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Background A new liquid levothyroxine (LT4) dissolved in glycerol and water has recently been developed by a Greek pharmaceutical company (Uni-Pharma, Athens, Greece). Objectives To evaluate the therapeutic equivalence of this new liquid LT4 preparation versus the already existing tablet formulation of the same manufacturer, in order to obtain approval by the Greek National Organization for Medicines. Methods This was a prospective, randomized, cross-over phase III study. The study included 50 patients (9 men and 41 non-pregnant women, with a mean age of 42.5 ± 12.5 years), with documented overt primary hypothyroidism. All subjects were well controlled on substitution therapy with various LT4 formulations. None of the patients had known LT4 malabsorption. The patients were randomized into 2 groups (A and B). The individuals of group A initially received T4® tablets for 10 ± 2 weeks and subsequently switched to T4® drops (100 μg/mL solution) at the same dose for another 10 ± 2 weeks. In group B, the reverse procedure was followed. Total T3 (T3), free T4 (fT4), and TSH were measured in all participants at enrollment and at the end of each 10 ± 2-week trial period. Results Out of the 50 recruited patients, 6 were lost to follow-up and 5 were excluded due to non-compliance with the study protocol. In the 39 patients who completed the study, the serum TSH levels after 10 ± 2 weeks of treatment either with T4® tablets or with T4® drops did not differ (1.759 ± 1.104 vs. 2.076 ± 1.334 mIU/L, mean ± SD). Conclusions In hypothyroid patients, the new liquid LT4 preparation (T4® drops) is therapeutically equivalent to the tablet form (T4® tablets).

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is a common and deleterious side effect of amiodarone use. There are two types of AIT, characterized by distinct pathogenic mechanisms and, hence, different treatments. Discriminating between type 1 (AIT1) and type 2 (AIT2) AIT is often very challenging. Beta-glucuronidase (β-G) is a lysosomal enzyme released into the extracellular fluid during inflammation. OBJECTIVES: To examine whether the determination of the plasma activity of β-G is useful in distinguishing AIT1 from AIT2. METHODS: The study included 67 subjects: 9 with AIT1, 9 with AIT2, 14 with hyperthyroidism due to Grave's disease or toxic multinodular goiter, 14 with subacute thyroiditis, and 21 euthyroid controls. Thyroid function tests and plasma β-G activity were determined in all participants, while thyrotoxic patients also underwent thyroid ultrasound/scintigraphy and urine iodine excretion assessment. RESULTS: Plasma β-G activity (expressed as mean ± SD in nmol 4-methylumbelliferone [4-MU]/mL plasma/h) in AIT2 was higher compared to AIT1 (2,263.6 ± 771 vs. 1,101.8 ± 201.9, p < 0.05) and similar to subacute thyroiditis (2,263.6 ± 771 vs. 2,083.2 ± 987.5, p = ns). β-G activity did not differ significantly between AIT1 and controls (1,101.8 ± 201.9 vs. 954.6 ± 248.6, p = ns). ROC curve analysis revealed that β-G activity had a high predictive value for destructive processes, namely AIT2 and subacute thyroiditis (AUC 0.846, 95% CI 0.748–0.943) and a cut-off value of 1,480.5 nmol 4-MU/mL plasma/h was able to discriminate between destructive and non-destructive thyroid conditions with 74% sensitivity and 82% specificity. CONCLUSION: In our study, plasma β-G activity performed well in distinguishing AIT1 from AIT2. Further studies are warranted to establish its usefulness as a discriminator between the two AIT types.

Several polymorphisms in the vitamin D receptor (VDR) are associated with the occurrence of chronic liver disease. Here, we investigated the association between BsmI, ApaI, TaqI and FokI VDR polymorphisms and the severity of liver cirrhosis in relation to serum cytokine and lipopolysaccharide binding protein (LBP) levels and their role on survival in cirrhotic patients. We found that patients harboring the BB genotype had higher MELD score, and they were mainly at CP stage C; patients harboring the AA genotype had increased LBP, IL-1β and IL-8 levels, and they were mostly at CP stage C; TT genotype carriers had higher MELD score and they were mainly at CP stage C and FF genotype carriers had lower IL-1β levels when compared to Bb/bb, Aa/aa, Tt/tt and Ff/ff genotypes respectively. In the multivariate analysis ApaI, BsmI and TaqI polymorphisms were independently associated with liver cirrhosis severity. In the survival analysis, the independent prognostic factors were CP score, MELD and the FF genotype. Our results indicate that the ApaI, TaqI and BsmI polymorphisms are associated with the severity of liver cirrhosis, through the immunoregulatory process. Survival is related to the FF genotype of FokI polymorphism, imparting a possible protective role in liver cirrhosis.

ContextAdrenal and extra-adrenal cortisol production may be involved in the development of metabolic syndrome (MetS).ObjectiveTo investigate the activity of the hypothalamic–pituitary–adrenal (HPA) axis and the expression of HSD11B1, nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptors) α (NR3C1α) and β (NR3C1β) in the liver, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of severely obese patients with and without MetS.MethodsThe study included 37 severely obese patients (BMI ≥40 kg/m2), 19 with MetS (MetS+ group) and 18 without (MetS− group), studied before and during bariatric surgery. Before the day of surgery, urinary free cortisol (UFC) and diurnal variation of serum and salivary cortisol were estimated. During surgery, biopsies of the liver, VAT and SAT were obtained. The expression of HSD11B1, NR3C1α and NR3C1β was evaluated by RT-PCR.ResultsUFC and area under the curve for 24-h profiles of serum and salivary cortisol were lower in the MetS− group. In the MetS− group, mRNA levels ofHSD11B1in liver exhibited a negative correlation with liver NR3C1α (LNR3C1α) and VAT expression of HSD11B1 was lower than the MetS+ group.ConclusionsWe observed a downregulation of the NR3C1α expression and lower VAT mRNA levels ofHSD11B1in the MetS− group, indicating a lower selective tissue cortisol production and action that could protect these patients from the metabolic consequences of obesity. In the MetS− group, a lower activity of the HPA axis was also detected. Taken together, cortisol in tissue and systematic level might play a role in the development of MetS in severely obese patients.

The indications for levothyroxine replacement therapy for subclinical hypothyroidism (SH) remain a subject of debate, especially when prescribed for older adults. The results of the recent TRUST trial indicate that levothyroxine does not improve clinical symptom scores among elderly patients with SH. While there is much concern regarding the dilemma of introducing or withholding levothyroxine, less attention may be paid to the differential diagnosis of an elevated TSH level, which is the prerequisite for diagnosing SH. Herein, we review these issues facing endocrinologists and internists/generalists either in practice or in training. When a patient presents abnormal thyroid test results compatible with SH, a series of issues need to be addressed before the implementation of replacement therapy is considered: first, an isolated TSH elevation not linked to a primary thyroid pathology should be excluded; second, the persistent nature of the patient’s TSH elevation and SH profile should be verified; third, SH symptoms and potential complications relevant for the specific patient should be documented; fourth, expectations from levothyroxine substitution therapy for SH in the specific patient should be clarified. Only then can the decision be made whether levothyroxine substitution should be introduced or not.

Aging and its underlying pathophysiological background has always attracted the attention of the scientific society. Defined as the gradual, time-dependent, heterogeneous decline of physiological functions, aging is orchestrated by a plethora of molecular mechanisms, which vividly interact to alter body homeostasis. The ability of an organism to adjust to these alterations, in conjunction with the dynamic effect of various environmental stimuli across lifespan, promotes longevity, frailty or disease. Endocrine function undergoes major changes during aging, as well. Specifically, alterations in hormonal networks and concomitant hormonal deficits/excess, augmented by poor sensitivity of tissues to their action, take place. As hypothalamic–pituitary unit is the central regulator of crucial body functions, these alterations can be translated in significant clinical sequelae that can impair the quality of life and promote frailty and disease. Delineating the hormonal signaling alterations that occur across lifespan and exploring possible remedial interventions could possibly help us improve the quality of life of the elderly and promote longevity.

BACKGROUND The current trend in the management of low risk differentiated thyroid carcinoma is to follow less aggressive strategies. OBJECTIVE To assess the long-term morbidity and mortality outcomes of low-risk papillary thyroid carcinoma (PTC) patients undergoing minimal intervention. DESIGN We retrospectively analyzed 137 patients with low-risk PTC (stage I: n=77; stage II: n=60). Of these patients, 107 (Group 1) had macro-PTC and underwent near-total thyroidectomy and received postoperatively 50mCi RAI. The remaining 30 patients (Group 2) had micro-PTC (

ObjectiveRelative corticosteroid insufficiency may be common in critically ill patients and is associated with a poor outcome; however, the response of the hypothalamic–pituitary–adrenal (HPA) axis in nursed patients is not known. Our aim was to evaluate the response of HPA axis to the severity of illness in non-critically ill nursed (NCIN) patients and the clinical outcome.Subjects and methodsFifty-six nursed patients who were divided into four groups (stroke, mild disease, sepsis and severe sepsis) as well as a control group (n=15) were studied. At admission (day 1), cortisol and ACTH were measured and a low-dose (1 μg) corticotrophin test was performed, followed 2 h later by a standard-dose (250 μg) corticotrophin test. Diurnal variation of cortisol was obtained on day 2. A second identical set of low-dose and standard-dose corticotrophin tests were performed on day 5 or 6 (recovery phase).ResultsIn patients with stroke and severe sepsis, cortisol had the highest values and its diurnal variation was abolished. Dissociation of ACTH and cortisol was found in all patients.The Δmax of cortisol after the 1-μg corticotrophin test did not differ among the groups, while after the 250-μg corticotrophin test, it was borderline higher in controls. The ratio of responders (Δmax of cortisol ≥9 μg/dl) to non-responders after 1- or 250-μg corticotrophin test did not differ among patients and controls. All patients had a good outcome without glucocorticoid treatment.ConclusionsDepending on the severity of illness, mild alterations in the HPA axis occurred. However, relative corticosteroid insufficiency was not confirmed in NCIN patients.

Treatment with recombinant human GH (rhGH) increases the mortality of critical illness. We postulated that combined GH-releasing peptide-2 (GHRP-2), TRH, and insulin infusion is a less toxic anabolic strategy through a putative inability to overstimulate the GH axis and a capacity to normalize thyroid hormone concentrations while foregoing excessive hyperglycemia. Burn-injured, parenterally fed, New Zealand White rabbits were randomized to receive 4-d treatment with saline (n=8); 60 microg/kg.h GHRP-2 and 60 microg/kg.h TRH, i.v. (n=9); or 3.5 mg/kg rhGH, s.c. (n=7). In the GHRP-2+TRH group, insulin was adjusted to maintain blood glucose below 180 mg/dl. Endocrine function and biochemical organ system function markers were studied. Animals were killed for assay of deiodinase activity in snap-frozen liver. Mortality, organ system function, hyperglycemia, and insulin requirement were equal in the three groups. GHRP-2+TRH increased pulsatile rabbit GH (rGH) and TSH release on d 1. After 4 d, rGH secretion and T4 and T3 concentrations were elevated, with a significant increase in hepatic activity of type 1 deiodinase and a decrease in type 3 deiodinase. Exogenous rhGH suppressed endogenous rGH secretion and increased IGF-I more than GHRP-2+TRH without altering thyroid hormone levels. Unlike GHRP-2+TRH, rhGH down-regulated liver type 3 deiodinase and did not affect type 1 deiodinase. We conclude that in experimentally induced critical illness, GHRP-2+TRH reactivated the GH and TSH axes and altered liver deiodinase activity, driving T4 to T3 conversion. In contrast to the human model, high dose rhGH was not rapidly lethal in this rabbit model. Whether this is explained by lack of rhGH-induced insulin resistance and hyperglycemia remains unclear.

High doses of GH, used to induce anabolism in prolonged critically ill patients, unexpectedly increased mortality. To further explore underlying mechanisms, a valid animal model is needed. Such a model is presented in this study. Seven days after arterial and venous cannulae placement, male New Zealand White rabbits were randomly allocated to a control or a critically ill group. To induce prolonged critical illness, a template controlled 15% deep dermal burn injury was imposed under combined general and regional (paravertebral) anesthesia. Subsequently, critically ill rabbits received supplemental analgesia and were parenterally fed with glucose, insulin, amino acids, and lipids. On d 1 and d 8 after randomization, acute and chronic spontaneous hormonal profiles of GH, TSH, and PRL secretion were obtained by sampling blood every 15 min for 7 h. Furthermore, GH, TSH, and PRL responses to an iv bolus of GH-releasing peptide 2 (GHRP-2) + TRH were documented on d 0, 1, and 8. Hemodynamic status and biochemical parameters were evaluated on d 0, 1, 3, 5, and 8, after which animals were killed and relative wet weight and water content of organs was determined. Compared with controls, critically ill animals exhibited transient metabolic acidosis on d 1 and weight loss, organ wasting, systolic hypertension, and pronounced anemia on d 8. On d 1, pulsatile GH secretion doubled in the critically ill animals compared with controls, and decreased again on d 8 in the presence of low plasma IGF-I concentrations from d 1 to d 8. GH responses to GHRP-2 + TRH were elevated on d 1 and increased further on d 8 in the critically ill animals. Mean TSH concentrations were identical in both groups on d 1 and 8, in the face of dramatically suppressed plasma T(4) and T(3) concentrations in the critically ill animals. PRL secretion was impaired in the critically ill animals exclusively on d 8. TSH and PRL responses to GHRP-2 and TRH were increased only on d 1. In conclusion, this rabbit model of acute and prolonged critical illness reveals several of the clinical, biochemical, and endocrine manifestations of the human counterpart.

OBJECTIVE: Adequate dietary iodine intake is necessary for normal thyroid gland function at all times, and most particularly during pregnancy. Increased iodine loss is cited, among other factors, as responsible for the increased iodine demand in this period. Our aim was to compare renal iodine excretion between women during all three pregnancy trimesters with that of their spouses and thereby to estimate the iodine intake in an a large sample of pregnant women in urban areas in Greece. DESIGN: Four hundred twenty-four healthy pregnant women were included prospectively (residents of Athens n=218, residents of Patras n=206). The spouses of 177 of these women following the same diet were also studied. Determinations included serum FT4, TSH and aTPO and urinary iodine excretion (UIE). RESULTS: No difference was found either in median UIE throughout pregnancy or between the UIE of the pregnant women and their spouses during the trimesters. Throughout pregnancy, mild iodine deficiency was noted and was classified as mild in 60%, moderate in 30% and severe in 10% of the women studied. Users of iodized salt had significantly higher median UIE compared with non-users. Serum FT4 levels decreased and TSH increased as pregnancy progressed. CONCLUSIONS: Our study indicates that renal iodine excretion is not increased during pregnancy. This finding needs to be confirmed by further investigation in other populations with different iodine intakes. Thus, increased iodine requirements in pregnancy are possibly due to extra-renal causes. The population of pregnant women in Greek urban areas is mildly-and often moderately and severely-iodopenic and needs to be treated accordingly.

The etiology of the prompt decline in serum T3 in patients with nonthyroidal illness syndrome has not been adequately explained. It has been attributed to various parameters, including test artifacts, inhibitors of T4 and T3 binding to proteins, decreased 5′-deiodinase activity, and circulating cytokines. Currently, much attention is centered on the role of IL-6 and TNFα in developing the nonthyroidal illness syndrome through an effect on the hypothalamus, pituitary, and possibly 5′-deiodinase activity. We therefore studied the relation of the endogenous serum IL-6 and TNFα rise early in the course of nonthyroidal illness syndrome to the early decline in serum T3 in 19 apparently healthy individuals, aged 43 ± 16 yr, who underwent elective abdominal surgery for cholelithiasis or gastroplasty. Serum T3, free T3, T4, free T4, rT3, TSH, IL-6, and TNFα were measured before and at various time intervals up to 42 h after skin incision. We observed a prompt decline in serum T3 30 min before skin incision, which continued to decline throughout the observational period. The magnitude of the decline reached 20% from the baseline value at 2 h. The early decline of T3 was attenuated and lasted from the 2–8 h, probably due to the sharp increase in serum TSH that started immediately after the entrance to the operating room and lasted for 2 h. In contrast, serum T4 and free T4 concentrations were increased soon after skin incision and remained elevated during the first postoperative day. Serum rT3 increased approximately 6 h after the initiation of surgery and remained elevated thereafter. Serum IL-6 remained essentially undetectable for 2 h after skin incision, whereas serum T3 was low. Two hours after skin incision, serum IL-6 increased sharply and remained elevated throughout the observational period. Serum TNFα remained essentially undetectable throughout the postoperative period. Serum cortisol increased rapidly upon entrance to the operating room and remained elevated throughout the postoperative period. We conclude that the decline in serum T3 early in the course of nonthyroidal illness syndrome is not due to increased serum IL-6 or TNFα levels. The brisk TSH secretion soon after the onset of the syndrome attenuates the decline in serum T3 due to T3 secretion from the thyroid. The early and brisk cortisol response to surgery may at least in part explain the early decrease in serum T3 in nonthyroidal illness syndrome.

Objective: Plasma cortisol in obese subjects does not differ from that in normoweight subjects. Extra-adrenal cortisol production by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) can result in local hypercortisolemia. The aim of the present study was to examine the role of visceral hypercortisolemia in the development of metabolic syndrome in severe obesity. Methods: Eight lean women during hysterectomy (controls) and 19 severely obese women during bariatric surgery were studied, 8 without metabolic syndrome (OM– group) and 11 with it (OM+ group). Biopsies of omental and subcutaneous fat were performed in the severely obese women during surgery, but only omental biopsies in the controls. Expression of 11β-HSD1, glucocorticoid receptor α (GRα) and glucocorticoid receptor β (GRβ) was evaluated using real-time PCR.Results: Omental 11β-HSD1 expression was different between groups (one-way ANOVA, p < 0.01). Post-hoc analysis revealed that mean omental 11β-HSD1 mRNA levels were higher in the OM– group compared to controls, whereas they were similar when comparing the OM+ group with lean controls. Expression of 11β-HSD1 in subcutaneous fat was not different between OM+ and OM– groups. GRα expression in omental fat did not differ among groups or between omental and subcutaneous fat in severely obese patients. An expression of GRβ was not detected.Conclusion: Contrary to our original hypothesis, omental 11β-HSD1 expression is not increased in the OM+ group.

Relative adrenal insufficiency (AI) occurs in patients with cirrhosis with sepsis, but not with variceal bleeding. We evaluated adrenal function in cirrhotic patients with and without bleeding.Twenty cirrhotic patients with variceal bleeding were evaluated using the short synacthen test (SST) and 10 using the low-dose synacthen test (LDSST) followed by SST. The control group included 60 stable cirrhotic patients, assessed by LDSST (n = 50) or SST (n = 10), and 14 healthy volunteers. AI was diagnosed using SST, based on peak cortisol levels ≤ 18 μg/dL in nonstressed patients or Δmax9 μg/dL or a total cortisol level10 μg/dL in stressed patients with variceal bleeding-the current criteria for critical illness-related corticosteroid insufficiency. Using LDSST, diagnosis was based on peak concentrations of cortisol ≤ 18 μg/dL in nonstressed patients and25 μg/dL (or Δmax9 μg/dL) in patients with variceal bleeding. We evaluated patients with levels of serum albumin2.5 g/dL, to indirectly assess cortisol binding.All healthy volunteers had normal results from LDSSTs and SSTs. Patients with variceal bleeding had higher median baseline concentrations of cortisol (15.4 μg/dL) than stable cirrhotic patients (8.7 μg/dL, P = .001) or healthy volunteers (10.1 μg/dL, P = .01). Patients with variceal bleeding had higher median peak concentrations of cortisol than stable cirrhotic patients (SST results of 32.7 vs 21 μg/dL, P = .001; LDSST results of 9.3 vs 8.1 μg/dL; nonsignificant), with no differences in Δmax in either test. These differences were greater with variceal bleeding than in stable cirrhotic patients with AI. Subanalysis of patients with albumin levels2.5 g/dL did not change these differences.Cirrhotic patients with variceal bleeding have AI. Despite higher baseline concentrations of serum cortisol and subnormal Δmax values, they did not have adequate responses to stress, and therefore had critical illness-related corticosteroid insufficiency.