Hypothyroidism: The difficulty in attributing symptoms to their underlying cause

Common symptoms of overt hypothyroidism are non-specific and include fatigue, lethargy, and dry skin. Although the diagnosis is considered to be straightforward, no single symptom can be used to identify patients with overt hypothyroidism, while many patients with subclinical hypothyroidism are asymptomatic. A large population-based study on the spectrum of symptoms in subclinical hypothyroidism showed similar rates of thyroid disease-related symptoms compared with euthyroid subjects, while the TSH concentration had no impact on symptom score. Together, these findings make it challenging to attribute symptoms to their underlying cause. This is also true in the case of unexplained persistent symptoms in levothyroxine-treated patients. Although generally considered a life-long replacement therapy, successful thyroid hormone discontinuation resulting in euthyroidism has been reported in approximately one third of patients. Thus, we overtreat patients with (subclinical) hypothyroidism, highlighting the importance of reliable diagnostic criteria. The diagnostic process, including the implementation of robust TSH and FT4 reference intervals, is especially challenging in specific situations including aging, pregnancy, non-thyroidal illness, and central hypothyroidism. There is a clear need for improved adherence to current guidelines from scientific societies and for willingness to manage symptoms without a clear pathological correlate, especially in the case of mild TSH elevations. This review will highlight recent literature on this topic and offers some practice points

Vitamin D: marker, measurand & measurement

The measurement of vitamin D metabolites aids in assessing vitamin D status and in diagnosing disorders of calcium homeostasis. Most laboratories measure total 25-hydroxyvitamin D (25(OH)D), while others have taken the extra effort to measure 25(OH)D2 and 25(OH)D3 separately and additional metabolites such as 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D. The aim of this review is to provide an updated overview of the main markers of vitamin D metabolism, define the intended measurands, and discuss the advantages and disadvantages of the two most widely used assays, automated assays and liquid chromatography–tandem mass spectrometry (LC-MS/MS). Whether using the easy and fast automated assays or the more complex LC-MS/MS, one should know the pitfalls of the used technique in order to interpret the measurements. In conclusion, automated assays are unable to accurately measure 25(OH)D in all patient groups, including persons using D2. In these cases, an LC-MS/MS method, when appropriately developed and standardized, produces a more reliable measurement

Plasma Ghrelin Levels Are Associated with Anorexia but Not Cachexia in Patients with NSCLC

Background and Aims: The ghrelin receptor is one of the new therapeutic targets in the cancer anorexia-cachexia syndrome. Previous studies revealed that plasma ghrelin levels were high in patients with anorexia nervosa and low in obese subjects. We studied to what extent ghrelin levels are related with anorexia and cachexia in patients with cancer. Materials and Methods: Fasted ghrelin levels were determined as well as anorexia and cachexia in patients with stage III/IV non-small cell lung cancer before chemotherapy. Total plasma ghrelin was measured by radioimmunoassay. Anorexia was measured with the FAACT-A/CS questionnaire (cut-off value ≤ 37). Cachexia was determined as > 5% weight loss (WL) in 6 months or > 2% WL in 6 months in combination with low BMI or low muscle mass. The Kruskal-Wallis test was performed to assess differences in plasma ghrelin levels between four groups: patients with (+) or without (-) anorexia (A) or cachexia (C). Multiple regression analyses were performed to assess differences in plasma ghrelin levels between patients C+ and C- and patients with A+ and A- (adjusted for age and sex). Results: Forty patients with stage III (33%) or stage IV (68%) were recruited, of which 50% was male. Mean age was 59.6 ± 10.3 years. Sixteen patients had no anorexia or cachexia (A-C-), seven patients had both anorexia and cachexia (A+C+), ten patients had anorexia without cachexia (A+C-) and seven patients had cachexia without anorexia (A-C+). The levels of total plasma ghrelin were significantly different between the four groups of patients with or without anorexia or cachexia (p = 0.032): the A+C- patients had significantly higher ghrelin levels [median (IQR): 1,754 (1,404-2,142) compared to the A-C+ patients 1,026 (952-1,357), p = 0.003]. A+ patients had significantly higher ghrelin levels compared A- patients (C+ and C- combined, β: 304, p = 0.020). Plasma ghrelin levels were not significantly different in C+ patients compared to C- patients (A+ and A- combined, β: -99, p = 0.450). Conclusions: Patients with anorexia had significantly higher ghrelin levels compared to patients without anorexia. We therefore hypothesize that patients with cancer anorexia might benefit from treatment with a ghrelin receptor agonist to prevent WL and deterioration in physical functioning

How low can we (reliably) go? A method comparison of thyroid-stimulating hormone assays with a focus on low concentrations

Objective: International guidelines concerning subclinical hyperthyroidism and thyroid cancer advice absolute cut-off values for aiding clinical decisi ons in the low range of thyroid-stimulating hormone (TSH) concentrations. As TSH assays are known to be poorly standardized in the normal to high range, we performed a TSH assay method comparison focusing on the low range. Methods: Sixty samples, selected to cover a wide range of TSH concentrat ions (<0.01 to 120 mIU/L) with oversampling in the lower range (<0.4 mIU/L) , were used for the method comparison between three TSH immunoassays (Cobas, Alinit y and Atellica). In addition, 20 samples were used to assess the coefficient of va riation from duplicate measurements in these three methods. Results: The TSH immunoassays showed standardization differences with a b ias of 7–16% for the total range and 1–14% for the low range. This cou ld lead to a different classification of 1.5% of all measured TSH concentrations <0.40 mIU/L measured in our laboratory over the last 6 months, regarding the clinically imp ortant cut-off value of TSH = 0.1 mIU/L. As the imprecision of the immunoassays varied from 1.6–5.5%, this could lead to a similar reclassification as the bias between imm unoassays. Conclusions: We established the standardization differences of frequently used TSH assays for the total and low concentration ranges. Based on the proportional bias and the imprecision, this effect seems to have limited clinical consequences for the low TSH concentration range. Nevertheless, as guidelines mention absolute TSH values to guide clinical decision-making, caution must be applied when interpreting values close to these cut-offs

Інноваційна діяльність через впровадження технопарків

Досвід усього світу показує, що економічне зростання країн вже давно базується на використанні сфери знань і високих технологій, а їх ефективне поєднання гарантує прогресивний розвиток нації та людства. Однією з найбільш вдалих форм такої інтеграції є технопарки. Саме тому розвитку технопарків на сьогоднішній день приділяють увагу вчені та економісти. Основною метою статті є інноваційна діяльність через впровадження технологічних парків, їх призначення та вплив на розвиток країни

Increased fT4 concentrations in patients using levothyroxine without complete suppression of TSH

Introduction: In our hospital, physicians noticed high free thyroxine (fT4) concentrations without complete suppression of thyroid-stimulating hormone (TSH) in blood samplesof patients at the outpatient clinic, which appeared to occur more often following the introduction of a new fT4 immunoassay. This discordance may be explained by incorrect reference intervals, analytical issues, or patient-related factors. We aimed to establish the contribution of the possible factors involved. Methods: Reference intervals of both fT4 immunoassays were re-evaluated using blood samples of healthy volunteers and the new immunoassay’s performance was assessed using internal quality controls and external quality rounds. The frequency of discordant fT4 and TSH pairings obtained from laboratory requests were retrospectively analysed using a Delfia (n = 3174) and Cobas cohort (n = 3408). Last, a literature search assessed whether the time of blood draw and the time of levothyroxine (L-T4) ingestion may contribute to higher fT4 concentrations in L-T4 users. Results: The original reference intervals of both fT4 immunoassays were confirmed and no evidence for analytical problems was found. The Delfia (n = 176, 5.5%) and Cobas cohorts (n = 295, 8.7%) showed comparable frequencies of discordance. Interestingly, 72–81% of the discordant results belonged to L-T4 users. Literature indicated the time of blood withdrawal of L-T4 users and, therefore, the time of L-T4 intake as possible explanations. Conclusions: High fT4 without suppressed TSH concentrations can mainly be explained by L-T4 intake. Physicians and laboratory specialists should be aware of this phenomenon to avoid questioning the assay’s performance or unnecessarily adapting the L-T4 dose in patients

Micronutrient Status of Critically Ill Patients with COVID-19 Pneumonia

Micronutrient deficiencies can develop in critically ill patients, arising from factors such as decreased intake, increased losses, drug interactions, and hypermetabolism. These deficiencies may compromise important immune functions, with potential implications for patient outcomes. Alternatively, micronutrient blood levels may become low due to inflammation-driven redistribution rather than consumption. This explorative pilot study investigates blood micronutrient concentrations during the first three weeks of ICU stay in critically ill COVID-19 patients and evaluates the impact of additional micronutrient administration. Moreover, associations between inflammation, disease severity, and micronutrient status were explored. We measured weekly concentrations of vitamins A, B6, D, and E; iron; zinc; copper; selenium; and CRP as a marker of inflammation state and the SOFA score indicating disease severity in 20 critically ill COVID-19 patients during three weeks of ICU stay. Half of the patients received additional (intravenous) micronutrient administration. Data were analyzed with linear mixed models and Pearson’s correlation coefficient. High deficiency rates of vitamins A, B6, and D; zinc; and selenium (50–100%) were found at ICU admission, along with low iron status. After three weeks, vitamins B6 and D deficiencies persisted, and iron status remained low. Plasma levels of vitamins A and E, zinc, and selenium improved. No significant differences in micronutrient levels were found between patient groups. Negative correlations were identified between the CRP level and levels of vitamins A and E, iron, transferrin, zinc, and selenium. SOFA scores negatively correlated with vitamin D and selenium levels. Our findings reveal high micronutrient deficiency rates at ICU admission. Additional micronutrient administration did not enhance levels or expedite their increase. Spontaneous increases in vitamins A and E, zinc, and selenium levels were associated with inflammation resolution, suggesting that observed low levels may be attributed, at least in part, to redistribution rather than true deficiencies.</p

Micronutrient Status of Critically Ill Patients with COVID-19 Pneumonia

Micronutrient deficiencies can develop in critically ill patients, arising from factors such as decreased intake, increased losses, drug interactions, and hypermetabolism. These deficiencies may compromise important immune functions, with potential implications for patient outcomes. Alternatively, micronutrient blood levels may become low due to inflammation-driven redistribution rather than consumption. This explorative pilot study investigates blood micronutrient concentrations during the first three weeks of ICU stay in critically ill COVID-19 patients and evaluates the impact of additional micronutrient administration. Moreover, associations between inflammation, disease severity, and micronutrient status were explored. We measured weekly concentrations of vitamins A, B6, D, and E; iron; zinc; copper; selenium; and CRP as a marker of inflammation state and the SOFA score indicating disease severity in 20 critically ill COVID-19 patients during three weeks of ICU stay. Half of the patients received additional (intravenous) micronutrient administration. Data were analyzed with linear mixed models and Pearson’s correlation coefficient. High deficiency rates of vitamins A, B6, and D; zinc; and selenium (50–100%) were found at ICU admission, along with low iron status. After three weeks, vitamins B6 and D deficiencies persisted, and iron status remained low. Plasma levels of vitamins A and E, zinc, and selenium improved. No significant differences in micronutrient levels were found between patient groups. Negative correlations were identified between the CRP level and levels of vitamins A and E, iron, transferrin, zinc, and selenium. SOFA scores negatively correlated with vitamin D and selenium levels. Our findings reveal high micronutrient deficiency rates at ICU admission. Additional micronutrient administration did not enhance levels or expedite their increase. Spontaneous increases in vitamins A and E, zinc, and selenium levels were associated with inflammation resolution, suggesting that observed low levels may be attributed, at least in part, to redistribution rather than true deficiencies.</p

Analytical performance specifications for 25-hydroxyvitamin d examinations

Currently the 25-hydroxy vitamin D (25(OH)D) concentration is thought to be the best estimate of the vitamin D status of an individual. Unfortunately, its measurement remains complex, despite recent technological advances. We evaluated the biological variation (BV) of 25(OH)D in order to set analytical performance specifications (APS) for measurement uncertainty (MU). Six European laboratories recruited 91 healthy participants. The 25(OH)D concentrations in K3-EDTA plasma were examined weekly for up to 10 weeks in duplicate on a Lumipulse G1200 (Fujirebio, Tokyo, Japan). The linear regression of the mean 25(OH)D concentrations at each blood collection showed that participants were not in a steady state. The dissection of the 10-sample collection into two subsets, namely collections 1–5 and 6–10, did not allow for correction of the lack of homogene-ity: estimates of the within-subject BV ranged from 5.8% to 7.1% and the between-subject BV ranged from 25.0% to 39.2%. Methods that would differentiate a difference induced by 25(OH)D supple-mentation at p < 0.05 should have MU < 13.6%, while at p < 0.01, the MU should be <9.6%. The development of APS using BV assumes a steady state of patients. The findings in this study suggest that patients are not in steady state. Therefore, APS that are based on MU appear to be more appro-priate

Falsely elevated plasma testosterone concentrations in neonates : importance of LC-MS/ MS measurements

CITATION: Hamer, H.M. et al. 2018. Falsely elevated plasma testosterone concentrations in neonates : importance of LC-MS/ MS measurements. Clinical Chemistry and Laboratory Medicine (CCLM), 56(6):e141–e143, doi:10.1515/cclm-2017-1028.The original publication is available at https://www.degruyter.com/view/j/cclmIn newborns with atypical genitalia, suspicious for a disorder of sex development (DSD), measurement of testosterone is an essential part in the diagnostic workup. Previously, direct testosterone immunoassays have proven to be inaccurate because they tend to overestimate testosterone concentrations in the lower ranges, such as those in females and infants, but specifically also in neonates. Based on the concern for cross-reactivity in neonatal samples, the recently revised UK guideline on the initial evaluation of DSD from the UK Society for Endocrinology recommends that steroids in plasma or serum are measured by either LC-MS/MS or immunoassays after organic solvent extraction. The use of LC-MS/MS was considered superior by a recent consensus meeting of DSD experts across Europe, although validation and quality control remain challenging.Publishers versio