Diagnosis Of Endocrine Diseases Research Articles

PartII: Interactive case:Drug‐inducedendocrine disorders

Part<scp>II</scp>: Interactive case:<scp>Drug‐induced</scp>endocrine disorders

DIAGNOSIS OF ENDOCRINE DISEASE: Usefulness of genetic testing of fine-needle aspirations for diagnosis of thyroid cancer.

Genetic testing is increasingly used to diagnose or rule out thyroid cancer in indeterminate fine-needle aspirations. This review evaluates the usefulness of these methods with considerations of advantages and limitations. Given the diagnostic problem associated with the increasing incidental detection of indeterminate thyroid nodules in the context of thyroid cancer overtreatment, we consider the conditions and respective necessary settings for the role of genetic testing to improve presurgical malignancy risk stratification. We review diagnostic pathway requirements and commercially available molecular tests with their respective advantages and disadvantages and discuss the prerequisites required for local application and implementation including quality assurance for local ultrasound and cytopathology practices. Recent improvements in available molecular diagnostic tests have brought high sensitivity and specificity in initial validation studies, but whether these promising results translate to other clinical settings depends on the quality of the local thyroid nodule diagnostic pathway. Genetic testing can meaningfully improve presurgical malignancy risk assessment, but more work is needed to implement and use genetic testing effectively in local settings.

Endogenous and exogenous interferences in thyroid function immunoassays

Laboratory diagnosis of endocrine diseases has undergone many important changes over the past decades, despite the progress of thyroid function immunoassays technologies interferences cannot be completely excluded. These interferences can affect measurement of analyte which leads to misinterpretation and subsequent wrong clinical decisions, the probability of which is about 1%. However, the scale of the problem may be greater due to the lack of awareness to the problem among doctors and the lack of laboratory screening for interfering factors. These factors can be both endogenous and exogenous, bind both to antibodies to the analyte and to the reagent in the test system. The specificity of the immunoassay depends not only on the binding properties of antibodies, the activity of reagent, but also on the composition of the test system and the format of the methodology (non-competitive two-site or “sandwich” and competitive assays). This review provides a description of the main interferences that can affect the measurement of thyroid hormones, in particular thyroid stimulating hormone, free thyroxine and triiodothyronine, calcitonin, and demonstrates clinical cases reported in the literature over the past few years.

DIAGNOSIS OF ENDOCRINE DISEASE: Sex steroid action in adolescence: too much, too little; too early, too late.

This review aims to cover the subject of sex steroid action in adolescence. It will include situations with too little sex steroid action, as seen in for example, Turners syndrome and androgen insensitivity issues, too much sex steroid action as seen in adolescent PCOS, CAH and gynecomastia, too late sex steroid action as seen in constitutional delay of growth and puberty and too early sex steroid action as seen in precocious puberty. This review will cover the etiology, the signs and symptoms which the clinician should be attentive to, important differential diagnoses to know and be able to distinguish, long-term health and social consequences of these hormonal disorders and the course of action with regards to medical treatment in the pediatric endocrinological department and for the general practitioner. This review also covers situations with exogenous sex steroid application for therapeutic purposes in the adolescent and young adult. This includes gender-affirming therapy in the transgender child and hormone treatment of tall statured children. It gives some background information of the cause of treatment, the patient's motivation for medicating (or self-medicating), long-term consequences of exogenous sex steroid treatment and clinical outcome of this treatment.

DIAGNOSIS OF ENDOCRINE DISEASE: Diagnosing and classifying diabetes in diseases of the exocrine pancreas.

Diabetes in the setting of diseases of the exocrine pancreas has long existed as a known, but underdiagnosed or misdiagnosed, disorder. It currently finds itself in a state of taxonomic dereliction and requires a long overdue refurbishment. Correct conceptualisation is a key precondition for knowledge development in this disorder. This article lays out the epistemological foundation for diabetes of the exocrine pancreas (DEP) and presents a synthesis of the current interdisciplinary discourse on diagnosing and classifying DEP. A diagnosis of DEP in people with no medical records of pre-existing diabetes is generally based on the most up-to-date biochemical criteria endorsed by the American Diabetes Association and European Association for the Study of Diabetes. The presence of exocrine pancreatic dysfunction is not considered a mandatory diagnostic criterion for DEP but is rather a significant risk factor for developing DEP. DEP principally comprises post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes, which are mutually exclusive with autoimmune diabetes and type 2 diabetes. Other exclusions and stipulations apply. The DEP criteria will be instrumental in aiding optimal design and conduct of clinical studies, uniform collection of health utilisation data, meaningful comparison of scientific findings across countries, and clear communication among stakeholders (healthcare providers, patients, medical regulatory authorities, pharmaceutical industry).

Schmidt syndrome in clinical practice

The analysis of this clinical case is devoted to the need for strategic forecasting in the diagnosis of endocrine diseases. Autoimmune aggression is not directed against one organ, the progression of autoimmune damage is often slow, which increases the chances of missing a disease, and sometimes leads to a diagnosis at the time of crisis and decompensation. With timely suspicion of autoimmune polyglandular syndromes, the appointment of the necessary screening 1 time in 2-3 years, as well as patient education, we save them from years of diagnostic research, and timely compensatory therapy significantly improves the quality of life of patients.

DIAGNOSIS OF ENDOCRINE DISEASE: Mosaic disorders of FGF23 excess: Fibrous dysplasia/McCune-Albright syndrome and cutaneous skeletal hypophosphatemia syndrome.

Fibrous dysplasia/McCune-Albright Syndrome (FD/MAS), arising from gain-of-function mutations in Gαs, and cutaneous skeletal hypophosphatemia syndrome (CSHS), arising from gain-of-function mutations in the Ras/MAPK pathway, are strikingly complex, mosaic diseases with overlapping phenotypes. Both disorders are defined by mosaic skin and bone involvement, and both are complicated by increased FGF23 production. These similarities have frequently led to mis-diagnoses, primarily in patients with CSHS who are often assumed to have FD/MAS. The intriguing similarities in skeletal involvement in these genetically distinct disorders have led to novel insights into FGF23 physiology, making an understanding of FD/MAS and CSHS relevant to both clinicians and researchers interested in bone and endocrine disorders. This review will give an overview of FD/MAS and CSHS, focusing on the roles of mosaicism and FGF23 in the pathogenesis and clinical presentation of these disorders.

DIAGNOSIS OF ENDOCRINE DISEASE: Pituitary stalk interruption syndrome: etiology and clinical manifestations.

Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. This syndrome is an antenatal developmental defect belonging to the holoprosencephaly phenotype spectrum. It is heterogeneous regarding clinical, biological and radiological presentation and is characterized by the following triad: thin (<1 mm) or interrupted pituitary stalk connecting the hypothalamus to the pituitary gland, no eutopic posterior lobe, and hypoplasia or aplasia of the anterior lobe. This review reports current knowledge about the composite pathogenesis, for which underlying mechanisms remain unclear. Current data suggest genetic origins involving early developmental gene mutations with complex inheritance patterns and environmental influence, placing PSIS at the crossroads between Mendelian and multifactorial diseases. The phenotype associated with PSIS is highly heterogeneous with a high incidence of various combinations of hormonal deficiencies, sometimes associated with extra-pituitary birth defects. The age at onset is variable, but typical presentation is evolutive combined anterior pituitary hormone deficiencies at pediatric age, which progress even during adulthood to panhypopituitarism. Therefore, patients' follow-up throughout life is essential for adequate management.

DIAGNOSIS OF ENDOCRINE DISEASE: Drug-induced endocrinopathies and diabetes: a combo-endocrinology overview.

In the currently overwhelming era of polypharmacy, the balance of the dynamic and delicate endocrine system can easily be disturbed by interfering pharmaceutical agents like medications. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the feedback axis, on hormonal transport, binding and signaling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can interfere with the hormonal assays, leading to erroneous laboratory results that disorientate clinicians from the right diagnosis. The purpose of this review is to cover a contemporary topic, the drug-induced endocrinopathies, which was presented in the monothematic annual Combo Endo Course 2018. This challenging part of endocrinology is constantly expanding particularly during the last decade, with the new oncological therapeutic agents, targeting novel molecular pathways in the process of malignancies. In this new context of drug-induced endocrine disease, clinicians should be aware that drugs can cause endocrine abnormalities via different mechanisms and mimic a variety of clinical scenarios. Therefore, it is extremely important for clinicians not only to promptly recognize drug-induced hormonal and metabolic abnormalities, but also to address the therapeutic issues for timely intervention.

DIAGNOSIS OF ENDOCRINE DISEASE: IgG4-related thyroid autoimmune disease.

IgG4-related disease (IgG4-RD) is fibro-inflammatory, immune-mediated, systemic disease recognized as a defined clinical condition only in 2001. The prevalence of IgG4-RD is 6/100 000, but it is likely to be underestimated due to insufficient awareness of the disease. The diagnostic approach is complex because of the heterogeneity of clinical presentation and because of rather variable diagnostic criteria. Indeed, high concentrations of IgG4 in tissue and serum are not a reliable diagnostic marker. The spectrum of IgG4-RD also includes well-known thyroid diseases including Riedel's thyroiditis, Hashimoto's thyroiditis and its fibrotic variant, Graves' disease and Graves' orbitopathy. Results from clinical studies indicate that a small subset of patients with the above-mentioned thyroid conditions present some features suggestive for IgG4-RD. However, according to more recent views, the use of the term thyroid disease with an elevation of IgG4 rather than IgG4-related thyroid diseases would appear more appropriate. Nevertheless, the occurrence of high IgG4 levels in patients with thyroid disease is relevant due to peculiarities of their clinical course.

DIAGNOSIS OF ENDOCRINE DISEASE: Evaluation of bone fragility in endocrine disorders.

An underlying disease affecting bone health is present in up to 40% and 60% of osteoporotic post-menopausal women and men respectively. Among the disorders leading to a secondary form of osteoporosis, the endocrine diseases are highly represented. A frequent finding in patients affected with an endocrine-related forms of bone disease is that the skeletal fragility is partially independent of the bone density, since the fracture risk in these patients is related more to a reduction of bone quality than to a decrease of bone mass. As a consequence, bone mineral density evaluation by dual-X-ray Absorptiometry may be inadequate for establishing the risk of fracture in the setting of the endocrine-related forms of osteoporosis. In the recent years several attempts to non-invasively estimating bone quality have been done. Nowadys, some new tools are available in the clinical practice for optimizing the fracture risk estimation in patients with endocrine disorders. The aim of this review is to summarise the evidences regarding the role of the different imaging tools for evaluating bone density and bone quality in the most frequent forms of endocrine-related osteoporosis, such as obesity, diabetes, acromegaly, thyrotoxicosis, primary hyperparathyroidism, hypercortisolism and hypogonadism. For each of these disorders, data regarding both the current available tools and the future possible new techniques for assessing bone fragility in patients with endocrine diseases are reported.

Dual sensory impairment among a cohort of older adults living in Ireland: A nested case-control study of the Irish Longitudinal Study on Ageing cohort

Background: Little information is available on the implications of hearing loss, visual impairment and dual sensory impairment among older adults with an intellectual disability (ID) living in Ireland and this paper aims to address the health concerns associated with sensory impairment among this population. Methods: A representative sample of 753 persons aged 40 years and older at all levels of ID and full range of residential circumstances from the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA) participants were matched with general older population TILDA participants on age, sex and geographic location within Ireland. Demographic data on samples included age, sex, visual impairment (yes/no), hearing impairment (yes/no) and dual sensory impairment (yes/no). For those with intellectual disability (ID) data was also gathered on level of intellectual disability, residence, needing assistance with activities of daily living (ADL) and instrumental activities of daily living, self-rated health, loneliness, doctor’s diagnosis of endocrine disease and of dementia and doctor’s report of two or more chronic health conditions. Bivariate analysis of associations between visual, hearing and dual sensory impairment with the measures of physical and mental health was completed and logistic regression analysis to generate adjusted odds ratios for associations between sensory impairment and physical and mental health conditions. Results: As compared to the matched general population participants, in participants with ID dual sensory impairment was more often associated with poor self-rated health, limitations with two or more ADLs, loneliness and multimorbidity. People with ID were 4.4 times more likely to be multimorbid if they were visually impaired compared with an odds ratio of 2.4 in TILDA participants. Conclusion: Previous studies found significant associations between hearing and visual impairment among older populations. Analysis here also suggests the burden of sensory impairment increases both with ID and then with level of ID

Multiple Endocrine Neoplasia in Children and the Importance of Screening: Part 2

VHL is another type of multiple endocrine neoplasia, and is inherited in an autosomal dominant manner like MEN1. Some families may have the VHL diagnosis without genetic testing, due to two or more clinical manifestations having been noted. The gene mutation is located at 3q26–25, so the long arm of chromosome 3, locus 26–25. The most common tumours identified within this syndrome are retinal and central nervous haemangioblastomas, renal cancers, renal, pancreatic and epididymal cysts, phaeochromocytomas and paragangliomas (Maher, Neumann, & Richard, 2011). VHL disease can be classified into subtypes, relating to whether there are phaeochromocytomas present. Clinical presentation can manifest usually in adulthood (Prasad et al., 2011), but can also present much earlier in childhood, resulting in the need for a screening protocol as seen in Table 1.

Clinical diagnosis of endocrine diseases

Clinical diagnosis of endocrine diseases

DIAGNOSIS OF ENDOCRINE DISEASE: The role of the desmopressin test in the diagnosis and follow-up of Cushing's syndrome.

Desmopressin is a vasopressin analogue selective for type 2 vasopressin receptors that mediate renal water retention. In contrast to the native hormone arginine vasopressin, a well-known ACTH secretagogue, desmopressin, exerts minimal or no activity on ACTH excretion. However, in a substantial proportion of patients with ACTH-dependent Cushing's syndrome (CS), desmopressin elicits an ACTH and cortisol response, which contrasts with the minimal responses obtained in healthy subjects. The mechanism underlying this paradoxical response involves upregulation of vasopressin type 3 and/or the aberrant expression of type 2 receptors by neoplastic ACTH-producing cells. This makes desmopressin administration a suitable test enabling the distinction between neoplastic from functional (formerly termed 'pseudo-Cushing syndrome') ACTH-dependent cortisol excess. Several studies have now established an adjunctive role of desmopressin in the initial diagnostic workup of CS. Despite some early data indicating that this test may also have a role in distinguishing between Cushing's disease (CD) and ectopic ACTH secretion, subsequent studies failed to confirm this observation. The ability of the paradoxical response to desmopressin to depict the presence of neoplastic ACTH-secreting cells was also exploited in the follow-up of patients with CD undergoing surgery. Loss of the desmopressin response, performed in the early postoperative period, was a good predictor for a favorable long-term outcome. Moreover, during follow-up, reappearance of desmopressin paradoxical response was an early indicator for recurrence. In conclusion, the desmopressin test is a valid tool in both the diagnosis and follow-up of patients with CD and should be more widely applied in the workup of these patients.

DIAGNOSIS OF ENDOCRINE DISEASE: Bone turnover markers: are they clinically useful?

Bone turnover markers (BTMs) are useful in clinical practice as they are inexpensive, and they have proven useful for treatment monitoring and identification of poor adherence. BTMs cannot be used in individual patients for identifying accelerated bone loss or an increase in fracture risk or in deciding on the optimal therapy. They are useful for monitoring both anti-resorptive and anabolic treatment. Response can be defined as a result that exceeds an absolute target, or by a change greater than the least significant change; if such a response is not present, then poor compliance or secondary osteoporosis are likely causes. A baseline BTM measurement is not always made; in that case, a value of BTM on anti-resorptive treatment that is low or low normal or above the reference interval for anabolic therapy may be taken to indicate a satisfactory response. We provide an approach to using these bone turnover markers in clinical practice by describing algorithms for anti-resorptive and anabolic therapy and describing the changes we observe in the clinical practice setting.

DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids?

Since the early 1980s 18-hydroxycortisol and 18-oxocortisol have attracted attention when it was shown that the urinary excretion of these hybrid steroids was increased in primary aldosteronism. The development and more widespread use of specific assays has improved the understanding of their role in the (patho)physiology of adrenal disorders. The adrenal site of synthesis is not fully understood although it is clear that for the synthesis of 18-hydroxycortisol and 18-oxocortisol the action of both aldosterone synthase (zona glomerulosa) and 17α-hydroxylase (zona fasciculata) is required with cortisol as main substrate. The major physiological regulator is ACTH and the biological activity of both steroids is very low and therefore only very high concentrations might be effective in vivo In healthy subjects, the secretion of both steroids is low with 18-hydroxycortisol being substantially higher than that of 18-oxocortisol. The highest secretion of both steroids has been found in familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism) and in familial hyperaldosteronism type 3. Lower but yet substantially increased secretion is found in patients with aldosterone-producing adenomas in contrast to bilateral hyperplasia in whom the levels are similar to patients with hypertension. Several studies have attempted to show that these steroids, in particular, peripheral venous plasma 18-oxocortisol, might be a useful discriminatory biomarker for subtyping PA patients. The current available limited evidence precludes the use of these steroids for subtyping. We review the biosynthesis, regulation and function of 18-hydroxycortisol and 18-oxocortisol and their potential utility for the diagnosis and differential diagnosis of patients with primary aldosteronism.

DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome)

Endogenous hypercortisolism (Cushing's syndrome) usually implies the presence of a pathologic condition caused by either an ACTH-secreting neoplasm or autonomous cortisol secretion from a benign or malignant adrenal neoplasm. However, sustained or intermittent hypercortisolism may also accompany many medical disorders that stimulate physiologic/non-neoplastic activation of the HPA axis (formerly known as pseudo-Cushing's syndrome); these two entities may share indistinguishable clinical and biochemical features. A thorough history and physical examination is often the best (and sometimes only) way to exclude pathologic/neoplastic hypercortisolism. The presence of alcoholism, renal failure, poorly controlled diabetes and severe neuropsychiatric disorders should always raise suspicion that the presence of hypercortisolism may be related to physiologic/non-neoplastic Cushing's syndrome. As late-night salivary cortisol and low-dose dexamethasone suppression have good sensitivity and negative predictive value, normal studies exclude Cushing's syndrome of any form. However, these tests have imperfect specificity and additional testing over time with clinical follow-up is often needed. When there is persistent diagnostic uncertainty, secondary tests such as the DDAVP stimulation test and the dexamethasone-CRH test may provide evidence for the presence or absence of an ACTH-secreting tumor. This review will define and characterize the numerous causes of physiologic/non-neoplastic hypercortisolism and provide a rational clinical and biochemical approach to distinguish it from pathologic/neoplastic hypercortisolism (true Cushing's syndrome).

DIAGNOSIS OF ENDOCRINE DISEASE: Endocrine late-effects of childhood cancer and its treatments.

Endocrine complications are frequently observed in childhood cancer survivors (CCS). One of two CCS will experience at least one endocrine complication during the course of his/her lifespan, most commonly as a late-effect of cancer treatments, especially radiotherapy and alkylating agent chemotherapy. Endocrine late-effects include impairments of the hypothalamus/pituitary, thyroid and gonads, as well as decreased bone mineral density and metabolic derangements leading to obesity and/or diabetes mellitus. A systematic approach where CCS are screened for endocrine late-effects based on their cancer history and treatment exposures may improve health outcomes by allowing the early diagnosis and treatment of these complications.

DIAGNOSIS OF ENDOCRINE DISEASE: How reliable are free thyroid and total T3 hormone assays?

Hypothyroidism is a very common disorder worldwide, for which the usual treatment is monotherapy with levothyroxine (L-T4). However, a number of patients treated with L-T4 continue to report symptoms of hypothyroidism despite seemingly normal levels of thyroid-stimulating hormone (TSH), free-T3 (FT3) and free-T4 (FT4) measured by immunoassay. This review summarizes the limitations of the immunoassays commonly used to measure thyroid hormone levels and emphasizes the advantages of the role of liquid chromatography-tandem mass spectrometry (LC-MS/MS). Immunoassays for free thyroid hormone are affected by alterations in serum binding proteins that occur in many physiological and disease states. Multiple studies show falsely normal values for T3, FT3 and FT4 by immunoassay that are below the reference interval when measured by (ultrafiltration) LC-MS/MS, a reference method. We suggest evaluation of thyroid hormone levels by ultrafiltration LC-MS/MS for patients who continue to experience hypothyroid symptoms on LT-4. This may help identify the approximately 20% subset of patients who would benefit from addition of T3 to their treatment regimen (combination therapy).