Showing papers in "Nature Clinical Practice Endocrinology & Metabolism in 2008"
TL;DR: Observations suggest that nonclassical metabolism and response to vitamin D might have a significant role in human physiology beyond skeletal and calcium homeostasis.
Abstract: Knowledge about the ability of vitamin D to function outside its established role in skeletal homeostasis is not a new phenomenon. Nonclassical immunomodulatory and antiproliferative responses triggered by active 1,25-dihydroxyvitamin D were first reported more than a quarter of a century ago. It is only in recent years, however, that there has been a significant improvement in our understanding of how these nonclassical effects of vitamin D can influence the pathophysiology and possible prevention of human disease. Three particular strands of evidence have been prominent: firstly, population studies have revised our interpretation of normal vitamin D status in humans, suggesting, in turn, that vitamin D insufficiency is a clinical problem of global proportions; secondly, epidemiology has linked vitamin D status with disease susceptibility and/or mortality; and, thirdly, expression of the machinery required to synthesize 1,25-dihydroxyvitamin D in normal human tissue seems to be much more widespread than originally thought. Collectively, these observations suggest that nonclassical metabolism and response to vitamin D might have a significant role in human physiology beyond skeletal and calcium homeostasis. Specific examples of this will be detailed in the current Review, with particular emphasis on the immunomodulatory properties of vitamin D.
706 citations
TL;DR: A summary of the latest published data dealing with mechanisms contributing to diabetic nephropathy, including alterations in various cytokines and their interaction with products of advanced glycation and oxidant stress is provided.
Abstract: Between 20% and 40% of patients with diabetes ultimately develop nephropathy. The bank of data on the multiple and complex mechanisms, disease markers and disease progression continues to grow. This article provides an overview of the current status of findings relating to underlying mechanisms and genetic susceptibility.
524 citations
TL;DR: It is proposed that the old clinical classifications of maturity-onset diabetes of the young and neonatal diabetes are obsolete and that specific genetic etiologies should be sought in four broad clinical situations because of their specific treatment implications.
Abstract: Monogenic diabetes resulting from mutations that primarily reduce beta-cell function accounts for 1-2% of diabetes cases, although it is often misdiagnosed as either type 1 or type 2 diabetes. Knowledge of the genetic etiology of diabetes enables more-appropriate treatment, better prediction of disease progression, screening of family members and genetic counseling. We propose that the old clinical classifications of maturity-onset diabetes of the young and neonatal diabetes are obsolete and that specific genetic etiologies should be sought in four broad clinical situations because of their specific treatment implications. Firstly, diabetes diagnosed before 6 months of age frequently results from mutation of genes that encode Kir6.2 (ATP-sensitive inward rectifier potassium channel) or sulfonylurea receptor 1 subunits of an ATP-sensitive potassium channel, and improved glycemic control can be achieved by treatment with high-dose sulfonylureas rather than insulin. Secondly, patients with stable, mild fasting hyperglycemia detected particularly when they are young could have a glucokinase mutation and might not require specific treatment. Thirdly, individuals with familial, young-onset diabetes that does not fit with either type 1 or type 2 diabetes might have mutations in the transcription factors HNF-1alpha (hepatocyte nuclear factor 1-alpha) or HNF-4alpha, and can be treated with low-dose sulfonylureas. Finally, extrapancreatic features, such as renal disease (caused by mutations in HNF-1beta) or deafness (caused by a mitochondrial m.3243A>G mutation), usually require early treatment with insulin.
477 citations
TL;DR: R roles for RAGE are chronicle and the hypothesis that, in addition to RAGE's central role in the inflammatory response, it is critically linked to the pathogenesis of types 1 and 2 diabetes is developed.
Abstract: Many important biochemical mechanisms are activated in the presence of high levels of glucose, which occur in diabetes. Elevated levels of glucose accelerate the formation of advanced glycation end-products (AGEs). Via their chief signaling receptor-the AGE-specific receptor (commonly abbreviated as RAGE)-AGEs generate reactive oxygen species and activate inflammatory signaling cascades. Consequently, AGEs have key roles in the pathogenesis of diabetic complications. Two discoveries have advanced our knowledge of the roles of RAGE in inflammation. First, this receptor has multiple ligands and binds not only AGEs but also proinflammatory, calcium-binding S100 proteins (also known as calgranulins) and nuclear high mobility group protein box-1. Second, RAGE is expressed on T lymphocytes, monocytes and macrophages; RAGE expression on T lymphocytes is essential for effective priming of immune responses in vivo. In this Review, we chronicle roles for RAGE in the pathogenesis of diabetic complications and develop the hypothesis that, in addition to RAGE's central role in the inflammatory response, it is critically linked to the pathogenesis of types 1 and 2 diabetes.
373 citations
TL;DR: Prevalence of thyroid autoimmunity is significantly higher among infertile women than among fertile women, especially among those whose infertility is caused by endometriosis or ovarian dysfunction.
Abstract: The thyroid gland and gonadal axes interact continuously before and during pregnancy. Hypothyroidism influences ovarian function by decreasing levels of sex-hormone-binding globulin and increasing the secretion of prolactin. In women of reproductive age, hypothyroidism can be reversed by thyroxine therapy to improve fertility and avoid the need for use of assisted reproduction technologies. For infertile women, preparation for medically assisted pregnancy comprises controlled ovarian hyperstimulation that substantially increase circulating estrogen concentrations, which in turn can severely impair thyroid function. In women without thyroid autoimmunity these changes are transient, but in those with thyroid autoimmunity estrogen stimulation might lead to abnormal thyroid function throughout the remaining pregnancy period. Prevalence of thyroid autoimmunity is significantly higher among infertile women than among fertile women, especially among those whose infertility is caused by endometriosis or ovarian dysfunction. Presence of thyroid autoimmunity does not interfere with normal embryo implantation, but the risk of early miscarriage is substantially raised. Subclinical and overt forms of hypothyroidism are associated with increased risk of pregnancy-related morbidity, for which thyroxine therapy can be beneficial. Systematic screening for thyroid disorders in pregnant women remains controversial but might be advantageous in women at high risk, particularly infertile women.
252 citations
TL;DR: This Review focuses on the stimuli and mechanisms that control classical and alternative activation of tissue macrophages, and how these macrophage activation programs modulate insulin action in peripheral tissues.
Abstract: Chronic inflammation is now recognized as a key step in the pathogenesis of obesity-induced insulin resistance and type 2 diabetes mellitus. This low-grade inflammation is mediated by the inflammatory (classical) activation of recruited and resident macrophages that populate metabolic tissues, including adipose tissue and liver. These findings have led to the concept that infiltration by and activation of macrophages in adipose tissue are causally linked to obesity-induced insulin resistance. Studies have shown, however, that alternatively activated macrophages taking residence in adipose tissue and liver perform beneficial functions in obesity-induced metabolic disease. Alternatively activated macrophages reduce insulin resistance in obese mice by attenuating tissue inflammation and increasing oxidative metabolism in liver and skeletal muscle. The discovery that distinct subsets of macrophages are involved in the promotion or attenuation of insulin resistance suggests that pathways controlling macrophage activation can potentially be targeted to treat these comorbidities of obesity. Thus, this Review focuses on the stimuli and mechanisms that control classical and alternative activation of tissue macrophages, and how these macrophage activation programs modulate insulin action in peripheral tissues. The functional importance of macrophage activation is further discussed in the context of host defense to highlight the crosstalk between innate immunity and metabolism.
242 citations
TL;DR: The study of monogenic disorders, which primarily result in severe, early-onset obesity, has provided a framework for the understanding of the mechanisms involved in the regulation of body weight in humans and how these mechanisms are disrupted in obesity.
Abstract: The global obesity epidemic is clearly driven by environmental factors; however, inherited factors can also influence human adiposity. In this Review, the authors focus on the genes implicated in monogenic obesity syndromes. These genes encode components of the leptin–melanocortin pathway, which is critical for regulation of food intake and body weight. Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes mellitus and certain cancers. The prevalence of obesity is increasing rapidly throughout the world and is now recognized as a major global public-health concern. Although the increased prevalence of obesity is undoubtedly driven by environmental factors, the evidence that inherited factors profoundly influence human fat mass is equally compelling. Twin and adoption studies indicate that up to 70% of the interindividual variance in fat mass is determined by genetic factors. Genetic strategies can, therefore, provide a useful tool with which to dissect the complex (and often heterogeneous) molecular and physiologic mechanisms involved in the regulation of body weight. In this Review, we have focused our attention on monogenic disorders, which primarily result in severe, early-onset obesity. The study of these genetic disorders has provided a framework for our understanding of the mechanisms involved in the regulation of body weight in humans and how these mechanisms are disrupted in obesity. The genes affected in these monogenic disorders all encode ligands and receptors of the highly conserved leptin–melanocortin pathway, which is critical for the regulation of food intake and body weight.
240 citations
TL;DR: Prevention strategies that can be implemented in routine clinical settings have been developed and evaluated, but widespread application has been limited by local financial considerations, even though cost-effectiveness might be achieved at the population level.
Abstract: Type 2 diabetes mellitus (T2DM) affects more than 7% of adults in the US and leads to substantial personal and economic burden. In prediabetic states insulin secretion and action--potential targets of preventive interventions--are impaired. In trials lifestyle modification (i.e. weight loss and exercise) has proven effective in preventing incident T2DM in high-risk groups, although weight loss has the greatest effect. Various medications (e.g. metformin, thiazolidinediones and acarbose) can also prevent or delay T2DM. Whether diabetes-prevention strategies also ultimately prevent the development of diabetic vascular complications is unknown, but cardiovascular risk factors are favorably affected. Preventive strategies that can be implemented in routine clinical settings have been developed and evaluated. Widespread application has, however, been limited by local financial considerations, even though cost-effectiveness might be achieved at the population level.
220 citations
TL;DR: The potential clinical uses of antagonists of growth-hormone-releasing hormone (GHRH) for tumor therapy, which include suppressing the growth of various human cancer lines xenografted into nude mice, are reviewed.
Abstract: This article reviews the potential clinical uses of antagonists of growth-hormone-releasing hormone (GHRH) for tumor therapy. GHRH antagonists suppress the growth of various human cancer lines xenografted into nude mice; such tumors include breast, ovarian, endometrial and prostate cancers, lung cancers (small-cell lung carcinomas and non-small-cell lung carcinomas), renal, pancreatic, gastric and colorectal carcinomas, brain tumors (malignant gliomas), osteogenic sarcomas and non-Hodgkin's lymphomas. The antitumor effects of GHRH antagonists are exerted in part indirectly through the inhibition of the secretion of GH from the pituitary and the resulting reduction in the levels of hepatic insulin-like growth factor I (IGF-I). The main effects of the GHRH antagonists are, however, exerted directly on tumors. GHRH ligand is present in various human cancers and might function as an autocrine and/or paracrine growth factor. Pituitary-type GHRH receptors and their splice variants are also found in many human cancers. The inhibitory effects of GHRH antagonists seem to be due to the blockade of action of tumoral GHRH. Antagonists of GHRH can also suppress cancer growth by blocking production of IGF-I and/or IGF-II by the tumor. Further development of GHRH antagonists that are still-more potent should lead to potential therapeutic agents for various cancers.
186 citations
TL;DR: Patients with distant metastases, in particular, might benefit from several novel compounds directed against angiogenesis and molecular targets in tumor cells, such as products of the proto-oncogene RET and mutants of it, and other signaling components.
Abstract: Medullary thyroid carcinoma (MTC) accounts for up to 8% of all thyroid cancers. Although primary surgery is curative in the vast majority of patients treated at an early stage, disease can persist or recur with deleterious effects on quality of life. Local and distant metastases can occur and are the major causes of mortality. Reoperation, embolization, and perhaps radiotherapy can improve the outcome for some patients who are not cured by primary surgery, but there is a need for novel treatments. No comprehensive clinical trial data are available on conventional cytotoxic agents for the treatment of MTC. Patients with distant metastases, in particular, might benefit from several novel compounds directed against angiogenesis and molecular targets in tumor cells, such as products of the proto-oncogene RET and mutants of it, and other signaling components. Well-conducted clinical trials are needed to assess and optimize these treatment strategies, and this article outlines how such trials should be conducted. Although RET mutations are common in hereditary MTC and can occur in some cases of sporadic MTC, knowledge of other molecular defects associated with the development of MTC should reveal new targets for therapy.
174 citations
TL;DR: It is critical that physicians understand the technical limitations inherent in thyroglobulin measurement in order to effectively use this test for the postoperative management of patients with differentiated thyroid cancers.
Abstract: Measurement of serum thyroglobulin is primarily used as a tumor marker in the postoperative management of patients with differentiated thyroid cancer. Unfortunately, the technical quality of current thyroglobulin assay methods varies and influences the clinical utility of this test. Two different methodologic approaches are used to measure serum thyroglobulin: the original competitive radioimmunoassay methodology and noncompetitive immunometric assay methods. Although the newer immunometric assays offer the technical benefits of eliminating the use of isotopes, using smaller specimen volumes, and having higher sensitivity potential, shorter turnaround times and the convenience of automation, immunometric assays also have a higher propensity for interference from both thyroglobulin autoantibodies and heterophilic antibodies, if present in the specimen. It is critical that physicians understand the technical limitations inherent in thyroglobulin measurement in order to effectively use this test for the postoperative management of patients with differentiated thyroid cancers.
TL;DR: Key endocrine alterations in Anorexia nervosa are summarized, with a particular focus on the profound bone loss that can occur in this disease.
Abstract: Anorexia nervosa (AN) is a psychiatric disease associated with notable medical complications and increased mortality. Endocrine abnormalities, including hypogonadotropic hypogonadism, hypercortisolemia, growth hormone resistance and sick euthyroid syndrome, mediate the clinical manifestations of this disease. Alterations in anorexigenic and orexigenic appetite-regulating pathways have also been described. Decreases in fat mass result in adipokine abnormalities. Although most of the endocrine changes that occur in AN represent physiologic adaptation to starvation, some persist after recovery and might contribute to susceptibility to AN recurrence. In this Review, we summarize key endocrine alterations in AN, with a particular focus on the profound bone loss that can occur in this disease. Although AN is increasingly prevalent among boys and men, the disorder predominantly affects girls and women who are, therefore, the focus of this Review.
TL;DR: Aquaporin subtypes 7 and 9 (AQP7 and AQP9) are the glycerol channels in adipocytes and hepatocytes, respectively, and the coordinated regulation of these channels leads to the optimum balance between release of Glycerol by adipocytesand its uptake by the liver.
Abstract: The discovery of aquaporins, which are plasma-membrane-associated water channels, has greatly influenced the medical sciences. So far, thirteen aquaporins have been identified in humans. Among them, types 3, 7, 9, and 10 are subcategorized as aquaglyceroporins, which enable the transport of glycerol as well as water. Although aquaporins have a proven crucial role in water homeostasis, the physiological and pathological importance of aquaporins as glycerol channels is not fully understood. Adipocytes are a major source of glycerol, one of the substrates for hepatic gluconeogenesis. Aquaporin subtypes 7 and 9 (AQP7 and AQP9) are the glycerol channels in adipocytes and hepatocytes, respectively. The coordinated regulation of these channels leads to the optimum balance between release of glycerol by adipocytes and its uptake by the liver. In addition, studies of AQP7 and AQP9 knockout or knockdown mice have clearly demonstrated in vivo the pathophysiological relevance of glycerol channels through effects on glycerol metabolism. Associations between various AQP7 gene mutations and obesity in humans have also been shown. Thus, further research of these two aquaporins might uncover novel targets for therapy.
TL;DR: Environmental factors have not yet been sufficiently investigated to clarify their roles in pathogenesis, and there is a need to assess their effects on development of the autoimmune process and the mechanisms of their interactions with susceptibility genes.
Abstract: Autoimmune thyroiditis, of which Hashimoto thyroiditis represents the most frequent form, is an inflammatory state of the thyroid gland that results from the interaction between genetic variants that promote susceptibility and environmental factors. High iodine intake, selenium deficiency, pollutants such as tobacco smoke, infectious diseases such as chronic hepatitis C, and certain drugs are implicated in the development of autoimmune thyroiditis, primarily in genetically predisposed people. Long-term iodine exposure leads to increased iodination of thyroglobulin, which increases its antigenicity and initiates the autoimmune process in genetically susceptible individuals. Selenium deficiency decreases the activity of selenoproteins, including glutathione peroxidases, which can lead to raised concentrations of hydrogen peroxide and thus promote inflammation and disease. Such environmental pollutants as smoke, polychlorinated biphenyls, solvents and metals have been implicated in the autoimmune process and inflammation. Environmental factors have not yet, however, been sufficiently investigated to clarify their roles in pathogenesis, and there is a need to assess their effects on development of the autoimmune process and the mechanisms of their interactions with susceptibility genes.
TL;DR: A 46-year-old man presented with headaches, paroxysmal palpitations, anxiety and hypertension, and was diagnosed with a familial pheochromocytoma-paraganglioma syndrome associated with a germline mutation in SDHC (gene encoding succinate dehydrogenase complex, subunit C, integral membrane protein, 15 kDa).
Abstract: There is a high frequency of germline mutations in patients with pheochromocytomas and paragangliomas. This article describes a patient with a pheochromocytoma and a novelSDHCmutation. The authors highlight the importance of genetic testing in patients with the pheochromocytoma–paraganglioma syndrome. Background A 46-year-old man presented with headaches, paroxysmal palpitations, anxiety and hypertension. The patient had undergone surgery for a retroperitoneal tumor at the age of 31 years, when histological examination revealed an extra-adrenal pheochromocytoma. The patient's 68-year-old mother had a history of a carotid body tumor, which had been resected when she was 34 years old. She was diagnosed with a meningioma at 54 years of age and a jugular paraganglioma at 68 years of age. Investigations A 24h urine catecholamine assay was performed. CT imaging of the abdomen and 123I-labeled metaiodobenzylguanidine scintigraphy revealed a right pheochromocytoma and left adrenal incidentaloma. An inherited neoplasia syndrome was suspected and molecular genetic analyses were performed. Diagnosis Right adrenal pheochromocytoma and left adrenal nonfunctioning incidentaloma, as part of a familial pheochromocytoma-paraganglioma syndrome associated with a germline mutation in SDHC (gene encoding succinate dehydrogenase complex, subunit C, integral membrane protein, 15 kDa). Management Predictive testing, with genetic counseling. Management included surgical resection of the existing pheochromocytoma. The patient continues to be monitored with MRI scans of the neck, thorax, abdomen and pelvis every 1–2 years and an annual 24h urine collection for the measurement of metanephrines and catecholamines.
TL;DR: This Review aims to summarize the current knowledge of the possible reproductive functions of ghrelin, such as the ability to modulate gonadotropin secretion, to influence puberty onset, and to directly regulate gonadal physiology.
Abstract: Reproductive maturation and function are under the influence of a wide variety of regulatory signals, which include nutritional and metabolic cues, as well as hormones that control energy homeostasis. Evidence is mounting that the gut hormone ghrelin--a putative signal of energy insufficiency and a functional antagonist of leptin--operates as a pleotrophic modulator of gonadal function and reproduction. This Review aims to summarize our current knowledge of the possible reproductive functions of ghrelin, such as the ability to modulate gonadotropin secretion, to influence puberty onset, and to directly regulate gonadal physiology. Notably, most of the actions of ghrelin upon the reproductive axis reported to date are inhibitory. This observation suggests that ghrelin might mediate at least part of the well-known suppressive effect of energy deficit on the onset of puberty, gonadal function and fertility. The reproductive actions of ghrelin have been described in a range of species, including humans, and expression of ghrelin and its canonical receptor has been detected in the gonads. As a consequence, it is tempting to speculate that ghrelin is an integral player in the dynamic regulation of gonadal function, and that through a multifaceted mode of action this hormone contributes to the integration of energy balance and reproduction.
TL;DR: There is, furthermore, no evidence to support the use of metformin during pregnancy to prevent spontaneous abortions or gestational diabetes mellitus in women with PCOS, and there is no evidence that they provide long-term health benefits in PCOS.
Abstract: Insulin resistance has a pivotal role in polycystic ovary syndrome. This Review evaluates the clinical implications of findings from several recent studies on the role of insulin-sensitizing drugs, such as metformin and thiazolidinediones in polycystic ovary syndrome, with particular regard to insulin action, cardiovascular disease, hyperandrogenism, infertility and pregnancy.
TL;DR: Treatment with an aromatase inhibitor, anastrozole, led to normalization of the patient's testosterone, luteinizing hormone and follicle-stimulating hormone levels, suppression of serum estradiol levels, and tonormalization of spermatogenesis and fertility.
Abstract: Obesity can be a cause of secondary hypogonadism. This article describes a male patient with infertility in the setting of obesity, who was successfully treated with the aromatase inhibitor anastrozole. The authors illustrate the connections between adiposity, aromatase expression, testosterone and estradiol levels, and the suppression of gonadotropin release and spermatogenesis. Background A 29-year-old man presented to a clinic with infertility and hypogonadism in the setting of morbid obesity. On presentation, he had notable gynecomastia and a low testicular volume. The patient's weight was 154 kg and his height was 168 cm (BMI 54.5 kg/m2). Before referral to the clinic, the patient had been treated with testosterone therapy for 4 months for hypogonadism. This treatment had caused his initially low sperm concentration to fall to undetectable levels. Investigations Measurement of reproductive hormone levels, pituitary MRI, and semen analysis. Diagnosis Infertility secondary to hypogonadotropic hypogonadism and an elevated estrogen:testosterone ratio. Management Treatment with an aromatase inhibitor, anastrozole, led to normalization of the patient's testosterone, luteinizing hormone and follicle-stimulating hormone levels, suppression of serum estradiol levels, and to normalization of spermatogenesis and fertility.
TL;DR: The structure of the ligand-binding domain of the glucocorticoid receptor has now been elucidated, and a series of studies have shown that even subtle changes to the ligands structure alter the final conformation of theligand–receptor complex, with consequences for both protein recruitment and the function of the receptor.
Abstract: Glucocorticoid hormones exert a wide spectrum of metabolic and immunological effects. They function through the glucocorticoid receptor, a member of the nuclear receptor superfamily. Glucocorticoids are particularly effective as anti-inflammatory agents but often cause severe side effects. The structure of the ligand-binding domain of the glucocorticoid receptor has now been elucidated, and a series of studies have shown that even subtle changes to the ligand structure alter the final conformation of the ligand-receptor complex, with consequences for both protein recruitment and the function of the receptor. This has led to concerted efforts to find selective ligands for the glucocorticoid receptor that preserve the beneficial anti-inflammatory activity but reduce the side-effect profile. The direct health-care benefits of such a simple, safe, orally active agent targeting the underlying inflammatory process in, for example, rheumatoid arthritis would be considerable in terms of reduced patient suffering; furthermore, the indirect benefits in terms of reducing the costs of therapeutic delivery and preventing loss of productivity would be even greater.
TL;DR: A novel role of D3 in the tissue response to injury and in the derangement of thyroid hormone homeostasis commonly observed during critical illness is revealed.
Abstract: Thyroid hormones influence gene expression in virtually all vertebrate tissues. Precise regulation of the active endogenous ligand, 3,5,3'-triiodothyronine (T(3)), is achieved by the sequential removal of iodine moieties from the thyroid hormone molecule. Type III iodothyronine deiodinase (D3) is the major inactivating enzyme terminating the action of T(3) and preventing activation of the prohormone, thyroxine (T(4)). Recent studies have revealed the induction of high D3 activity in diverse animal models of tissue injury including starvation, cryolesion, cardiac hypertrophy, infarction, and chronic inflammation. By analyzing serum and tissues taken from hospitalized patients at the time of death, investigators have also documented the robust induction of D3 activity in several human tissues that normally have none, including the liver and skeletal muscle, and shown clinically relevant consequences to systemic thyroid status. These studies reveal a novel role of D3 in the tissue response to injury and in the derangement of thyroid hormone homeostasis commonly observed during critical illness.
TL;DR: Although there is a paucity of data in regard to cardiovascular event rates and mortality in PCOS, an increased prevalence of cardiovascular risk factors has been well documented.
Abstract: Polycystic ovary syndrome (PCOS) is a complex disorder comprising both hormonal and metabolic abnormalities that include impaired glucose tolerance, type 2 diabetes, vascular disease, dyslipidemia, and obstructive sleep apnea. Insulin resistance is a central pathogenetic factor in PCOS that seems to result from a post-receptor-binding defect in insulin action. Insulin resistance and the consequent development of hyperinsulinemia contribute to the constellation of cardiometabolic abnormalities noted above. Although there is a paucity of data in regard to cardiovascular event rates and mortality in PCOS, an increased prevalence of cardiovascular risk factors has been well documented. Attention to the metabolic risks associated with PCOS, starting as early as adolescence, is essential to the medical care of these patients.
TL;DR: Until the debate has been settled, it is recommended that use of glucocorticoid therapy in critically ill patients should continue to be based on the clinician's judgment and that routine adjuvant use should be avoided.
Abstract: Critical illness is generally hallmarked by activation of the hypothalamic-pituitary-adrenal axis. The development of very high levels of cortisol has been associated with severe illness and a raised risk of death. Likewise, a response that is inadequate relative to the degree of stress, termed relative adrenal insufficiency (also known as critical-illness-related corticosteroid insufficiency) has been associated with increased mortality. Much controversy exists with regard to the definition and biochemical testing of an adequate adrenal response to critical illness, which hampers diagnosis. High doses of glucocorticoids have been shown to have no effect in this setting and might be harmful. Moderate doses have been advocated, however, for critically ill patients with inflammatory conditions, such as acute respiratory distress syndrome and septic shock syndrome. Initial results from proof-of-concept studies were promising but thus far have not been reproduced in large, multicenter trials, although the latter were underpowered to yield definite conclusions. The role of glucocorticoid therapy in intensive care, therefore, remains uncertain. Until the debate has been settled, we recommend that use of glucocorticoid therapy in critically ill patients should continue to be based on the clinician's judgment and that routine adjuvant use should be avoided.
TL;DR: Late-night salivary cortisol measurement yields excellent overall diagnostic accuracy for Cushing's syndrome, with a sensitivity of 92–100% and a specificity of 93–100%.
Abstract: Making a definite diagnosis of Cushing's syndrome is a challenging problem. Unsuspected Cushing's syndrome occurs in 2-3% of patients with poorly controlled diabetes, 0.5-1% with hypertension, 6-9% with incidental adrenal masses, and 11% with unexplained osteoporosis and vertebral fractures. The increasing recognition of this syndrome highlights the need for a simple, sensitive, and specific diagnostic test. Patients with Cushing's syndrome consistently do not reach a normal nadir of cortisol secretion at night. The measurement of late-night salivary cortisol levels might, therefore, provide a new diagnostic approach for this disorder. Salivary cortisol concentrations reflect those of active free cortisol in plasma and saliva samples can easily be obtained in a nonstressful environment (e.g. at home). Late-night salivary cortisol measurement yields excellent overall diagnostic accuracy for Cushing's syndrome, with a sensitivity of 92-100% and a specificity of 93-100%. Several factors can, however, make interpretation of results difficult; these factors include disturbed sleep-wake cycles, contamination of samples (particularly by topical corticosteroids), and illnesses known to cause physiologic activation of the pituitary-adrenal axis. In this Review, we discuss the methods and value of measuring salivary cortisol for the diagnosis of Cushing's syndrome, and put forward some recommendations to maximize accuracy of results.
TL;DR: High doses of levothyroxine for T4 replacement therapy have not been confirmed, but might need to be higher than presently used empirically in patients with CH and should be adjusted according to age and other hormone deficiencies, to achieve free T4 concentrations in the upper end of the normal range.
Abstract: Central hypothyroidism (CH) is defined as hypothyroidism due to insufficient stimulation of the thyroid gland by TSH, for which secretion or activity can be impaired at the hypothalamic or pituitary levels. Patients with CH frequently present with multiple other pituitary hormone deficiencies. In addition to classic CH induced by hypothalamic-pituitary tumors or Sheehan syndrome, novel causes include traumatic brain injury or subarachnoid hemorrhage, bexarotene (a retinoid X receptor agonist) therapy, neonates being born to mothers with insufficiently controlled Graves disease, and lymphocytic hypophysitis. Growth hormone therapy, which may be used in children and adults, is now also recognized as a possible cause of unmasking CH in susceptible individuals. In addition, mutations in genes, such as TRHR, POU1F1, PROP1, HESX1, SOX3, LHX3, LHX4 and TSHB, have been associated with CH. The difficulty in making a clear diagnosis of CH is that the serum TSH levels can vary; values are normal in most cases, but in some might be low or slightly elevated. Levels of endogenous T(4) in serum might also be subnormal. Appropriate doses of levothyroxine for T(4) replacement therapy have not been confirmed, but might need to be higher than presently used empirically in patients with CH and should be adjusted according to age and other hormone deficiencies, to achieve free T(4) concentrations in the upper end of the normal range.
TL;DR: Current guidelines for postpartum screening for type 2 diabetes mellitus, how they might be implemented, and who should take responsibility for screening individuals at risk of T2DM are discussed.
Abstract: Gestational diabetes mellitus (GDM) affects approximately 4% of all pregnant women in the US and represents 90% of all cases of diabetes mellitus diagnosed during pregnancy. In addition to the adverse pregnancy outcomes associated with this complication, a history of GDM predisposes women to the future development of type 2 diabetes mellitus (T2DM). Incidence rates of GDM are increasing in the US. As a consequence, a growing number of women are now at increased risk for T2DM. Opportunities to diagnose and prevent T2DM in women with a history of GDM include early diagnosis by postpartum screening and implementation of diabetes prevention measures. In this Review, we discuss current guidelines for postpartum screening, how they might be implemented, and who should take responsibility for screening individuals at risk of T2DM. In addition, we describe measures to prevent the onset of T2DM in women with a history of GDM, focusing on lifestyle modifications, such as diet and breast-feeding.
TL;DR: A diagnostic algorithm for the diagnosis of these disorders that is based on concentrations of total cholesterol, triglyceride and apoB is presented, which can be used by any physician to make an accurate diagnosis without use of specialist research laboratories.
Abstract: Given the high prevalence of the atherogenic forms of apolipoprotein B (apoB) dyslipoproteinemias and the effectiveness of appropriate therapy, we feel that access for all physicians to simple, effective diagnostic aids that enable use of widely available technology is vitally important in clinical lipidology. In this Review, therefore, we present a diagnostic algorithm for the diagnosis of these disorders that is based on concentrations of total cholesterol, triglyceride and apoB. By including apoB values, lipoprotein number and composition can be deduced and each of the classic dyslipoproteinemias identified. All three parameters can be accurately and inexpensively determined in clinical laboratories and, therefore, this algorithm can be used by any physician to make an accurate diagnosis without use of specialist research laboratories. Just as the application of LDL cholesterol measurement moved clinical practice forward from plasma lipids to lipoprotein lipids, we believe that the use of apoB will further advance diagnosis and treatment of dyslipoproteinemias.
TL;DR: DNA from a parathyroid tumor from the sister of a patient with FIHP revealed a loss of heterozygosity in which the mutant allele was retained, consistent with Knudson's 'two-hit' model of hereditary cancer and a tumor suppressor role for MEN1 in FIHP.
Abstract: Primary hyperparathyroidism is hereditary in 10% of patients. This article describes a patient with familial isolated hyperparathyroidism (FIHP) caused by a novel MEN1 missense mutation. The genetics, differential diagnosis and management of hereditary hyperparathyroidism are illustrated. Background Familial isolated primary hyperparathyroidism (FIHP) is an autosomal dominant disorder that can represent an early stage of either the multiple endocrine neoplasia type 1 (MEN1) or hyperparathyroidism-jaw tumor (HPT-JT) syndromes; alternatively, the condition can be caused by an allelic variant of MEN1 or HRPT2 (hyperparathyroidism 2 gene), or caused by a distinct entity involving another locus. We have explored these possibilities in a patient with primary hyperparathyroidism, whose mother had a history of renal calculi and primary hyperparathyroidism. Investigations Serum biochemistry and radiological investigations for primary hyperparathyroidism, MEN1 and HPT-JT, and genetic testing for MEN1 and HRPT2 mutations were undertaken. Diagnosis FIHP with primary hyperparathyroidism as the sole endocrinopathy due to a previously unreported heterozygous missense germline MEN1 mutation, Tyr351Asn. In addition, another unreported heterozygous missense germline MEN1 mutation, Trp220Leu, was identified in an unrelated male patient with FIHP, whose mother and sister also had primary hyperparathyroidism. DNA from a parathyroid tumor from the sister revealed a loss of heterozygosity in which the mutant allele was retained. This is consistent with Knudson's 'two-hit' model of hereditary cancer and a tumor suppressor role for MEN1 in FIHP. Management The patient underwent parathyroidectomy and has remained normocalcemic over a follow-up period of 6 years. The other four patients have remained normocalcemic for a follow-up period of 4–15 years following parathyroidectomy. None has developed abnormalities of the MEN1 syndrome, providing further support that FIHP is a distinct genetic variant of the MEN1 syndrome.
TL;DR: A 25-year-old woman presented to her gynecologist with pelvic pain and was referred to an endocrinology clinic for further investigations, which proved to be a struma ovarii with numerous microscopic foci of papillary thyroid carcinoma.
Abstract: Struma ovarii is a rare tumor, characterized by the presence of thyroid tissue in an ovarian teratoma. In this article Yassa et al. describe a patient who presented to her gynecologist with a pelvic mass, which was found to be a malignant struma ovarii. The investigations and treatment options for this tumor are described. Background A 25-year-old woman presented to her gynecologist with pelvic pain. Pelvic ultrasonography showed a 9 cm left ovarian mass. The patient underwent left oophorectomy, omental biopsy, and lymph node sampling. The ovarian mass proved to be a struma ovarii with numerous microscopic foci of papillary thyroid carcinoma. The patient had no symptoms of hyperthyroidism, and her thyroid function and serum thyroglobulin levels were normal. Investigations Investigations included a pelvic ultrasound scan, histological examination of the ovarian mass and omental nodules, and lymph node sampling. Diagnosis Malignant struma ovarii. Management The patient was referred to an endocrinology clinic for further investigations. Serum levels of TSH, thyroglobulin and thyroglobulin antibodies were measured. In addition, the patient underwent thyroid ultrasonography, which showed a 1 cm nodule that proved benign on biopsy. She was treated with thyroxine to reduce TSH secretion. Follow-up pelvic ultrasonography 1 year later showed no evidence of recurrent disease, and her serum thyroglobulin levels remained normal.
TL;DR: The authors of this Viewpoint propose that these paradoxical results might reflect how obesity is currently measured and highlight the importance of differentiating between body fat and lean mass.
Abstract: Patients defined as overweight or obese on the basis of BMI have reduced mortality and cardiovascular risk when compared with their normal-weight counterparts. The authors of this Viewpoint propose that these paradoxical results might reflect how obesity is currently measured and highlight the importance of differentiating between body fat and lean mass.
TL;DR: Pending data from future randomized, controlled trials of the association between thiazolidinediones and low bone mass, prescribers should consider use of these drugs as a risk factor for the development of osteoporosis in postmenopausal women.
Abstract: Thiazolidinediones, also known as glitazones, are insulin-sensitizing medications that account for approximately 21% of oral antihyperglycemic drugs used in the US. Although the main therapeutic effects occur in adipose tissue, muscles and the liver, studies suggest effects in bone as well. Currently, two thiazolidinediones are marketed in the US-rosiglitazone and pioglitazone-and several others are under investigation. This Review examines the evidence regarding the effects of thiazolidinediones on skeletal health. These drugs appear to trigger preferential differentiation of mesenchymal stem cells into adipocytes rather than osteoblasts, leading to decreased bone formation and increased adipogenesis. Although only a few small, randomized studies have examined the effects of thiazolidinediones on bone in humans, the available data suggest that these agents contribute to bone loss in postmenopausal women; the relationship is less clear in men. On the basis of this limited evidence, the absolute increase in fracture risk associated with thiazolidinediones seems to be small. Pending data from future randomized, controlled trials of the association between thiazolidinediones and low bone mass, prescribers should consider use of these drugs as a risk factor for the development of osteoporosis in postmenopausal women.