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Approach to the patient: Diagnosis of Cushing's syndrome

Savas, Mesut; Mehta, Sonal; Agrawal, Nidhi; van Rossum, Elisabeth F C; Feelders, Richard A
Cushing's syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing's syndrome) or autonomous cortisol overproduction, whether or not adrenocorticotropin hormone (ACTH) dependent (endogenous Cushing's syndrome). An early diagnosis of Cushing's syndrome is warranted, however, in clinical practice very challenging partly due to resemblance with other common conditions (i.e. pseudo-Cushing's syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing's syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing's syndrome. Interpretation of results can be difficult due to individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing's syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80-85%) or ACTH-independent (15-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of 'Approach to the patient' the diagnostic workup of Cushing's syndrome is discussed with answering the questions when to screen, how to screen and how to differentiate the different causes. In this respect, latest developments in biochemical and imaging techniques are discussed as well.
PMID: 36036941
ISSN: 1945-7197
CID: 5308662

Reduction of nucleolar NOC1 accumulates pre-rRNAs and induces Xrp1 affecting growth and resulting in cell competition

Destefanis, Francesca; Manara, Valeria; Santarelli, Stefania; Zola, Sheri; Brambilla, Marco; Viola, Giacomo; Maragno, Paola; Signoria, Ilaria; Viero, Gabriella; Pasini, Maria Enrica; Penzo, Marianna; Bellosta, Paola
NOC1 is a nucleolar protein necessary in yeast for both transport and maturation of ribosomal subunits. Here, we show that Drosophila NOC1 is necessary for rRNAs maturation and for a correct animal development. Its ubiquitous downregulation results in a dramatic decrease in polysome level and of protein synthesis. NOC1 expression in multiple organs, such as the prothoracic gland and the fat body, is necessary for their proper functioning. Reduction of NOC1 in epithelial cells from the imaginal discs results in clones that die by apoptosis, an event that is partially rescued in a M/+ background, suggesting that reduction of NOC1 induces the cells to become less fitted and to acquire a loser state. NOC1 downregulation activates the pro-apoptotic eiger-JNK pathway and leads to an increase of Xrp1 that results in Dilp8 upregulation. These data underline NOC1 as an essential gene in ribosome biogenesis and highlight its novel functions in the control of growth and cell competition.
PMID: 36314272
ISSN: 1477-9137
CID: 5358462

Bone mineral density, osteopenia and osteoporosis among US adults with cancer

Huang, J-F; Tan, Q-C; Bai, H; Wang, J; Bergman, M; Wu, Z
BACKGROUND:Bone mineral deficits are one of the most common complications in cancer survivors. However, there are no studies evaluating bone mineral density (BMD) and the prevalence of osteopenia and osteoporosis among patients with different types of cancers. AIM/OBJECTIVE:The objective was to assess BMD and evaluate the prevalence of osteopenia and osteoporosis among US adults with cancer. DESIGN/METHODS:A cross-section propensity score matching study. METHODS:We extracted data from National Health and Nutrition Examination Survey database from 2005 to 2018. We compared BMD in participants with and without cancer which was further analyzed according to cancer type. We conducted logistic regression to evaluate adjusted odds ratios of osteopenia and osteoporosis and determine risk factors for their development. RESULTS:We found that BMD was significantly higher in participants without cancer than cancer patients. Furthermore, the median BMD of patients with breast cancer or skin cancer (including melanoma) was significantly lower than participants without cancer. People with breast, lung, genitourinary and skin cancers were more likely to incur osteopenia/osteoporosis than those without cancer. CONCLUSIONS:BMD differs depending upon type in survivors. Individuals with a history of cancer have a poor understanding of osteoporosis and its risk factors. Understanding risk factors in patients with cancers identified in our study may be helpful for preventing osteoporosis and fractures and the development of screening guidelines.
PMID: 35092293
ISSN: 1460-2393
CID: 5155012

Association between depression, happiness, and sleep duration: data from the UAE healthy future pilot study

Al Balushi, Mitha; Al Balushi, Sara; Javaid, Syed; Leinberger-Jabari, Andrea; Al-Maskari, Fatma; Al-Houqani, Mohammed; Al Dhaheri, Ayesha; Al Nuaimi, Abdullah; Al Junaibi, Abdullah; Oumeziane, Naima; Kazim, Marina; Al Hamiz, Aisha; Haji, Muna; Al Hosani, Ayesha; Abdel Wareth, Leila; AlMahmeed, Wael; Alsafar, Habiba; AlAnouti, Fatme; Al Zaabi, Eiman; K Inman, Claire; Shahawy, Omar El; Weitzman, Michael; Schmidt, Ann Marie; Sherman, Scott; Abdulle, Abdishakur; Ahmad, Amar; Ali, Raghib
BACKGROUND:The United Arab Emirates Healthy Future Study (UAEHFS) is one of the first large prospective cohort studies and one of the few studies in the region which examines causes and risk factors for chronic diseases among the nationals of the United Arab Emirates (UAE). The aim of this study is to investigate the eight-item Patient Health Questionnaire (PHQ-8) as a screening instrument for depression among the UAEHFS pilot participants. METHODS:The UAEHFS pilot data were analyzed to examine the relationship between the PHQ-8 and possible confounding factors, such as self-reported happiness, and self-reported sleep duration (hours) after adjusting for age, body mass index (BMI), and gender. RESULTS:Out of 517 participants who met the inclusion criteria, 487 (94.2%) participants filled out the questionnaire and were included in the statistical analysis using 100 multiple imputations. 231 (44.7%) were included in the primary statistical analysis after omitting the missing values. Participants' median age was 32.0 years (Interquartile Range: 24.0, 39.0). In total, 22 (9.5%) of the participant reported depression. Females have shown significantly higher odds of reporting depression than males with an odds ratio = 3.2 (95% CI:1.17, 8.88), and there were approximately 5-fold higher odds of reporting depression for unhappy than for happy individuals. For one interquartile-range increase in age and BMI, the odds ratio of reporting depression was 0.34 (95% CI: 0.1, 1.0) and 1.8 (95% CI: 0.97, 3.32) respectively. CONCLUSION/CONCLUSIONS:Females are more likely to report depression compared to males. Increasing age may decrease the risk of reporting depression. Unhappy individuals have approximately 5-fold higher odds of reporting depression compared to happy individuals. A higher BMI was associated with a higher risk of reporting depression. In a sensitivity analysis, individuals who reported less than 6 h of sleep per 24 h were more likely to report depression than those who reported 7 h of sleep.
PMID: 36271400
ISSN: 2050-7283
CID: 5352582

Case Report: Giant Thyroid Angiolipoma-Challenging Clinical Diagnosis and Novel Genetic Alterations

Wilkins, Reid; Zan, Elcin; Leonardi, Olga; Patel, Kepal N; Jacobson, Adam S; Jour, George; Liu, Cheng Z; Zhou, Fang
BACKGROUND:A 64-year-old man presented with a 7.8 cm lipomatous thyroid mass discovered on magnetic resonance imaging. METHODS:After two non-diagnostic fine needle aspirations (FNAs) were performed, computed tomography (CT) revealed features concerning for malignancy including central necrosis and infiltrative borders. A third FNA was still non-diagnostic. Total thyroidectomy was performed. RESULTS:Upon pathologic examination, the final diagnosis was primary thyroid angiolipoma. The lesion contained central fat necrosis with ischemic features, attributable to the FNAs. CONCLUSION/CONCLUSIONS:Ours is the third published case report of this rare entity. To date, no lipomatous thyroid tumor has undergone extensive genomic testing. Next-generation sequencing of our case revealed multiple genetic alterations, supporting the concept of angiolipomas being true neoplasms. Whereas the two previously reported cases in the literature were radiographically much smaller and appeared indolent, the large tumor in our case exhibited radiographic features concerning for liposarcoma, which belied the benign final pathologic diagnosis. Our case demonstrates that conservative surgical management (partial thyroidectomy) may be considered for lipomatous thyroid tumors, with further interventions to be determined only after final pathologic diagnosis.
PMID: 36255668
ISSN: 1936-0568
CID: 5360392

Implementation of a formal sleep center-based screening protocol for primary aldosteronism in patients with obstructive sleep apnea

Wright, Kyla; Mahmoudi, Mandana; Agrawal, Nidhi; Simpson, Hope; Lui, Michael S; Pachter, H Leon; Patel, Kepal; Prescott, Jason; Suh, Insoo
BACKGROUND:There is a bidirectional association between primary aldosteronism and obstructive sleep apnea, with evidence suggesting that the treatment of primary aldosteronism can reduce obstructive sleep apnea severity. Current guidelines recommend screening for primary aldosteronism in patients with comorbid hypertension and obstructive sleep apnea, identifying potential candidates for treatment. However, emerging data suggest current screening practices are unsatisfactory. Moreover, data regarding the true incidence of primary aldosteronism among this population are limited. This study aimed to assess the primary aldosteronism screening rate among patients with obstructive sleep apnea and hypertension at our institution and estimate the prevalence of primary aldosteronism among this population. METHODS:Sleep studies conducted at our institution between January and September 2021 were retrospectively reviewed. Adult patients with a sleep study diagnostic of obstructive sleep apnea (respiratory disturbance index ≥5) and a diagnosis of hypertension were included. Patient medical records were reviewed and laboratory data of those with biochemical screening for primary aldosteronism were assessed by an experienced endocrinologist. Screening rates were compared before and after initiation of a screening protocol in accordance with the 2016 Endocrine Society guidelines. RESULTS:A total of 1,005 patients undergoing sleep studies were reviewed; 354 patients had comorbid obstructive sleep apnea and hypertension. Patients were predominantly male (67%), with a mean age of 58 years (standard deviation = 12.9) and mean body mass index of 34 (standard deviation = 8.1). The screening rate for primary aldosteronism among included patients was 19% (n = 67). The screening rate was significantly higher after initiation of a dedicated primary aldosteronism screening protocol (23% vs 12% prior; P = .01). Fourteen screens (21%) were positive for primary aldosteronism, whereas 45 (67%) were negative and 8 (12%) were indeterminate. Four had prior abdominal cross-sectional imaging, with 3 revealing an adrenal adenoma. Compared with patients without primary aldosteronism, patients with positive primary aldosteronism screens were more likely to have a history of hypokalemia (36% vs 4.4%; P = .002). The frequency of hyperlipidemia, diabetes mellitus, and left ventricular hypertrophy did not differ between patients with positive versus negative screens. CONCLUSION/CONCLUSIONS:Current screening practices for primary aldosteronism among patients with comorbid obstructive sleep apnea and hypertension are suboptimal. Patients evaluated at sleep centers may represent an optimal population for screening, as the prevalence of primary aldosteronism among this cohort appears high.
PMID: 36198493
ISSN: 1532-7361
CID: 5361722

1-h post-load plasma glucose for detecting early stages of prediabetes

Buysschaert, M; Bergman, M; Valensi, P
Prediabetes is a very prevalent condition associated with an increased risk of developing diabetes and/or other chronic complications, in particular cardiovascular disorders. Early detection is therefore mandatory since therapeutic interventions may limit the development of these complications. Diagnosis of prediabetes is currently based on glycemic criteria (fasting plasma glucose (PG), and/or glycemia at 120 min during a 75 g oral glucose tolerance test (OGTT) and/or glycated hemoglobin (HbA1c). Accumulating longitudinal evidence suggests that a 1-hour PG ≥155 mg/dl (8.6 mmol/l) during the OGTT is an earlier marker of prediabetes than fasting PG, 2-h post-load PG, or HbA1c. There is substantial evidence demonstrating that the 1-h post-load PG is a more sensitive predictor of type 2 diabetes, cardiovascular disease, microangiopathy and mortality compared with conventional glucose criteria. The aim of this review is to highlight the paramount importance of detecting prediabetes early in its pathophysiological course. Accordingly, as recommended by an international panel in a recent petition, 1-h post-load PG could replace current criteria for diagnosing early stages of "prediabetes" before prediabetes evolves as conventionally defined.
PMID: 36184047
ISSN: 1878-1780
CID: 5361442

Guidance for the diagnosis and treatment of hypolipidemia disorders

Bredefeld, Cindy; Hussain, M Mahmood; Averna, Maurizio; Black, Dennis D; Brin, Mitchell F; Burnett, John R; Charrière, Sybil; Cuerq, Charlotte; Davidson, Nicholas O; Deckelbaum, Richard J; Goldberg, Ira J; Granot, Esther; Hegele, Robert A; Ishibashi, Shun; Karmally, Wahida; Levy, Emile; Moulin, Philippe; Okazaki, Hiroaki; Poinsot, Pierre; Rader, Daniel J; Takahashi, Manabu; Tarugi, Patrizia; Traber, Maret G; Di Filippo, Mathilde; Peretti, Noel
The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals.
PMID: 36243606
ISSN: 1933-2874
CID: 5361332

A simulation model estimates lifetime health and economic outcomes of screening prediabetes using the 1-h plasma glucose

Andellini, Martina; Manco, Melania; Esposito, Maria Teresa; Tozzi, Alberto Eugenio; Bergman, Michael; Ritrovato, Matteo
AIMS/OBJECTIVE:The current method to diagnose impaired glucose tolerance (IGT) is based on the 2-h plasma glucose (2-hPG) value during a 75-g oral glucose tolerance test (OGTT). Robust evidence demonstrates that the 1-h post-load plasma glucose (1-hPG) ≥ 8.6 mmol/L in those with normal glucose tolerance is highly predictive of type 2 diabetes (T2D), micro and macrovascular complications and mortality. The aim of this study was to conduct a health economic analysis to estimate long-term cost-effectiveness of using the 1-hPG compared to the 2-hPG for screening and assessing the risk of diabetes over 35 years. The main outcome was cost per quality-adjusted life year (QALY) gained. METHODS:A Monte Carlo-based Markov simulation model was developed to forecast long-term effects of two screening strategies with regards to clinical and cost-effectiveness outcomes. The base case model included 20,000 simulated patients over 35-years follow-up. Transition probabilities on disease progression, mortality, effects on preventive treatments and complications were retrieved from landmark diabetes studies. Direct medical costs were sourced from published literature and inflated to 2019 Euros. RESULTS:In the lifetime analysis, the 1-hPG was projected to increase the number of years free from disease (2 years per patient); to delay the onset of T2D (1 year per patient); to reduce the incidence of T2D complications (0·6 RR-Relative Risk per patient) and to increase the QALY gained (0·58 per patient). Even if the 1-hPG diagnostic method resulted in higher initial costs associated with preventive treatment, long-term diabetes-related costs as well as complications costs were reduced leading to a lifetime saving of - 31225719.82€. The incremental cost-effectiveness ratio was - 8214.7€ per each QALY gained for the overall population. CONCLUSIONS:Screening prediabetes with the 1-hPG is feasible and cost-effective resulting in reduced costs per QALY. Notwithstanding, the higher initial costs of testing with the 1-hPG compared to the 2-hPG due to incremental preventive intervention, long-term diabetes and complications costs were reduced projecting an overall cost saving of - 8214.7€ per each QALY gained.
PMID: 36127565
ISSN: 1432-5233
CID: 5335372

"Blocking lipid uptake pathways does not prevent toxicity in adipose triglyceride lipase (ATGL) deficiency"

Oluwadare, Jide; Cabodevilla, Ainara G; Son, Ni-Huiping; Hu, Yunying; Mullick, Adam E; Verano, Michael; Alemán, Jose O; Ramasamy, Ravichandran; Goldberg, Ira J
Lipid accumulation in non-adipose tissues can cause lipotoxicity, leading to cell death and severe organ dysfunction. Adipose triglyceride lipase (ATGL) deficiency causes human Neutral Lipid Storage Disease and leads to cardiomyopathy; ATGL deficiency has no current treatment. One possible approach to alleviate this disorder has been to alter the diet and reduce the supply of dietary lipids and, hence, myocardial lipid uptake. However, in this study, when we supplied cardiac Atgl knockout mice a low- or high-fat diet, we found heart lipid accumulation, heart dysfunction, and death were not altered. We next deleted lipid uptake pathways in the ATGL-deficient mice through the generation of double knockout mice also deficient in either cardiac lipoprotein lipase (LpL) or cluster of differentiation (CD) 36, which is involved in an LpL-independent pathway for fatty acid uptake in the heart. We show neither deletion ameliorated ATGL-deficient heart dysfunction. Similarly, we determined non-lipid-containing media did not prevent lipid accumulation by cultured myocytes; rather, the cells switched to increased de novo fatty acid synthesis. Thus, we conclude pathological storage of lipids in ATGL deficiency cannot be corrected by reducing heart lipid uptake.
PMID: 36115595
ISSN: 1539-7262
CID: 5336622