Amrit Bhangoo

The clinical and molecular heterogeneity of 17βHSD-3 enzyme deficiency.

17-β-hydroxysteroid dehydrogenase type 3 (17βHSD-3) deficiency is a rare, but frequently misdiagnosed autosomal recessive cause of 46,XY disorder of sex development (DSD). 17βHSD-3 enzyme is present almost exclusively in the testes and converts Δ4-androstenedione (Δ4) to testosterone (T). The diagnosis can be easily missed in early childhood as the clinical presentation may be subtle. Any young girl with an inguinal hernia, mild clitoromegaly, single urethral opening or urogenital sinus should raise suspicion. If not diagnosed early, patients present with severe virilization and primary amenorrhea in adolescence and may undergo a change from a female to male gender role. A low T/Δ4 ratio on baseline or hCG (human chorionic gonadotropin)-stimulated testing is suggestive of 17βHSD-3 deficiency. The diagnosis can be confirmed with molecular genetic studies. This review summarizes the clinical presentations, reported mutations, diagnosis, treatment and clinical course of this disorder. The Arg80 site in exon 3 is the most common location of repeated mutations and can be considered a hot spot in certain Arab populations.

Endothelial function as measured by peripheral arterial tonometry increases during pubertal advancement.

Background/Aims:Sex steroids, such as estrogens, are known to influence endothelial function by their vasodilator action. The aim of this study was to study the relation of puberty and sex steroids with endothelial function using peripheral arterial tonometry (PAT). Methods: In 89 healthy school boys and girls, we determined height, weight, waist circumference, percent body fat, BMI, BMI z-score, blood pressure (BP), BP percentiles, lipid profile, insulin, and glucose levels after overnight fast. Estrone (E1), estradiol (E2), DHEAS and E1-sulfate were measured using ultrasensitive assays. Participants were divided into 3 pubertal groups on the basis of their estrogen levels: group 1 (Tanner stage I), group 2 (Tanner stages II–III), and group 3 (Tanner stages IV–V). Endothelial function was measured by Endo-PAT 2000® and expressed as PAT index. A higher PAT index represents a higher reactive hyperemia response. Results: The PAT index was lowest at 1.42 ± 0.44 (mean ± SD) in group 1 and significantly increased in group 2 at 1.71 ± 0.35 (p = 0.02) and group 3 at 1.92 ± 0.38 (p < 0.001). The PAT index correlated positively with E2, DHEAS and age. Conclusion: Enhancement of the PAT index was associated with an increment in Tanner stages. The changes in E2 and DHEAS levels may contribute to increasing endothelial response to shear stress or arterial blood flow.

Insulin resistance, lipodystrophy and cardiometabolic syndrome in HIV/AIDS.

HIV associated insulin resistance, lipodistrophy and cardiometabolic syndrome have been extensively studied and continue to be the scope of much research. There is compelling evidence that both the HIV itself and the therapeutical regimes are major contributors to all of these associated comorbidities. HIV has increasingly been recognized as a disease of accelerated aging, manifested by increased progression of vascular disease and cellular markers of aging. The antiretroviral medication can increase insulin resistance and cause lipotoxocity and HIV-associated lipodystrophy leading to cardiovascular pathology. In this article we review the pathogenesis, management, and prevention of the long-term complications of HIV and its therapies, including cardiovascular disease, lipodystrophy, and insulin resistance along with the growing focus on biomarkers to predict development of end-organ disease. Through a focused literature search we review the established evidence, the developing research about the treatment strategies in treated HIV infection as well as identify potential areas for future research.

Functional and Physiological Consequences of StAR Deficiency: Role in Lipoid Congenital Adrenal Hyperplasia

The steroidogenic acute regulatory (StAR) protein is essential for all hormone-stimulated steroid biosynthesis. Accordingly, its absence gives rise to the most severe form of congenital adrenal hyperplasia (CAH), lipoid CAH. This life-threatening condition typically manifests itself in the perinatal period. Partial loss-of-function StAR mutations incompletely manifest the condition later in life and are a cause of familial glucocorticoid deficiency type 3. Here, we discuss StAR, its expression pattern and the clinical consequences of the loss of its activity.

Bone and vitamin D metabolism in HIV

Human immunodeficiency virus (HIV) infection has progressed to a chronic disease and HIV positive individuals are living longer lives. This has lead to an increase in morbidity and mortality due to secondary issues, one being HIV bone disease. HIV infected pediatric and adult populations have a greater incidence in reduction of BMD as compared to the controls. Osteoporosis has been reported to be present in up to 15xa0% of HIV positive patients. We are starting to understand the mechanism behind the changes in HIV bone disease. Viral proteins interfere with osteoblastic activity either by direct interaction or by the inflammatory process that they induce. Anti-viral management, including highly active antiretroviral therapy (HAART), protease inhibitors, and nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) also are involved in disrupting proper bone metabolism. Vitamin D levels have strong correlation with bone disease in HIV patients, and are dependent not only to chronic disease state, but interaction of pharmacologic management and inflammatory process as well. Work up of the secondary causes of osteopenia and osteoporosis should be undertaken in all patients. DEXA scan is recommended in all post-menopausal women with HIV, all HIV infected men 50xa0years of age or older and in those with a history of fragility fractures regardless of age or gender. Preventive measures include adequate nutrition, calcium and Vitamin D intake daily, muscle strengthening and balance exercises to increase BMD and reduce fractures. Bisphosphonates are considered to be the first line for the treatment of HIV associated bone disease. This review will describe how the balanced mechanism of bone metabolism is interrupted by the HIV infection itself, the complications that arise from HIV/AIDS, and its treatment options.

Racial/ethnic Differences in Clinical and Biochemical Type 2 Diabetes Mellitus Risk Factors in Children

To examine whether periadolescent children demonstrate the significant racial/ethnic differences in body fatness relative to BMI and in the prevalence and relationship of body composition to risk factors for type 2 diabetes (T2DM) as in adults.

HIV and thyroid dysfunction

Human Immunodeficiency virus (HIV) infection and Acquired Immunodeficiency Syndrome (AIDS) are associated with dysfunction of many endocrine organs and their axis. HIV infectivity leads to altered metabolism, poor oral intake and increased prevalence of weight loss and wasting which may have a role in thyroid dysfunction. Overt thyroid dysfunction occurs at similar rates as the general population while subclinical disease such as nonthyroidal illness (sick euthyroid syndrome), subclinical hypothyroidism and isolated low T4 levels are more frequent. Moreover, HAART therapy can complicate thyroid function further through drug interactions and the immune reconstitution inflammatory syndrome (IRIS). In this review we report the common thyroid dysfunctions associated with HIV before and after HAART therapy. We discuss presentation, diagnostic work up, treatment and follow up in each condition.

Human immune deficiency virus (HIV) infection and the hypothalamic pituitary adrenal axis

The hypothalamic pituitary adrenal (HPA) axis is the most common of the endocrine lines/axis’ to be affected by HIV infection. There are multiple factors that contribute to this HPA axis dysregulation. Direct invasion of the various organs in the axis can be either by opportunistic infections or infiltrative diseases. The soluble factors or cytokines released during viral infection and the chronic inflammatory state that follows, also contribute to these alterations. The actions of these cytokines released by the immune response can both activate the HPA axis and cause a glucocorticoid resistant state. Further, many of the anti-retroviral and other medications used to treat HIV infection can contribute to HPA axis dysfunction. While the diagnosis and treatment of endocrine dysfunction is the same as in any other patient, management pathways may be quite different. While some may be adaptive responses, life threatening adrenal insufficiency can also be present. It is important the latter be picked up expeditiously and treated promptly to avoid mortality.

Isolated mild clitoral hypertrophy may reveal 46,XY disorders of sex development in infancy due to 17βHSD-3 defect confirmed by molecular analysis.

Aims.u200317-β-Hydroxysteroid dehydrogenase type 3 (17βHSD-3) is expressed exclusively in the testes where it converts Δ4 androstenedione (Δ4) to testosterone (T). Here, we report a patient with a rare mutation at a critical site in HSD17B3 gene leading to deficiency of 17β HSD-3 enzyme. Methods.u2003We describe a 3-year old healthy female of consanguineous Lebanese descent, who presented to the endocrine service with isolated mild clitoromegaly. Adrenocorticotropic hormone (ACTH) and human chorionic gonadotrophin (hCG) stimulation tests were performed. Genes for sex-determining region Y (SRY), steroidogenic factor-1 (SF-1) and 17βHSD-3 (HSD17B3) were sequenced. Results.u2003The post-hCG stimulation T levels and T/Δ4 ratio was low. Patient had a 46,XY karyotype. Sequence analysis of the HSD17B3 gene revealed a homozygous R80W missense mutation on exon 3. No mutation was found in SRY and SF1 genes. Mullerian structures were not detected on pelvic imaging. Conclusions.u2003A low T/Δ4 ratio is indicative of 17βHSD-3 deficiency and associated with isolated clitoromegaly. The R80 site is critical for NADPH binding, thus the mutation at this site leads to 17βHSD-3 deficiency presenting as 46,XY disorder of sex development.

Endocrinopathies in HIV, AIDS and HAART

The United Nations AIDS Report in 2012 states that there are 34 million people living in the world with HIV/AIDS at the end of 2011; of these 69 % live in sub-Saharan Africa [1]. The Caribbean islands, Eastern Europe and Central Asia are the next three most affected regions of the world. The rate of new infections HIV has decreased to 2.5 million per year. In 2011 the number of people dying from AIDS had fallen down to 1.7 million from 2.3 million in 2005. The number of children who got infected with HIV was approximately 330,000 which have significantly fallen in the last 10 years. New perinatal HIV cases have substantially decreased due to HIV education, screening for HIV in pregnancy, peripartum, intrapartum care for HIV infected mother, formula feeding, postpartum care of the infant and new HAART medications. HIV infection has progressed from an acute disease to a chronic illness with developments in antiretroviral therapies (HAART) along with better prophylaxis and treatment of opportunistic infections are the main contributors to the above advances [2]. In centers such as ours in Brooklyn, a significant cohort of long term survivors of perinatal HIV as well as a concentration large numbers of adults with HIV/AIDS help highlight the evolving clinical picture of this chronic disease and the impact of long term exposure to antiretroviral medications. There is an increase in morbidity and mortality due to secondary issues such as endocrine dys-regulation, although hormonal misbalance is not commonly seen. HIV and AIDS do involve almost all of the hormonal systems and axis (Fig. 1 and Table 1). There are multiple factors that contribute to this hypothalamic pituitary hormonal axis dys-regulation. Direct invasion of the various organs in the axis can be either by opportunistic infections or infiltrative diseases. Viral proteins or cytokines released during viral infection and the chronic inflammatory state that follows, also contribute to these alterations. The actions of these cytokines released by the immune response can both activate or inhibit the hormonal systems. Further, HAART and other medications used to treat HIV infection can contribute to the hypothalamic pituitary hormonal axis dysfunctions. The hypothalamic pituitary adrenal (HPA) axis is the most common of the endocrine axis to be affected by HIV infection [3, 4]. The presentation results in a spectrum of adrenal gland malfunction from overt adrenal insufficiency, impaired adrenal reserves to increased cortisol levels due to a glucocorticoid resistant state. The degree of the thyroid hormone disorders also vary in presentation from nonthyroidal illness or sick euthyroid syndrome to subclinical hypothyroidism, overt hypothyroidism, isolated low T4 levels and hyperthyroidism at the other end of the spectrum. Thyroid hormone dysfunction in HIV is also associated with altered metabolism, poor oral intake and increased prevalence of weight loss and wasting syndrome. HIV infected pediatric and adult populations have a greater incidence in reduction of BMD as compared to the controls [5–12]. Osteoporosis has been reported to be present in up to 15 % of HIV positive patients and a 67 % reduction in BMD. Viral proteins interfere with osteoblastic activity either by direct interaction or by the inflammatory process that they induce. Anti-viral management such as HAART, protease inhibitors, and nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) also are involved in disrupting proper bone metabolism (Fig. 1). The interaction of pharmacologic management and inflammatory process A. Bhangoo Pediatric Endocrinology, Miller Children’s Hospital, Long Beach, CA, USA