Uso adecuado de las pruebas de laboratorio para la evaluación de la función tiroidea en pediatría / Appropriate use of laboratory tests for evaluation of thyroid function in pediatrics

Las pruebas de función tiroidea (PFT) son esenciales para el diagnóstico preciso y el seguimiento eficaz de la disfunción tiroidea. Existe un incremento progresivo y estable de los pedidos de PFT, incluso se han incorporado las mismas a los exámenes de salud anuales en niños sanos. Representan más del 60% de las pruebas realizadas en el laboratorio de endocrinología, tanto en adultos como en los laboratorios especializados en pediatría. Para hacer un uso eficiente de las PFT, antes de solicitarlas debemos preguntarnos… ¿Para quién? ¿Cuándo solicitarlas? ¿Qué pruebas solicitar? ¿Cómo solicitarlas? y ¿Cómo interpretar correctamente los resultados? Un resultado anormal en las PFT no siempre implica patología tiroidea asociada. Las PFT tienen importante variabilidad intra e interindividual lo que hace más compleja su correcta interpretación. La pesquisa de enfermedad tiroidea neonatal es un importante aporte a la prevención de la deficiencia mental en la infancia, su aplicación obligatoria posibilita un diagnóstico temprano, para asegurar su éxito debe considerarse en el marco de un programa integral de detección con estrategias de confirmación, tratamiento temprano y seguimiento a corto, mediano y largo plazo. No debe hacerse un uso indiscriminado de la prueba de estímulo con TRH en el diagnóstico de la patología tiroidea. En pediatría la estrategia de tamiz de enfermedad tiroidea es conveniente realizarla mediante la medición de por lo menos TSH y T4 libre e incluir la determinación de ATPO en grupos de riesgo, a diferencia de la determinación aislada de TSH como es recomendado en adultos. (AU)

Thyroid function tests (TFTs) are essential for accurate diagnosis and effective monitoring of thyroid dysfunction. There is a progressive and steady increase in requests for TFTs, and they have even been incorporated into annual health examinations in healthy children. They represent more than 60% of the tests performed in the endocrinology laboratory, both in adults and in specialized pediatric laboratories. To efficiently use TFTs, before requesting them we should ask ourselves... For whom? When to request them? Which tests to request? How to request them? and How to correctly interpret the results? An abnormal TFT result does not always imply thyroid disease. TFTs have significant intra- and inter-individual variability, which makes their correct interpretation more complex. Screening for newborn thyroid disease is an important contribution to the prevention of intellectual disability in childhood and its mandatory use enables early diagnosis; however, to ensure the test to be successful, it should be considered within the framework of a comprehensive screening program with strategies for confirmation, early treatment, and short-, medium-, and long-term follow-up. The TRH stimulation test in the diagnosis of thyroid disease should not be used indiscriminately. In children, the screening strategy for thyroid disease should be performed by measuring at least TSH and free T4 and include the measurement of TPO-ab in risk groups, as opposed to the isolated measurement of TSH as recommended in adults. (AU)

Human Genetics to Identify Therapeutic Targets for NAFLD: Challenges and Opportunities.

Non-alcoholic fatty liver disease (NAFLD) is a continuous progression of pathophysiologic stages that is challenging to diagnose due to its inherent heterogeneity and poor standardization across a wide variety of diagnostic measures. NAFLD is heritable, and several loci have been robustly associated with various stages of disease. In the past few years, larger genetic association studies using new methodology have identified novel genes associated with NAFLD, some of which have shown therapeutic promise. This mini-review provides an overview of the heterogeneity in NAFLD phenotypes and diagnostic methods, discusses genetic associations in relation to the specific stages for which they were identified, and offers a perspective on the design of future genetic mapping studies to accelerate therapeutic target identification.

Latent Adrenal Insufficiency: From Concept to Diagnosis.

Primary adrenal insufficiency (PAI) is a rare disease and potentially fatal if unrecognized. It is characterized by destruction of the adrenal cortex, most frequently of autoimmune origin, resulting in glucocorticoid, mineralocorticoid, and adrenal androgen deficiencies. Initial signs and symptoms can be nonspecific, contributing to late diagnosis. Loss of zona glomerulosa function may precede zona fasciculata and reticularis deficiencies. Patients present with hallmark manifestations including fatigue, weight loss, abdominal pain, melanoderma, hypotension, salt craving, hyponatremia, hyperkalemia, or acute adrenal crisis. Diagnosis is established by unequivocally low morning serum cortisol/aldosterone and elevated ACTH and renin concentrations. A standard dose (250 µg) Cosyntropin stimulation test may be needed to confirm adrenal insufficiency (AI) in partial deficiencies. Glucocorticoid and mineralocorticoid substitution is the hallmark of treatment, alongside patient education regarding dose adjustments in periods of stress and prevention of acute adrenal crisis. Recent studies identified partial residual adrenocortical function in patients with AI and rare cases have recuperated normal hormonal function. Modulating therapies using rituximab or ACTH injections are in early stages of investigation hoping it could maintain glucocorticoid residual function and delay complete destruction of adrenal cortex.

New types of localization methods for adrenocorticotropic hormone-dependent Cushing's syndrome.

The management of endogenous Cushing's syndrome (CS) typically involves two key steps: (i) confirmation of autonomous hypercortisolism and (ii) localization of the cause to guide treatment. Adrenocorticotropic hormone (ACTH)-dependent CS is most commonly due to a pituitary corticotrope tumor which may be so small as to evade detection on conventional magnetic resonance imaging (MRI). Although biochemical testing (e.g., corticotropin stimulation; dexamethasone suppression) can provide an indication of the likely origin of ACTH excess, bilateral inferior petrosal sinus catheterization offers greater accuracy to distinguish pituitary-driven CS [Cushing's Disease (CD)] from the ectopic ACTH syndrome [EAS, e.g., due to a bronchial or pancreatic neuroendocrine tumor (NET)]. In patients with CD, 40-50% may not have a pituitary adenoma (PA) readily visualized on standard clinical MRI. In these subjects, alternative MR sequences (e.g., dynamic, volumetric, fluid attenuation inversion recovery) and higher magnetic field strength (7T > 3T > 1.5T) may aid tumor localization but carry a risk of identifying coincidental (non-causative) pituitary lesions. Molecular imaging is therefore increasingly being deployed to detect small ACTH-secreting PA, with hybrid imaging [e.g., positron emission tomography (PET) combined with MRI] allowing precise anatomical localization of sites of radiotracer (e.g., 11C-methionine) uptake. Similarly, small ACTH-secreting NETs, missed on initial cross-sectional imaging, may be detected using PET tracers targeting abnormal glucose metabolism (e.g., 18F-fluorodeoxyglucose), somatostatin receptor (SSTR) expression (e.g., 68Ga-DOTATATE), amine precursor (e.g., 18F-DOPA) or amino acid (e.g., 11C-methionine) uptake. Therefore, modern management of ACTH-dependent CS should ideally be undertaken in specialist centers which have an array of cross-sectional and functional imaging techniques at their disposal.

How to Classify and Define Pituitary Tumors: Recent Advances and Current Controversies.

Pituitary tumors are very complex and heterogeneous and have a very wide range of proliferative and aggressive behaviors, and how to define and classify these tumors remains controversial. This review summarizes the epidemiology and progress in the classification and definition of pituitary tumors, as well as controversial issues. Based on the results of radiologic and autopsy studies, the prevalence of pituitary tumors has recently increased significantly. However, the majority of pituitary tumors are incidentally discovered and asymptomatic, and such tumors are called pituitary incidentalomas. Most of these incidentalomas do not induce symptoms, remain stable in size, and do not need treatment. The recent revised classification strategies mainly depend on immunohistochemistry (IHC) to detect pituitary hormones and pituitary transcription factors; therefore, the accuracy of diagnosing pituitary tumors has improved. Although new classification strategies and definitions for pituitary tumors have been presented, there are still some controversies. The term pituitary neuroendocrine tumor (PitNET) was proposed by the International Pituitary Pathology Club, and this terminology can encompass the unpredictable malignant behavior seen in the subset of aggressive pituitary adenomas (PAs). However, some endocrinologists who oppose this change in terminology have argued that the use of tumor in the terminology is misleading, as it gives PAs a harmful connotation when the majority are not aggressive. Such terminology may add new ambiguity to the origin of PAs and unnecessary anxiety and frustration for the majority of patients with benign PAs. The classification of aggressive PAs mainly relies on subjective judgment of clinical behavior and lacks objective biomarkers and unified diagnostic criteria. However, the term "refractory" could more accurately represent the characteristics of these tumors, including their clinical behaviors, radiological features, and pathologic characteristics. Moreover, the diagnostic criteria for refractory PAs are stricter, more objective, and more accurate than those for aggressive PAs. Early identification of patients with these tumors through recognition and increased awareness of the definition of refractory PAs will encourage the early use of aggressive therapeutic strategies.

Novel biomarkers of diabetic kidney disease: current status and potential clinical application.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Although both albuminuria and glomerular filtration rate (GFR) are well-established diagnostic/prognostic biomarkers of DKD, they have important limitations. There is, thus, increasing quest to find novel biomarkers to identify the disease in an early stage and to improve risk stratification. In this review, we will outline the major pitfalls of currently available markers, describe promising novel biomarkers, and discuss their potential clinical relevance. In particular, we will focus on the importance of recent advancements in multi-omic technologies in the discovery of new DKD biomarkers. In addition, we will provide an update on new emerging approaches to explore renal function and structure, using functional tests and imaging.

DIAGNOSIS OF ENDOCRINE DISEASE: Post-pancreatitis diabetes mellitus: prime time for secondary disease.

While most people with diabetes have type 2 disease, a non-negligible minority develops a secondary diabetes. Post-pancreatitis diabetes mellitus (PPDM) is an exemplar secondary diabetes that represents a sequela of pancreatitis - the most common disease of the exocrine pancreas. Although this type of diabetes has been known as a clinical entity since the late 19th century, early 21st century high-quality epidemiological, clinical, and translational studies from around the world have amassed a sizeable body of knowledge that have led to a renewed understanding of PPDM. People have at least two-fold higher lifetime risk of developing diabetes after an attack of pancreatitis than those in the general population without a history of diseases of the exocrine pancreas. PPDM is caused by acute pancreatitis (including non-necrotising pancreatitis, which constitutes the majority of acute pancreatitis) in four-fifth of cases and chronic pancreatitis in one-fifth of cases. Moreover, the frequency of incident diabetes is not considerably lower after acute pancreatitis than after chronic pancreatitis. Recurrent attacks of pancreatitis and exocrine pancreatic dysfunction portend high risk for PPDM, but are not mandatory for its development. Further, young- or middle-aged non-obese men have an increased risk of developing PPDM. In comparison with type 2 diabetes, PPDM is characterised by poorer glycaemic control, higher risk of developing cancer (in particular, pancreatic cancer), younger age at death, and a higher risk of mortality. Metformin monotherapy is recommended as the first-line therapy for PPDM. Appropriate screening of individuals after an attack of pancreatitis, correct identification of PPDM, and apposite management is crucial with a view to improving the outcomes of this secondary but not inappreciable disease.

Analysis of steroid profiles by mass spectrometry: A new tool for exploring adrenal tumors?

The assay of multiple steroids by mass spectrometry coupled with chromatography, combined with data analysis using an artificial intelligence approach, has become more widely accessible in recent years. Multiple applications for this technology exist for the study of adrenocortical tumors. Taking advantage of the capacity of malignant cortical tumor secretion of non-bioactive precursors, it provides an additional diagnostic approach that can point to the nature of a tumor. These encouraging perspectives have been based to date only on pilot retrospective studies. However, this has changed in 2020 with the publication of data from the EURINE-ACT study. This very large prospective European study provided more nuanced evidence for the benefit of combining the measurement of a panel of steroids with essential imaging tools. This study also facilitated our understanding and provided more precise characterisation of autonomous steroid secretion, particularly in the case of sublinical cortisol-secreting adrenocortical adenomas. This article will focus on our current knowledge on the potential utility of mass spectrometry for diagnosis of both the nature of an adrenal tumors and their secretion.

Evolution of the Primary Aldosteronism Syndrome: Updating the Approach.

CONTEXT: New approaches are needed to address the evolution of the primary aldosteronism syndrome and to increase its recognition. Herein, we review evidence indicating that primary aldosteronism is a prevalent syndrome that is mostly unrecognized, and present a pragmatic and pathophysiology-based approach to improve diagnosis and treatment. METHODS: Evidence was gathered from published guidelines and studies identified from PubMed by searching for primary aldosteronism, aldosterone, renin, and hypertension. This evidence was supplemented by the authors' personal knowledge, research experience, and clinical encounters in primary aldosteronism. INTERPRETATION OF EVIDENCE: Renin-independent aldosterone production is a prevalent phenotype that is diagnosed as primary aldosteronism when severe in magnitude, but is largely unrecognized when milder in severity. Renin-independent aldosterone production can be detected in normotensive and hypertensive individuals, and the magnitude of this biochemical phenotype parallels the magnitude of blood pressure elevation, the risk for incident hypertension and cardiovascular disease, and the likelihood and magnitude of blood pressure reduction with mineralocorticoid receptor antagonist therapy. Expansion of the indications to screen for primary aldosteronism, combined with the use of a pathophysiology-based approach that emphasizes inappropriate aldosterone production in the context of renin suppression, will substantially increase the diagnostic and therapeutic yields for primary aldosteronism. CONCLUSIONS: The landscape of primary aldosteronism has evolved to recognize that it is a prevalent syndrome of renin-independent aldosterone production that contributes to the pathogenesis of hypertension and cardiovascular disease. Expanding screening indications and simplifying the diagnostic approach will enable implementation of targeted treatment for primary aldosteronism.

Diabetes Insipidus: An Update.

The differential diagnosis of diabetes insipidus involves the distinction between central or nephrogenic diabetes insipidus and primary polydipsia. Differentiation is important because treatment strategies vary; the wrong treatment can be dangerous. Reliable differentiation is difficult especially in patients with primary polydipsia or partial forms of diabetes insipidus. New diagnostic algorithms are based on the measurement of copeptin after osmotic stimulation by hypertonic saline infusion or after nonosmotic stimulation by arginine and have a higher diagnostic accuracy than the water deprivation test. Treatment involves correcting preexisting water deficits, but is different for central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia.

Multimodal imaging of thyroid cancer.

PURPOSE OF REVIEW: Thyroid cancer is the most common endocrine cancer in adults with rising incidence. Challenges in imaging thyroid cancer are twofold: distinguishing thyroid cancer from benign thyroid nodules, which occur in 50% of the population over 50 years; and correct staging of thyroid cancer to facilitate appropriate radical surgery in a single session. The clinical management of thyroid cancer patients has been covered in detail by the 2015 guidelines of the American Thyroid Association (ATA). The purpose of this review is to state the principles underlying optimal multimodal imaging of thyroid cancer and aid clinicians in avoiding important pitfalls. RECENT FINDINGS: Recent additions to the literature include assessment of ultrasound-based scoring systems to improve selection of nodules for fine needle biopsy (FNB) and the evaluation of new radioactive tracers for imaging thyroid cancer. SUMMARY: The mainstay of diagnosing thyroid cancer is thyroid ultrasound with ultrasound-guided FNB. Contrast-enhanced computed tomography and PET with [F]-fluorodeoxyglucose (FDG) and MRI are reserved for advanced and/or recurrent cases of differentiated thyroid cancer and anaplastic thyroid cancer, while [F]FDOPA and [Ga]DOTATOC are the preferred tracers for medullary thyroid cancer.

Fingernail cortisol - State of research and future directions.

The extraction of cortisol from fingernails represents a recent advancement in the retrospective, long-term assessment of hypothalamic-pituitaryadrenal (HPA) axis activity: Fingernail cortisol has the potential to overcome some of the major disadvantages of established HPA axis markers. However, the introduction of any novel methodology also raises certain caveats. This review provides a comprehensive summary of the current state of research on fingernail cortisol. It identifies a number of strengths of his novel methodology (e.g., its high feasibility), while also pointing out open questions which currently challenge the interpretability of fingernail findings, in particular regarding the time period of cortisol secretion reflected in fingernail samples, as well as regarding potential determinants or confounders of fingernail cortisol (e.g. sociodemographic, lifestyle, or health characteristics). Clarification of these issues in the context of further methodological studies is necessary to validate the use of fingernail cortisol as a retrospective marker of HPA axis activity.

Contemporary evaluation and management of tall cell variant of papillary thyroid carcinoma.

PURPOSE OF REVIEW: The purpose of this review is to describe the contemporary evaluation and management of tall cell variant of papillary thyroid carcinoma with an emphasis on the clinical features. RECENT FINDINGS: Tall cell variant of papillary thyroid carcinoma is the most common aggressive subtype. Within the last few years, the diagnostic criteria for this entity have evolved. Studies have elucidated a better understanding of the clinical implications and pathophysiology of this variant. In this review, the studies presented reflect cumulative and aggregated data from metaanalyses, systematic reviews, and large database investigations utilizing the current diagnostic criteria. SUMMARY: Overall, tall cell variant of papillary thyroid carcinoma represents an aggressive subtype of well-differentiated thyroid carcinoma with more prevalent high-risk features and a poorer clinical outcome.

Central diabetes insipidus in children: Diagnosis and management.

Central diabetes insipidus (CDI) is a complex disorder in which large volumes of dilute urine are excreted due to arginine-vasopressin deficiency, and it is caused by a variety of conditions (genetic, congenital, inflammatory, neoplastic, traumatic) that arise mainly from the hypothalamus. The differential diagnosis between diseases presenting with polyuria and polydipsia is challenging and requires a detailed medical history, physical examination, biochemical approach, imaging studies and, in some cases, histological confirmation. Magnetic resonance imaging is the gold standard method for evaluating the sellar-suprasellar region in CDI. Pituitary stalk size at presentation is variable and can change over time, depending on the underlying condition, and other brain areas or other organs - in specific diseases - may become involved during follow up. An early diagnosis and treatment are preferable in order to avoid central nervous system damage and the risk of dissemination of germ cell tumor, or progression of Langerhans Cell Histiocytosis, and in order to start treatment of additional pituitary defects without further delay. This review focuses on current diagnostic work-up and on the role of neuroimaging in the differential diagnosis of CDI in children and adolescents. It provides an update on the best approach for diagnosis - including novel biochemical markers such as copeptin - treatment and follow up of children and adolescents with CDI; it also describes the best approach to challenging situations such as post-surgical patients, adipsic patients, patients undergoing chemotherapy and/or in critical care.

Contemporary Thyroid Nodule Evaluation and Management.

CONTEXT: Approximately 60% of adults harbor 1 or more thyroid nodules. The possibility of cancer is the overriding concern, but only about 5% prove to be malignant. The widespread use of diagnostic imaging and improved access to health care favor the discovery of small, subclinical nodules and small papillary cancers. Overdiagnosis and overtreatment is associated with potentially excessive costs and nonnegligible morbidity for patients. EVIDENCE ACQUISITION: We conducted a PubMed search for the recent English-language articles dealing with thyroid nodule management. EVIDENCE SYNTHESIS: The initial assessment includes an evaluation of clinical risk factors and sonographic examination of the neck. Sonographic risk-stratification systems (e.g., Thyroid Imaging Reporting and Data Systems) can be used to estimate the risk of malignancy and the need for biopsy based on nodule features and size. When cytology findings are indeterminate, molecular analysis of the aspirate may obviate the need for diagnostic surgery. Many nodules will not require biopsy. These nodules and those that are cytologically benign can be managed with long-term follow-up alone. If malignancy is suspected, options include surgery (increasingly less extensive), active surveillance or, in selected cases, minimally invasive techniques. CONCLUSION: Thyroid nodule evaluation is no longer a 1-size-fits-all proposition. For most nodules, the likelihood of malignancy can be confidently estimated without resorting to cytology or molecular testing, and low-frequency surveillance is sufficient for most patients. When there are multiple options for diagnosis and/or treatment, they should be discussed with patients as frankly as possible to identify an approach that best meets their needs.

Diagnosis and differential diagnosis of diabetes insipidus: Update.

The two main differential diagnoses of central diabetes insipidus are nephrogenic diabetes insipidus and primary polydipsia. Reliable distinction between those entities is essential as treatment differs substantially with the wrong treatment potentially leading to serious complications. Past diagnostic measures using the indirect water deprivation test had several pitfalls, resulting in a low diagnostic accuracy. With the introduction of copeptin, a stable and reliable surrogate marker for arginine vasopressin, diagnosis of diabetes insipidus was new evaluated. While unstimulated basal copeptin measurement reliably diagnoses nephrogenic diabetes insipidus, a stimulation test is needed to differentiate patients with central diabetes insipidus from patients with primary polydipsia. Stimulation can either be achieved through hypertonic saline infusion or arginine infusion. While the former showed high diagnostic accuracy and superiority over the indirect water deprivation test in a recent validation study, the diagnostic accuracy for arginine-stimulated copeptin was slightly lower, but superior in test tolerance. In summary of the recent findings, a new copeptin based diagnostic algorithm is proposed for the reliable diagnosis of diabetes insipidus.

What do you need to know about mass spectrometry? A brief guide for endocrinologists.

In routine hormonology, liquid chromatography mass spectrometry (LCMS) is now an established technique for androgen, urinary cortisol and metanephrine assay. It has the undeniable advantage of great analytical specificity, but with sensitivity that clearly depends on financial investment in a very high-end spectrometer. We describe the general principles of LCMS and the routine applications so far developed in hormonology. The purpose is to familiarise endocrinologists with the techniques under development and their pros and cons.

Disease monitoring of Primary Aldosteronism.

Primary aldosteronism (PA) is a highly prevalent cause of arterial hypertension featuring excess cardiovascular events. A timely diagnosis and treatment of PA cures hyperaldosteronism and can provide resolution or improvement of arterial hypertension, even when the latter is resistant to drug treatment. Accordingly, strategies to screen early and widely the hypertensive patients for PA by means of simplified diagnostic algorithms are justified. Such strategies are particularly beneficial in subgroups of hypertensive patients, who are at the highest cardiovascular risk. Broadening of screening strategies means facing with an increased number of patients where monitoring the disease becomes necessary. Hence, after identification of the surgically and non surgically curable cases of PA and implementation of targeted treatment physicians are faced with the challenges of follow-up, which are scantly discussed in the literature. Hence, the purpose of this paper is to provide some recommendations on how to optimize the monitoring of patients in whom the PA subtype has been diagnosed and treatment, either with unilateral laparoscopic adrenalectomy or medically, has been instituted.

Cushing's syndrome: Overview of clinical presentation, diagnostic tools and complications.

Cushing's syndrome (CS) is a severe condition that results from chronic exposure to elevated circulating cortisol levels; it is a rare but potentially life-threating condition, especially when not timely diagnosed and treated. Even though the diagnosis can be straightforward in florid cases due to their typical phenotype, milder forms can be missed. Despite the availability of different screening tests, the diagnosis remains challenging as none of the available tools proved to be fully accurate. Due to the ubiquitous effect of cortisol, it is easy understandable that its excess leads to a variety of systemic complications including hypertension, metabolic syndrome, bone damages and neurocognitive impairment. This article discusses clinical presentation of CS with an eye on the most frequent cortisol-related comorbidities and discuss the main pitfalls of first- and second-line tests in endogenous hypercortisolism diagnostic workup.