity of anidulafungin (AFG) in combination with voriconazole (VRC) against experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits and further explored the in vitro and in vivo correlations by using Bliss independence drug interaction analysis. Treatment groups consisted of those receiving AFG at 5 (AFG5 group) and 10 (AFG10 group) mg/kg of body weight/day, VRC at 10 mg/kg every 8 h (VRC group), AFG5 plus VRC (AFG5+VRC group), and AFG10 plus VRC (AFG10+VRC group) and untreated controls. Survival throughout the study was 60% for the AFG5+VRC group, 50% for the VRC group, 27% for the AFG10+VRC group, 22% for the AFG5 group, 18% for the AFG10 group, and 0% for control rabbits (P < 0.001). There was a significant reduction of organism-mediated pulmonary injury, measured by infarct scores, lung weights, residual fungal burdens, and galactomannan indexes, in AFG5+VRC-treated rabbits versus those treated with AFG5 and VRC alone (P < 0.05). In comparison, AFG10+VRC significantly lowered only infarct scores and lung weights in comparison to those of AFG10-treated animals (P < 0.05). AFG10+VRC showed no significant difference in other outcome variables. Significant Bliss synergy was found in vivo between AFG5 and VRC, with observed effects being 24 to 30% higher than expected levels if the drugs were acting independently. These synergistic interactions were also found between AFG and VRC in vitro. However, for AFG10+VRC, only independence and antagonism were observed among the outcome variables. We concluded that the combination of AFG with VRC in treatment of experimental IPA in persistently neutropenic rabbits was independent to synergistic at a dosage of 5 mg/kg/day but independent to antagonistic at 10 mg/kg/day, as assessed by Bliss independence analysis, suggesting that higher dosages of an echinocandin may be deleterious to the combination.

Diagnostic imaging of experimental invasive pulmonary aspergillosis.

Pulmonary infiltrates in neutropenic hosts with invasive aspergillosis are caused by organism-mediated tissue injury, vascular invasion, and hemorrhagic infarction. Ultrafast computed tomography (UFCT) scanning reproducibly measures these lesions in experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. The pulmonary lesion score from UFCT scanning is a useful outcome variable for measuring differences in efficacy of antifungal compounds alone and in combination, as well as the virulence of different strains and species of Aspergillus. Several studies demonstrate that the course of pulmonary lesions treated with amphotericin B, lipid formulations of amphotericin B, triazoles, echinocandins, and combination therapy measured by serial UFCT scans correlate with those measured by survival, histopathological resolution of lesions, microbiological clearance of Aspergillus fumigatus, and resolution of galactomannan index. We further developed a multidimensional volumetric imaging (MDVI) method for analysis of the volume of pulmonary infiltrates over time in response to antifungal therapy. Volumetric data by MDVI correlate with UFCT pulmonary lesion scores and validated biological endpoints. A recent pilot clinical study demonstrated the applicability of MDVI to human pulmonary fungal infections. MDVI also improves objectivity of radiological assessment of therapeutic response to antifungal therapy and merits more extensive evaluation in patients with invasive aspergillosis, as well as other fungal and bacterial pneumonias.

Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome.

RATIONALE: Pulmonary nontuberculous mycobacterial (PNTM) disease is increasing, but predisposing features have been elusive. OBJECTIVES: To prospectively determine the morphotype, immunophenotype, and cystic fibrosis transmembrane conductance regulator genotype in a large cohort with PNTM. METHODS: We prospectively enrolled 63 patients with PNTM infection, each of whom had computerized tomography, echocardiogram, pulmonary function, and flow cytometry of peripheral blood. In vitro cytokine production in response to mitogen, LPS, and cytokines was performed. Anthropometric measurements were compared with National Health and Nutrition Examination Survey (NHANES) age- and ethnicity-matched female control subjects extracted from the NHANES 2001-2002 dataset. MEASUREMENTS AND MAIN RESULTS: Patients were 59.9 (+/-9.8 yr [SD]) old, and 5.4 (+/-7.9 yr) from diagnosis to enrollment. Patients were 95% female, 91% white, and 68% lifetime nonsmokers. A total of 46 were infected with Mycobacterium avium complex, M. xenopi, or M. kansasii; 17 were infected with rapidly growing mycobacteria. Female patients were significantly taller (164.7 vs. 161.0 cm; P < 0.001) and thinner (body mass index, 21.1 vs. 28.2; P < 0.001) than matched NHANES control subjects, and thinner (body mass index, 21.1 vs. 26.8; P = 0.002) than patients with disseminated nontuberculous mycobacterial infection. A total of 51% of patients had scoliosis, 11% pectus excavatum, and 9% mitral valve prolapse, all significantly more than reference populations. Stimulated cytokine production was similar to that of healthy control subjects, including the IFN-gamma/IL-12 pathway. CD4(+), CD8(+), B, and natural killer cell numbers were normal. A total of 36% of patients had mutations in the cystic fibrosis transmembrane conductance regulator gene. CONCLUSIONS: Patients with PNTM infection are taller and leaner than control subjects, with high rates of scoliosis, pectus excavatum, mitral valve prolapse, and cystic fibrosis transmembrane conductance regulator mutations, but without recognized immune defects.

Progressive preclinical interstitial lung disease in rheumatoid arthritis.

BACKGROUND: Early detection and treatment for interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) may ameliorate disease progression. The objective of this study was to identify asymptomatic lung disease and potential therapeutic targets in patients having RA and preclinical ILD (RA-ILD). METHODS: Sixty-four adults with RA and 10 adults with RA and pulmonary fibrosis (RAPF) were referred to the National Institutes of Health, Bethesda, Maryland, and underwent high-resolution computed tomography (HRCT) and pulmonary physiology testing. Proteins capable of modulating fibrosis were quantified in alveolar fluid. RESULTS: Twenty-one of 64 patients (33%) having RA without dyspnea or cough had preclinical ILD identified by HRCT. Compared with patients without lung disease, patients with RA-ILD had statistically significantly longer histories of cigarette smoking (P< .001), increased frequencies of crackles (P= .02), higher alveolar-arterial oxygen gradients (P= .004), and higher HRCT scores (P< .001). The HRCT abnormalities progressed in 12 of 21 patients (57%) with RA-ILD. The alveolar concentrations of platelet-derived growth factor-AB and platelet-derived growth factor-BB were statistically significantly higher in patients having RA-ILD (mean [SE], 497.3 [78.6] and 1473 [264] pg/mL, respectively) than in patients having RA without ILD (mean [SE], 24.9 [42.4] and 792.7 [195.0] pg/mL, respectively) (P< .001 and P=.047, respectively). The concentrations of interferon gamma and transforming growth factor beta(2) were statistically significantly lower in patients having RAPF (mean [SE], 5.59 [1.11] pg/mL and 0.94 [0.46] ng/mL, respectively) than in patients having RA without ILD (mean [SE], 14.1 [1.9] pg/mL and 2.30 [0.39] ng/mL, respectively) (P=.001 and P=.006, respectively) or with preclinical ILD (mean [SD], 11.4 [2.6] pg/mL and 3.63 [0.66] ng/mL, respectively) (P=.04 and P=.007, respectively). Compared with patients having stable RA-ILD, patients having progressive RA-ILD had statistically significantly higher frequencies of treatment using methotrexate and higher alveolar concentrations of interferon gamma and transforming growth factor beta(1) (P=.046, P=.04, and P=.04, respectively). CONCLUSIONS: Asymptomatic preclinical ILD, which is detectable by HRCT, may be prevalent and progressive among patients having RA. Cigarette smoking seems to be associated with preclinical ILD in patients having RA, and treatment using methotrexate may be a risk factor for progression of preclinical ILD. Quantification of alveolar proteins indicates that potential pathogenic mechanisms seem to differ in patients having RA-ILD and symptomatic RAPF.

18F-FDG PET Imaging Features of Patients With Autoimmune Lymphoproliferative Syndrome.

INTRODUCTION: Autoimmune lymphoproliferative syndrome (ALPS) is a rare immune dysregulatory condition, usually presenting in childhood with massive lymphadenopathy, splenomegaly, and an increased incidence of lymphoma. Methods to differentiate between benign ALPS adenopathy and lymphoma are needed. To this end, we evaluated the usefulness of FDG PET. METHODS: We prospectively evaluated 76 ALPS/ALPS-like patients including FS-7-associated surface antigen (FAS) germline mutation with (n = 4) and without lymphoma (n = 50), FAS-somatic (n = 6), ALPS-unknown (n = 6), and others (n = 10) who underwent FDG PET. Uptakes in 14 nodal sites, liver, and spleen were determined. RESULTS: In 76 ALPS patients, FDG PET showed uptake in multiple nodal sites in all but 1 patient. The highest SUVmax values in FAS mutation without lymphoma, FAS mutation with lymphoma, FAS somatic, ALPS-unknown, and other genetic mutations were a median (range) 9.2 (4.3-25), 16.2 (10.7-37.2), 7.6 (4.6-18.1), 11.5 (4.8-17.2), and 5.5 (0-15.3), respectively. Differences between uptake in the FAS group with and without lymphoma were statistically significant, but overlapped, making discrimination between individuals with/without lymphoma impossible. The spleen:liver uptake ratio was greater than 1 in 82% of patients. CONCLUSIONS: While statistically significant differences were observed in FAS mutation ALPS with and without lymphoma, the significant overlap in FDG uptake and visual appearance in many patients prevents discrimination between patients with and without lymphoma. Similar patterns of FDG biodistribution were noted between the various ALPS subgroups.

Use of CT Imaging to Quantify Progression and Response to Treatment in Lymphangioleiomyomatosis.

BACKGROUND: In lymphangioleiomyomatosis (LAM), infiltration of the lungs with smooth muscle-like LAM cells results in cystic destruction and decline in lung function, effects stabilized by sirolimus therapy. LAM lung disease is followed, in part, by high-resolution CT scans. To obtain further information from these scans, we quantified changes in lung parenchyma by analyzing image "texture." METHODS: Twenty-six texture properties were quantified by analyzing the distribution and intensity of pixels with a computer-aided system. Both cross-sectional and longitudinal studies were performed to examine the relationships between texture properties, cyst score (percentage of lung occupied by cysts), FEV1, and diffusion capacity for carbon monoxide (Dlco), and to determine the effect of sirolimus treatment. RESULTS: In the cross-sectional study, 18 texture properties showed significant positive correlations with cyst score. Cyst score and 13 of the 18 texture properties showed significant differences in rates of change after sirolimus treatment; 11 also significantly predicted FEV1 and Dlco. CONCLUSIONS: Increased cyst score was associated with increased texture degradation near cysts. Sirolimus treatment improved lung texture surrounding cysts and stabilized cyst score. Eleven texture properties were associated with FEV1, Dlco, cyst score, and response to sirolimus. Texture analysis may be valuable in evaluating LAM severity and treatment response.

The NHLBI LAM Registry: Prognostic Physiologic and Radiologic Biomarkers Emerge From a 15-Year Prospective Longitudinal Analysis.

BACKGROUND: The natural history of lymphangioleiomyomatosis (LAM) is mainly derived from retrospective cohort analyses, and it remains incompletely understood. A National Institutes of Health LAM Registry was established to define the natural history and identify prognostic biomarkers that can help guide management and decision-making in patients with LAM. METHODS: A linear mixed effects model was used to compute the rate of decline of FEV1 and to identify variables affecting FEV1 decline among 217 registry patients who enrolled from 1998 to 2001. Prognostic variables associated with progression to death/lung transplantation were identified by using a Cox proportional hazards model. RESULTS: Mean annual decline of FEV1 was 89 ± 53 mL/year and remained remarkably constant regardless of baseline lung function. FEV1 decline was more rapid in those with greater cyst profusion on CT scanning (P = .02) and in premenopausal subjects (118 mL/year) compared with postmenopausal subjects (74 mL/year) (P = .003). There were 26 deaths and 43 lung transplantations during the evaluation period. The estimated 5-, 10-, 15-, and 20-year transplant-free survival rates were 94%, 85%, 75%, and 64%, respectively. Postmenopausal status (hazard ratio, 0.30; P = .0002) and higher baseline FEV1 (hazard ratio, 0.97; P = .008) or diffusion capacity of lung for carbon monoxide (hazard ratio, 0.97; P = .001) were independently associated with a lower risk of progression to death or lung transplantation. CONCLUSIONS: The median transplant-free survival in patients with LAM is > 20 years. Menopausal status, as well as structural and physiologic markers of disease severity, significantly affect the rate of decline of FEV1 and progression to death or lung transplantation in LAM.

Metabolic syndrome traits in long-term survivors of pediatric sarcoma.

PURPOSE: The metabolic syndrome (MS), a cluster of central obesity, dyslipidemia, hyperglycemia, and hypertension, conveys an increased risk of type 2 diabetes and cardiovascular disease. This cross-sectional study investigated the prevalence of metabolic syndrome traits (MST) in long-term survivors of pediatric sarcoma (SARC) who received multi-modality therapy (MMT). METHODS: Thirty-two SARC survivors (predominantly Ewings; median age 36.5; median age at MMT 15) underwent body composition, activity, and psychosocial analysis. Serum endocrine and inflammatory parameters and urine beta(2)-microglobulin (B2M) were evaluated. The prevalence of MST was compared to age- and gender-matched U.S. population data. RESULTS: SARC survivors were more likely to have two or more MST (OR 2.38 95% CI: [1.14, 5.04]). Analysis of individual MST demonstrated higher prevalence of hypertension (OR 2.61 95% CI: [1.20, 5.59]), hypertriglyceridemia (OR 3.63 95% CI: [1.75, 7.60]), and male visceral abdominal obesity (20-39 years old OR 4.63 95% CI: [0.91, 21.63], 40-59 years old OR infinity). Survivors 18-39 years old had a higher prevalence of the MS (OR 4.29 95% CI: [1.50, 11.21]), defined as three or more MST. Plasminogen activator inhibitory activity (P = 0.016) and B2M (P = 0.027) increased with increasing numbers of MST. In males, total testosterone declined (P = 0.0027) as the number of MST increased. Average (P = 0.014) and maximum (P = 0.021) activity levels decreased as the number of MST increased. CONCLUSION: After a median follow up of 17 years, adult SARC survivors of MMT had an increased prevalence of MST, especially those less than 40 years old. The development of MST in this population was associated with decreased testosterone and activity levels.

The Comparative Associations of Ultrasound and Computed Tomography Estimates of Muscle Quality with Physical Performance and Metabolic Parameters in Older Men.

Estimates of muscle tissue composition may have greater prognostic value than lean body mass levels regarding health-related outcomes. Ultrasound provides a relatively low cost, safe, and accessible mode of imaging to assess muscle morphology. The purpose of this study was to determine the construct validity of muscle echogenicity as a surrogate measure of muscle quality in a sample of older, predominantly African American (AA) participants. We examined the association of rectus femoris echogenicity with mid-thigh computed tomography (CT) scan estimates of intra- and intermuscular adipose tissue (IMAT), basic metabolic parameters via blood sample analysis, muscle strength, and mobility status. This observational study was conducted at a federal medical center and included 30 community-dwelling men (age, 62.5 ± 9.2; AA, n = 24; Caucasian, n = 6). IMAT estimates were significantly associated with echogenicity (r = 0.73, p < 0.001). Echogenicity and IMAT exhibited similar associations with the two-hour postprandial glucose values and high-density lipoproteins values (p < 0.04), as well as grip and isokinetic (180°/s) knee extension strength adjusted for body size (p < 0.03). The significant relationship between ultrasound and CT muscle composition estimates, and their comparative association with key health-related outcomes, suggests that echogenicity should be further considered as a surrogate measure of muscle quality.

Immunologic, virologic, and neuropsychologic responses in human immunodeficiency virus-infected children receiving their first highly active antiretroviral therapy regimen.

Our objective was to measure the early dynamics, evolution, and durability over 96 wk of immunologic responses in children receiving their first highly active antiretroviral therapy (HAART) regimen. The study was designed as a prospective, single-arm study. Twelve human immunodeficiency virus (HIV)-infected children (median age, 11.8 yr) were enrolled. All subjects received stavudine, nevirapine, and ritonavir. Serial measurements included HIV viral load, lymphocyte subsets, thymic volume by computed tomography (CT), neurocognitive testing, and brain CT. Baseline median CD4(+) T cell count was 589 cells/mm(3) , viral load was 3.9 log(10) HIV RNA copies/mL, and thymic volume was 16.3 cm(3) . Ten children had an undetectable viral load at week 48. Eight maintained an undetectable viral load at 96 wk. The median increase in absolute CD4(+) T cell count was 225 cells/mm(3) by week 48, and 307 cells/mm(3) by week 96. The median increase in naive (CD45RA(+) CD62L(+) ) CD4(+) T cells was 133 cells/mm(3) by week 48, and 147 cells/mm(3) by week 96. The median number of naive CD8(+) T cells increased from 205 to 284 cells/mm(3) by week 24; this increase was sustained to week 96. The number of B cells increased and was associated with a decrease in immunoglobulin levels. The number of natural killer cells was stable. There were no significant changes in thymic volume. Most children exhibited stable cognitive function over the course of the study. We conclude that, in this cohort of relatively immunocompetent HIV-infected children, an initial HAART regimen was associated with rapid and sustained increases in total CD4(+) T cells, in naive CD4(+) and CD8(+) T cells, and in B cells through 96 wk.

11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency.

Context: Patients with 21-hydroxylase deficiency (21OHD) have long-term complications, resulting from poor disease control and/or glucocorticoid overtreatment. Lack of optimal biomarkers has made it challenging to tailor therapy and predict long-term outcomes. Objective: To identify biomarkers of disease control and long-term complications in 21OHD. Setting and Participants: Cross-sectional study of 114 patients (70 males), ages 2 to 67 years (median, 15 years), seen in a tertiary referral center. Methods: We correlated a mass-spectrometry panel of 23 steroids, obtained before first morning medication, with bone age advancement (children), adrenal volume (adults), testicular adrenal rest tumors (TART), hirsutism, menstrual disorders, and pituitary hormones. Results: Total adrenal volume correlated positively with 18 steroids, most prominently 21-deoxycortisol and four 11-oxygenated-C19 (11oxC19) steroids: 11ß-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11ketoA4), 11ß-hydroxytestosterone (11OHT), and 11-ketotestosterone (11ketoT) (r ≈ 0.7, P < 0.0001). Nine steroids were significantly higher (P ≤ 0.01) in males with TART compared with those without TART, including 11OHA4 (6.8-fold), 11OHT (4.9-fold), 11ketoT (3.6-fold), 11ketoA4 (3.3-fold), and pregnenolone sulfate (PregS; 4.8-fold). PregS (28.5-fold) and 17-hydroxypregnenolone sulfate (19-fold) levels were higher (P < 0.01) in postpubertal females with menstrual disorders. In males, testosterone levels correlated positively with all 11oxC19 steroids in Tanner stages 1 and 2 (r ≈ 0.7; P < 0.001) but negatively in Tanner stage 5 (r = -0.3 and P < 0.05 for 11ketoA4 and 11ketoT). In females, testosterone level correlated positively with all four 11oxC19 steroids across all Tanner stages (r ≈ 0.8; P < 0.0001). Conclusion: 11oxC19 steroids and PregS might serve as clinically useful biomarkers of disease control and long-term complications in 21OHD.

NIH conference. Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia describes a group of inherited autosomal recessive disorders characterized by an enzymatic defect in cortisol biosynthesis, compensatory increases in corticotropin secretion, and adrenocortical hyperplasia. 21-Hydroxylase deficiency is responsible for more than 95% of cases and is one of the most common known autosomal recessive disorders. The classic or severe type presents in the newborn period or early childhood with virilization and adrenal insufficiency, with or without salt loss; the mild or nonclassic form presents in late childhood or early adulthood with mild hyperandrogenism and is an important cause of masculinization and infertility in women. This wide range of phenotypic expression is mostly explained by genetic variation, although genotype-phenotype discrepancies have been described. Reproductive, metabolic, and other comorbid conditions, including risk for tumors, are currently under investigation in both forms of the disease. A high proportion of patients with adrenal incidentalomas may be homozygous or heterozygous for 21-hydroxylase deficiency. Women with congenital adrenal hyperplasia often develop the polycystic ovary syndrome. Ectopic adrenal rest tissue is often found in the testes of men with congenital adrenal hyperplasia; characteristic clinical and radiologic findings help differentiate this tissue from other tumors. Levels of corticotropin-releasing hormone are elevated in patients with depression and anxiety and are expected to be elevated in patients with congenital adrenal hyperplasia; it is unknown whether patients with 21-hydroxylase deficiency have an increased incidence of these psychiatric disorders. Abnormalities in both the structure and function of the adrenal medulla have been shown in patients with classic congenital adrenal hyperplasia, and the degree of adrenomedullary impairment may be a biomarker of disease severity. The 21-hydroxylase-deficient mouse has provided a useful model with which to examine disease mechanisms and test new therapeutic interventions in classic disease, including gene therapy. Treatment of this condition is intended to reduce excessive corticotropin secretion and replace both glucocorticoids and mineralocorticoids. However, clinical management is often complicated by inadequately treated hyperandrogenism, iatrogenic hypercortisolism, or both. New treatment approaches currently under investigation include combination therapy to block androgen action and inhibit estrogen production, and bilateral adrenalectomy in the most severely affected patients. Other approaches, which are in a preclinical stage of investigation, include treatment with a corticotropin-releasing hormone antagonist and gene therapy.

Use of PET/CT with cosyntropin stimulation to identify and localize adrenal rest tissue following adrenalectomy in a woman with congenital adrenal hyperplasia.

CONTEXT: Adrenalectomy is an experimental treatment option for select patients with congenital adrenal hyperplasia who have failed medical therapy. After adrenalectomy, adrenal rest tissue can remain in extraadrenal locations, cause recurrent hyperandrogenism, and be difficult to localize. OBJECTIVE: The aim of the study was to investigate the usefulness of positron emission tomography/computerized tomography (PET/CT) in identifying adrenal rest tissue. SUBJECT: A female with salt-wasting 21-hydroxylase deficiency who had bilateral adrenalectomy at age 17 yr presented with hyperandrogenism at age 32 yr. Pelvic magnetic resonance imaging and ultrasound imaging were nondiagnostic for the source of androgen production. METHODS AND RESULTS: A baseline F-18 labeled fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT scan showed no active uptake; however, a second scan preceded by a 250-µg cosyntropin injection identified three areas of active uptake near both ovaries. Subsequent ovarian venous sampling showed elevations in 17-hydroxyprogesterone, androstenedione, and 21-deoxycortisol in both ovarian veins compared to a peripheral vein at baseline and more so after cosyntropin administration. At laparoscopy, three well-circumscribed nodules (2.4 × 0.9 × 1.3 cm, 1.2 × 1.5 × 1.5 cm, and 2 × 1.5 × 1 cm) lying lateral to the fallopian tubes adjacent to the broad ligaments were removed. The paraovarian nodules and previously removed adrenal glands had similar histology and immunohistochemistry. Postoperatively, androgen concentrations were undetectable, with no response to cosyntropin stimulation. CONCLUSIONS: Patients with CAH after an adrenalectomy may experience recurrent hyperandrogenism due to adrenal rest tissue. 18F-FDG PET/CT with cosyntropin stimulation accurately identified adrenal rest tissue not visualized with conventional imaging, allowing for successful surgical resection.

Automated quantification of high-resolution CT scan findings in individuals at risk for pulmonary fibrosis.

BACKGROUND: Automated methods to quantify interstitial lung disease (ILD) on high-resolution CT (HRCT) scans in people at risk for pulmonary fibrosis have not been developed and validated. METHODS: Cohorts with familial pulmonary fibrosis (n = 126) or rheumatoid arthritis with and without ILD (n = 86) were used to develop and validate a computer program capable of quantifying ILD on HRCT scans, which imaged the lungs semicontinuously from the apices to the lung bases during end-inspiration in the prone position. This method uses segmentation, texture analysis, training, classification, and grading to score ILD. RESULTS: Quantification of HRCT scan findings of ILD using an automated computer program correlated with radiologist readings and detected disease of varying severity in a derivation cohort with familial pulmonary fibrosis or their first-degree relatives. This algorithm was validated in an independent cohort of subjects with rheumatoid arthritis with and without ILD. Automated classification of HRCT scans as normal or ILD was significant in the derivation and validation cohorts (P < .001 and P < .001, respectively). Areas under receiver operating characteristic curves performed independently for each group were 0.888 for the derivation cohort and 0.885 for the validation cohort. Pulmonary function test results, including FVC and diffusion capacity, correlated with computer-generated HRCT scan scores for ILD (r = -0.483 and r = -0.532, respectively). CONCLUSIONS: Automated computer scoring of HRCT scans can objectively identify ILD and potentially quantify radiographic severity of lung disease in populations at risk for pulmonary fibrosis.

Prevalence of uterine leiomyomas in lymphangioleiomyomatosis.

OBJECTIVE: To determine the frequency of uterine leiomyomas and hysterectomy in patients with lymphangioleiomyomatosis (LAM), a disease characterized by proliferation of abnormal-appearing smooth muscle-like cells. DESIGN: Retrospective study. SETTING: Natural history study at the National Institutes of Health. PATIENT(S): 456 patients with sporadic LAM and LAM associated with tuberous sclerosis complex (LAM/TSC). INTERVENTION(S): Review of records and pelvic computed axial tomography scans. MAIN OUTCOME MEASURE(S): Prevalence of uterine leiomyomas and hysterectomy. RESULT(S): A total of 174 women had uterine leiomyomas (38%). One hundred eighteen were diagnosed by computed tomographic scan and 56 were diagnosed by hysterectomy. Among 323 patients who did not have hysterectomy, 105 of 270 patients (39%) with sporadic LAM and 13 of 53 (25%) with LAM/TSC had uterine leiomyomas. Hysterectomy was performed in 108 of 378 subjects with sporadic LAM and 25 of 78 with LAM/TSC. Fifty-six patients were found to have uterine fibroids on hysterectomy. The most common indications for hysterectomy were uterine leiomyoma, LAM, and endometriosis. CONCLUSION(S): Uterine leiomyomas are not more common in LAM than in the general population. However, in LAM, the frequency of hysterectomy is higher because of it having been recommended for treatment of LAM.