Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of Candida albicans strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene

Haematologica

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Should we fear the perchlorate ion in the environment?

International audiencePerchlorate ions (ClO4-) are present in groundwater and are then present in distribution networks of drinking water destined for human consumption. The perchlorate ion comes mainly from ammonium salt manufactured for industrial activities or from arms of the First World War. Perchlorate ion is a competitive inhibitor of the sodium-iodide symporter and inhibits the synthesis of thyroid hormones. Values of toxicity have been published by the French agency ANSES and are used by authorities to limit the consumption of drinking water of some distribution networks by children and pregnant women especially in Nord-Pas-de-Calais and Picardie. Epidemiological data in other countries show no or little clinical effect in areas with similar contamination; it is therefore a precautionary principle. An effective substitution with iodine would limit the effects of the iodine deficiency itself but also would counteract the potential effects of an excess of perchlorate ions and also of other symporter inhibitors (thiocyanate, nitrate). Further studies are nevertheless needed to determine possible extra-thyroid effects of perchlorate ions

Has the thyroid something to fear from the environment?

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Hypoglycaemia related to inherited metabolic diseases in adults

<p>Abstract</p> <p>In non-diabetic adult patients, hypoglycaemia may be related to drugs, critical illness, cortisol or glucagon insufficiency, non-islet cell tumour, insulinoma, or it may be surreptitious. Nevertheless, some hypoglycaemic episodes remain unexplained, and inborn errors of metabolism (IEM) should be considered, particularly in cases of multisystemic involvement. In children, IEM are considered a differential diagnosis in cases of hypoglycaemia. In adulthood, IEM-related hypoglycaemia can persist in a previously diagnosed childhood disease. Hypoglycaemia may sometimes be a presenting sign of the IEM. Short stature, hepatomegaly, hypogonadism, dysmorphia or muscular symptoms are signs suggestive of IEM-related hypoglycaemia. In both adults and children, hypoglycaemia can be clinically classified according to its timing. <it>Postprandial</it> hypoglycaemia can be an indicator of either endogenous hyperinsulinism linked to non-insulinoma pancreatogenic hypoglycaemia syndrome (NIPHS, unknown incidence in adults) or very rarely, inherited fructose intolerance. Glucokinase-activating mutations (one family) are the only genetic disorder responsible for NIPH in adults that has been clearly identified so far. <it>Exercise-induced</it> hyperinsulinism is linked to an activating mutation of the monocarboxylate transporter 1 (one family). <it>Fasting</it> hypoglycaemia may be caused by IEM that were already diagnosed in childhood and persist into adulthood: glycogen storage disease (GSD) type I, III, 0, VI and IX; glucose transporter 2 deficiency; fatty acid oxidation; ketogenesis disorders; and gluconeogenesis disorders. Fasting hypoglycaemia in adulthood can also be a rare presenting sign of an IEM, especially in GSD type III, fatty acid oxidation [medium-chain acyl-CoA dehydrogenase (MCAD), ketogenesis disorders (3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) lyase deficiency, and gluconeogenesis disorders (fructose-1,6-biphosphatase deficiency)].</p

Endocrine manifestations related to inherited metabolic diseases in adults

Abstract Most inborn errors of metabolism (IEM) are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.). IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects), and metal (hemochromatosis) and storage disorders (cystinosis). Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes), whereas primary hypogonadism is reported in Alström disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction) and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure), congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last). This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses.</p

Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1

International audienceAutoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of Candida albicans strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene

Reply on the Letter by Stott et al. 'The Dilemma of Treating Subclinical Hypothyroidism: Risk that Current Guidelines Do More Harm than Good'

We appreciate the interest of Stott et al. [1] in the Management of Subclinical Hypothyroidism ETA Guidelines 2013 [2]. We are, however, somewhat puzzled by the authors' statement that the guidelines ‘risk doing more harm than good’, probably the result of misinterpretation of some recommendations of the guidelines. The ETA Guidelines represent a meticulous interpretation of more than 140 articles and were, moreover, posted on the ETA website for about a month for criticism and comments. They offer a unique platform of expertise, supporting those involved in the diagnosis and treatment of both younger and older patients with subclinical hypothyroidism (SCH), in a spirit of collaboration for the benefit of our patients. Stott et al. [1] basically agree with the guidelines that the wait-and-see approach and repeat thyroid testing in patients with SCH is a widely accepted concept. The measurement of thyroid auto-antibodies determines the risk of progression to overt hypothyroidism, especially if the thyroid-stimulating hormone (TSH) level is above 2.5 mU/l [3]. The guidelines are misrepresented by these comments, as we definitely do not recommend treatment based on auto-antibodies. The categorization of the patients by age (60-70 years as moderately old, >70 years as older and >80-85 years as oldest old) is essential for the establishment of a diagnosis that should also consider ‘age-specific reference ranges for serum TSH’ (recommendation 14) in older people. It has clearly been shown that there is a widening of the reference range for serum TSH with increasing age [4,5]. In fact, a recent study from a large population in Scotland demonstrated a significant increase in the 97.5th centile of TSH (3.98-5.94 mU/l, respectively) with increasing age [6]. In addition, there are differences in the nature of the TSH changes with age between iodine-deficient and iodine-replete populations. We therefore do not agree with the authors that the consideration of age-specific guidelines is ‘premature and overly complex’ [1], but feel that this is important information that cannot be omitted from the guideline in an artificial attempt to avoid complexity. Stott et al. [1] are in agreement that levothyroxine treatment, depending on the degree of TSH suppression and age, is associated with lower bone density, increased risk of fractures and atrial fibrillation. The guidelines specifically recommend (recommendation 15) that the oldest old subjects (>80-85 years) with elevated serum TSH ≤10 mU/l should be carefully followed with a wait-and-see strategy, generally avoiding hormonal treatment. This procedure is supported by a recent study showing that older patients are at particular risk for overtreatment, as their upper limit of normal for the level of TSH is slightly higher than that in younger patients [7]. Among 3,900 community-dwelling apparently euthyroid Caucasian Australian men over 70 years of age, those whose free thyroxine was normal but in the highest quartile were 20% more likely to have died over 6 years of follow-up. Finally, we absolutely agree that a randomized controlled trial, such as the one by the TRUST-IEMO collaboration, is needed to reinforce decision making as to whether levothyroxine treatment is required and is beneficial in older patients with SCH and also to determine whether the oldest old may benefit from treatment. Accordingly, the guideline states that appropriately powered randomized controlled trials of levothyroxine in SCH patients, examining hard cardiovascular end points in various classes of age, are clearly warranted. Based on these data and the present joint statement, it is therefore evident that the guidelines, especially recommendation 21 stating ‘In the elderly, any treatment for SCH should be individualized, gradual and closely monitored’, can be of undoubted assistance and will certainly not do harm