Renal Function and Plasma Renin activity as Potential Factors Causing Hyperkalemia in Patients with Thyroid Carcinoma Undergoing Thyroid Hormone Withdrawal For Radioactive Iodine Therapy

Objective: Hypothyroidism is not commonly considered a cause of hyperkalemia. We previously reported that hyperkalemia was observed mainly in elderly patients treated with renin-angiotensin-aldosterone system (RAS) inhibitors when levothyroxine treatment was withdrawn for the thyroidectomized patients with thyroid carcinoma to undergo radioactive iodine treatment. Here, we investigated whether acute hypothyroidism causes hyperkalemia in patients who were not treated with RAS inhibitors. We also investigated factors influencing potassium metabolism in hypothyroid patients.Methods: We conducted a single-center, prospective cohort study of 46 Japanese patients with thyroid carcinoma undergoing levothyroxine withdrawal prior to radioiodine therapy. All patients were normokalemic before levothyroxine withdrawal. Blood samples were analyzed 3 times: before, and at 3 and 4 weeks after levothyroxine withdrawal. We investigated factors that may be associated with the elevation of serum potassium levels from a euthyroid state to a hypothyroid state.Results: None of the patients developed symptomatic hyperkalemia. The mean serum potassium level was significantly higher at 4 weeks after levothyroxine withdrawal compared to baseline. The serum sodium levels, the estimated glomerular filtration rate (eGFR), and the plasma renin activity (PRA) decreased significantly as hypothyroidism advanced. In contrast, the plasma levels of adrenocorticotropic hormone, cortisol, aldosterone, and antidiuretic hormone were not changed, while serum thyroid hormone decreased. At 4 weeks after their levothyroxine withdrawal, the patients' serum potassium values were significantly correlated with the eGFR and the PRA.Conclusion: Acute hypothyroidism can cause a significant increase in the serum potassium level, which may be associated with a decreased eGFR and decreased circulating RAS.Abbreviations: ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; ATPase = adenosine triphosphatase; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; K⁺ = potassium; Na⁺ = sodium; PRA = plasma renin activity; RAS = renin-angiotensin-aldosterone system; T4 = thyroxine; TSH = thyroid-stimulating hormone     

Optimal Free Thyroxine Levels for Thyroid Hormone Replacement in Hypothyroidism

ObjectiveTo determine whether a difference exists in the free thyroxine level required to achieve a normal thyrotropin (thyroid-stimulating hormone or TSH) level between patients with primary hypothyroidism and euthyroid control subjects and compare the free thyroxine levels in patients with primary and secondary hypothyroidism receiving thyroid hormone replacement.MethodsWe retrospectively assessed TSH and free thyroxine values in 58 patients with primary hypothyroidism and 78 euthyroid control subjects for whom screening thyroid function tests had been performed. From the medical records, we also obtained free thyroxine values for 23 patients with central hypothyroidism receiving stable levothyroxine replacement therapy.ResultsThe mean free thyroxine level was significantly higher in patients with primary hypothyroidism than in euthyroid control subjects (1.36 ± 0.201 ng/dL versus 1.10 ± 0.155 ng/dL, respectively, P < .0001), whereas the corresponding mean TSH concentrations did not differ significantly (1.60 ± 1.183 mlU/L versus 1.73 ± 0.792 mlU/L, P = .46). The mean free thyroxine value was also significantly higher in the patients with central hypothyroidism in comparison with that in the euthyroid control subjects (1.31 ± 0.278 ng/dL versus 1.10 ± 0.155 ng/dL, respectively, P < .0001), and no significant difference was noted between the patients with primary and central hypothyroidism (1.36 ng/dL versus 1.31 ng/dL, P = .60).ConclusionPatients with hypothyroidism require a higher level of serum free thyroxine to achieve a normal TSH value in comparison with euthyroid control subjects. This finding suggests that patients with central hypothy-roidism should be treated to achieve free thyroxine levels in the upper part of the reference range. (Endocr Pract. 2008;14:550-555)     

Impact of Lifestyle Changes During Ramadan on Thyroid Function Tests in Hypothyroid Patients Taking Levothyroxine

Objective: The holy month of Ramadan poses a challenge for levothyroxine-treated patients due to altered eating habits and time restrictions. The aim of this study was to examine the impact of lifestyle changes during Ramadan on thyroid function tests in hypothyroid patients taking levothyroxine in the United Arab Emirates.Methods: Retrospective design whereby levothyroxine-treated hypothyroid patients who had thyroid function tests within 3 months pre-Ramadan and within 2 months post-Ramadan were included. We looked at adherence to levothyroxine, eating pattern, and levothyroxine administration in relation to meal times during Ramadan. Pre- and post-Ramadan thyroid function tests and the potential impact of independent variables using a random-intercept mixed effects linear model were examined.Results: A total of 112 patients (89 females) were recruited in the study, with a mean age ± standard error (SE) of 44.70 ± 1.36 years (range, 19.0 to 79.0 years). The mean thyroid-stimulating hormone (TSH) within 3 months before Ramadan was 1.809 ± 0.094 mIU/L (median, 41.5 days; interquartile range &lsqb;IQR], 25.0 to 73.0 days), while the mean TSH within 2 months post-Ramadan was higher at 3.072 ± 0.312 mIU/L (median, 27.5 days; IQR, 14.0 to 42.0 days). Post-Ramadan, 36 out of 112 patients had a plasma TSH outside of the normal reference range. The independent variable outcomes model showed that older patients and males were more likely to have an increased plasma TSH post-Ramadan. There was no relationship between the time of levothyroxine administration and change in TSH level.Conclusion: Levothyroxine-treated hypothyroid patients showed a significant increase in plasma TSH post-Ramadan, amounting to 2.525 standard deviations, with older patients and males more likely to be affected.Abbreviations: IQR = interquartile range; T4 = thyroxine; TSH = thyroid-stimulating hormone     

Levothyroxine Liquid Solution Versus Tablet for Replacement Treatment in Hypothyroid Patients

BackgroundAlthough replacement treatment with L-thyroxine (LT4) seems easy to manage, about one-third of hypothyroid patients show thyroid-stimulating hormone (TSH) values outside the normal range.ObjectivesTo explore whether LT4 liquid formulation (monodose vials or drops) affects TSH stability values and to assess its ability to maintain TSH within the normal range compared to tablets.MethodsA total of 100 hypothyroid patients on replacement treatment with LT4 liquid solution were enrolled (Liquid Group) at a follow-up visit (revisit). The inclusion criteria were 1) treatment for surgical hypothyroidism for at least 2 years or autoimmune hypothyroidism for at least 5 years, 2) normal TSH at the previous visit 12 months before enrollment (baseline visit), and 3) maintenance of the same LT4 dosage during the time interval between the baseline and the follow-up visit. Using the same selection process, we also enrolled 100 hypothyroid patients on replacement treatment with LT4 tablets (Tablet Group).ResultsAt the follow-up visit, 19 patients of the Tablet Group and 8 patients of the Liquid Group had abnormal TSH values (P = .023). Weekly and daily LT4 dosage per kilogram were higher in Tablet Group (P = .016 and .006, respectively). The magnitude of TSH change from baseline to follow-up visit was greater in the Tablet Group (P < .001).ConclusionThe use of LT4 liquid formulation compared to tablet resulted in a significantly higher number of hypothyroid patients who maintained the euthyroid state in a 12-month follow-up period and a reduced variability in TSH values. (Endocr Pract. 2014;20:901-906)     

Factors Influencing the Successful Maintenance of Euthyroidism after Lobectomy in Patients with Papillary Thyroid Microcarcinoma: A Single-Center Study

Objective: This study aimed to evaluate factors influencing the successful maintenance of postoperative euthyroidism in patients who did not undergo immediate thyroid hormone replacement after lobectomy for papillary thyroid microcarcinoma (PTMC).Methods: From September 2015 to June 2017, 186 patients underwent lobectomy for PTMC in our hospital. Patients taking medications for hypothyroidism and hyperthyroidism before and after lobectomy were excluded. Multiple parameters, including sex, age, pre-operative free thyroxine (T4), thyroid-stimulating hormone (TSH), thyroglobulin (TG), and thyroid autoantibody levels, body mass index (BMI), postoperative histopathology of the thyroid gland, remnant thyroid gland volume, and session number of levothyroxine discontinuation were retrospectively evaluated. These factors were compared between groups based on the maintenance of postoperative euthyroidism.Results: In 88 of the 175 patients (50.3%), postoperative euthyroidism was successfully maintained without thyroid hormone replacement during the first year after lobectomy. There were significant differences in sex (P = .003), pre-operative TSH levels (P = .002), and histopathology of the thyroid gland (P = .035) between the groups showing maintenance success and failure. The group showing successful maintenance had a higher percentage of male patients, lower levels of pre-operative TSH, and normal parenchymal histology of the thyroid gland. However, there were no significant between-group differences in age, pre-operative free T4, TG, and thyroid autoantibody levels, BMI, remnant thyroid gland volume, and session number of levothyroxine discontinuation.Conclusion: Patient sex, pre-operative TSH levels, and histopathology of the thyroid gland may influence the maintenance of postoperative euthyroidism after lobectomy.Abbreviations: BMI = body mass index; PTMC = papillary thyroid microcarcinoma; RR = reference range; T4 = thyroxine; TFT = thyroid function test; TG = thyroglobulin; TSH = thyroid-stimulating hormone     

Effect of Proton Pump Inhibitors on Serum Thyroid-Stimulating Hormone Level in Euthyroid Patients Treated with Levothyroxine for Hypothyroidism

ObjectiveTo examine retrospectively the effect of proton pump inhibitors (PPIs) on thyrotropin (thyroid-stimulating hormone or TSH) values in patients with hypothyroidism and normal TSH levels receiving levothyroxine (LT₄) replacement therapy.MethodsThe data collection was done by retrospective review of electronic medical records from the period of December 2002 to August 2005 from patients with hypothyroidism who were receiving at least 25 μg of LT₄ replacement daily at Queens Hospital Center. The first 92 patients meeting all inclusion and exclusion criteria were included in the study. The study group (N = 37) patient data were collected by selecting euthyroid patients who had received stable LT₄ replacement for at least 6 months and in whom PPI therapy (lansoprazole) was later initiated. TSH levels were collected before and at least 2 months after the PPI treatment was started. The control group (N = 55) patient data were collected by reviewing TSH levels among euthyroid patients with a history of hypothyroidism receiving stable LT₄ therapy and not receiving a PPI during the period of data collection. The statistical analysis was done by comparing the mean change in TSH level in each group with use of the Student t test.ResultsIn the study group, the mean change in the TSH level from before to at least 2 months after initiation of PPI therapy, 0.69 ± 1.9 μIU/mL, was statistically significant (P = 0.035). In the control group, the mean change in the TSH level during the study period, 0.11 ± 1.06 μIU/mL, was not statistically significant (P = 0.45).ConclusionTo our best knowledge, this is the first study in humans with hypothyroidism demonstrating the effect of PPIs on serum TSH levels. PPIs should be added to the list of medications affecting the level of thyroid hormone in patients with hypothyroidism treated with LT₄ replacement. Patients with hypothyroidism and normal TSH values during LT₄ replacement therapy may need additional thyroid function testing after treatment with PPIs and may need adjustment of their LT₄ dose. (Endocr Pract. 2007;13:345-349)     

Hyperkalemia Develops in Some Thyroidectomized Patients Undergoing Thyroid Hormone Withdrawal in Preparation for Radioactive Iodine Ablation for Thyroid Carcinoma

Objective: Hyponatremia is observed in hypothyroidism, but it is not known if hypo- or hyperkalemia is associated with hypothyroidism. To study these questions, we determined serum potassium (K⁺) levels in thyroidectomized patients undergoing levothyroxine withdrawal before radioactive iodine (RAI) therapy for thyroid carcinoma.Methods: We retrospectively studied the records of 108 patients who had undergone total thyroidectomy for thyroid carcinoma followed by levothyroxine withdrawal and then ablation with RAI at Nagasaki University Hospital from 2009–2013. Blood samples were analyzed for serum K⁺ concentrations when patients were euthyroid just before levothyroxine withdrawal and hypothyroid 21 days after levothyroxine withdrawal. We determined the proportion of patients who developed hyperkalemia (K⁺ ≥5 mEq/L) and hypokalemia (K⁺ ≤3.5 mEq/L).Results: Five (4.6%) patients developed hyperkalemia and 2 (1.9%) patients developed hypokalemia after levothyroxine withdrawal. The mean serum K⁺ level after levothyroxine withdrawal was significantly higher than before levothyroxine withdrawal (4.23 ± 0.50 mEq/L vs. 4.09 ± 0.34 mEq/L; P<.001). After levothyroxine withdrawal, serum K⁺ values were significantly correlated with age, serum sodium and creatinine levels, and the estimated glomerular filtration rate but not with serum free thyroxine or thyroid-stimulating hormone concentrations. The finding of an elevated serum K⁺ of >0.5 mEq/L after levothyroxine withdrawal was more prevalent with age >60 years (odds ratio [OR], 4.66; P = .026) and with the use of angiotensin-II receptor blockers or angiotensin-converting enzyme inhibitors (OR, 3.53; P = .033) in a multivariate analysis.Conclusion: Hyperkalemia develops in a small percentage of hypothyroid patients after thyroid hormone withdrawal, especially in patients over 60 years of age who are using antihypertensive agents that inhibit the reninangiotensin- aldosterone system.Abbreviations: ACE-I = angiotensin-converting enzyme inhibitor ARB = angiotensin-II receptor blocker Cr = creatinine eGFR = estimated glomerular filtration rate Eu-K⁺ = serum level of K⁺ in the euthyroid state Hypo-K⁺ = serum level of K⁺ in the hypothyroid state K⁺ = potassium Na⁺ = sodium ?K⁺ = Hypo-K⁺ value minus Eu-K⁺ value RAI = radioactive iodine TSH = thyroid-stimulating hormone     

The Long-Term Impact Of Controlled Ovarian Hyperstimulation On Thyroid Function

Objective: Evidence on the long-term impact of controlled ovarian hyperstimulation (COH) on thyroid function is scarce. To investigate this, we report on serum thyroid-stimulating hormone (TSH) modifications in euthyroid and hypothyroid women during COH and 3 months after the end of the stimulation cycle.Methods: Women who underwent in vitro fertilization (IVF) and who did not become pregnant were eligible. Cases were women with treated hypothyroidism and basal serum TSH <2.5 mIU/L. Controls were euthyroid women matched to cases by age and basal serum TSH. Women could be included if serum TSH was available at 4 time points: prior to initiating COH (time 1); at the time of human chorionic gonadotropin (hCG) administration (time 2); 16 days after hCG administration (time 3); and 3 months after the end of the IVF cycle (time 4).Results: Thirty-seven case-control pairs were included. Serum TSH at times 1, 2, 3, and 4 was 1.7 ± 0.6, 3.1 ± 1.4, 3.1 ± 1.3, and 2.7 ± 1.7 mIU/L, and 1.7 ± 0.6, 2.9 ± 1.0, 2.7 ± 1.0, and 1.9 ± 0.7 mIU/L among cases and controls, respectively. A statistically significant difference emerged at time 4 (P<.001). In both groups, serum TSH was higher at time 4 compared to time 1. Serum TSH exceeded the recommended threshold of 2.5 mIU/L at time 4 in 51% of cases (95% confidence interval &lsqb;CI], 35 to 68%) and in 16% of controls (95% CI, 4 to 28%) (P = .003).Conclusion: COH seems to have a long-term impact on TSH levels. The magnitude of this effect is particularly pronounced in hypothyroid women.Abbreviations:CI = confidence intervalCOH = controlled ovarian hyperstimulationFT4 = free thyroxinehCG = human chorionic gonadotropinIVF = in vitro fertilizationT4 = thyroxineTBG = thyroxine-binding globulinTGAb = anti-thyroglobulin antibodiesTPOAb = anti-thyroperoxidase antibodiesTSH = thyroid-stimulating hormone     

Impact of Ramadan Fasting on Thyroid Status and Quality of Life in Patients with Primary Hypothyroidism: a Prospective Cohort Study from karachi,pakistan

Objective: Ramadan is the ninth month in the lunar calendar, during which Muslims fast from predawn to sunset and major changes occur in their dietary, sleep, and physical activity patterns. Most patients with hypothyroidism are unable to comply with the proper timings of levothyroxine (LT4) administration. The objective of the study was to determine the change in thyroid-stimulating hormone (TSH) level and quality of life (QOL) before and after Ramadan in patients with primary hypothyroidism.Methods: This prospective cohort study included adult patients on stable doses of LT4 who fasted for at least 20 days during the month of Ramadan in the Islamic year 1437 Hijri (June/July 2016). Baseline characteristics and TSH levels were recorded on all consenting patients within 6 weeks prior to Ramadan. Post-Ramadan TSH was tested within 1 to 2 weeks after Eid-ul-Fitr.Results: During the study period, 64 patients with hypothyroidism were enrolled, of which 58 were female. The mean age of participants was 44.2 ± 13.2 years. Average daily dose of LT4 was 95.3 ± 35.4 μg. On average, patients fasted for 26.5 days and missed a dose of LT4 on 1.27 days. Mean TSH pre-Ramadan was 2.37 ± 1.35 mIU/L, and post-Ramadan, it was 4.69 ± 3.87 mIU/L. Mean difference between TSH pre- and post-Ramadan was 2.32 ± 3.80 mIU/L (P<.001). However, the difference in TSH was not significantly different between those who were compliant with meals and LT4 interval versus those who were not (compliant, 2.04 mIU/L; noncompliant, 3.15 mIU/L; P = .30). Overall, an increase in QOL scores in the domains of physical health, psychological health, and social relationships was observed after Ramadan.Conclusion: We observed statistically significant changes in TSH concentrations after the month of Ramadan in hypothyroid patients who fasted. The change in TSH was not affected by timing of LT4 intake and interval from meal.Abbreviations: AKUH = Aga Khan University Hospital; LT4 = levothyroxine; QOL = quality of life; TSH = thyroid-stimulating hormone     

Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients

Context

Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients.

Objective

To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback.

Design

Retrospective study.

Setting

Academic hospital.

Patients

1,811 athyreotic patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls.

Measurements

TSH, FT4 and FT3 concentrations by immunoassays.

Results

FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals. The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients.

Conclusions

Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.     

Thyroid Function in Patients Treated with Radioactive Iodine for Thyrotoxicosis

A series of 105 patients treated at least two years earlier with radioactive iodine for thyrotoxicosis have been surveyed. Eighty-five patients (81%) were euthyroid clinically and on the basis of routine thyroid function tests. Of the euthyroid patients 46 (54%) had normal thyroid-stimulating hormone (TSH) levels and 39 (46%) had raised TSH levels. There was no difference in serum triiodothyronine levels between these two groups but the serum protein bound iodine and serum thyroxine, though still well within the normal range, were significantly lower in the group with raised TSH levels. The serum cholesterol was also significantly higher in this latter group.Most of the euthyroid patients were seen again a year later. None had become hypothyroid and neither those with normal nor those with raised TSH levels showed any evidence of a decline in the level of serum thyroxine.It is concluded that raised serum TSH levels in patients treated with iodine-131 are not necessarily indicative of hypothyroidism. There is no indication that patients who have this abnormality become overtly hypothyroid over a 12-month follow up.     

Case Finding for Hypothyroidism Should Include Type 2 Diabetes and Metabolic Syndrome Patients: A Latin American Thyroid Society (LATS) Position Statement

Objective: Latin American Thyroid Society (LATS) Hypothyroidism Clinical Practice Guidelines recommend case finding of hypothyroid patients in multiple and different situations that agree with other Society guidelines. However, the detection of hypothyroidism in type 2 diabetes mellitus (T2DM) or metabolic syndrome (MetS) patients is not mentioned in particular. In the recent years, several basic and epidemiologic studies have appeared showing that a lower thyroid function and MetS/T2DM are associated. Hence, the aim of this review is to manifest the LATS position on the diagnosis of hypothyroidism in both MetS and T2DM patients.Methods: A search was made in PubMed using the following terms: “hypothyroidism” AND “diabetes” OR “metabolic syndrome.” The most relevant studies describing the prevalence and complications due to hypothyroidism in both MetS and T2DM patients were selected.Results: The current document reviews new information from studies that have shown that the prevalence of hypothyroidism is higher in T2DM patients (odds ratio &lsqb;OR], 3.45; 95% confidence interval &lsqb;CI], 2.5 to 4.7) and that diabetic complications are more prevalent in subclinical hypothyroidism (ScH). The incidence of T2DM is 1.09-fold higher with each doubling of thyroid-stimulating hormone (TSH) mIU/L (95% CI, 1.06 to 1.12), and the incidence of prediabetes increases 15% (hazard ratio, 1.15; 95% CI, 1.04 to 1.26) in patients with TSH >5 mIU/L. Similarly, MetS is more prevalent in ScH compared to euthyroid individuals (OR, 1.31; 95% CI, 1.08 to 1.60).Conclusion: Thyroid function is affected in MetS and T2DM, and hypothyroidism is more common in these patients. Diabetic complications are more frequent in ScH patients. Therefore, LATS now recommends aggressive case finding of hypothyroidism in both MetS and T2DM patients.Abbreviations: CI = confidence interval; GLUT4 = glucose transporter 4; HOMA-IR = homeostatic model assessment for insulin resistance; HR = hazard ratio; LATS = Latin American Thyroid Society; MetS = metabolic syndrome; OR = odds ratio; ScH = subclinical hypothyroidism; T2DM = type 2 diabetes mellitus; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone     

Italian Association of Clinical Endocrinologists Statement–Replacement Therapy for Primary Hypothyroidism: A Brief Guide for Clinical Practice

Objective: Hypothyroidism requires life-long thyroid hormone replacement therapy in most patients. Oral levothyroxine (LT4) is an established safe and effective treatment for hypothyroidism, but some issues remain unsettled.Methods: The Italian Association of Clinical Endocrinologists appointed a panel of experts to provide an updated statement for appropriate use of thyroid hormone formulations for hypothyroidism replacement therapy. The American Association of Clinical Endocrinologists' protocol for standardized production of clinical practice guidelines was followed.Results: LT4 is the first choice in replacement therapy. Thyroid-stimulating hormone (TSH) should be maintained between 1.0 and 3.0 mIU/L in young subjects and at the upper normal limit in elderly or fragile patients. Achievement of biochemical targets, patient well-being, and adherence to treatment should be addressed. In patients with unstable serum TSH, a search for interfering factors and patient compliance is warranted. Liquid or gel formulations may be considered in subjects with hampered LT4 absorption or who do not allow sufficient time before or after meals and LT4 replacement. Replacement therapy with LT4 and L-triiodothyronine (LT3) combination is generally not recommended. A trial may be considered in patients with normal values of serum TSH who continue to complain of symptoms of hypothyroidism only after co-existent nonthyroid problems have been excluded or optimally managed. LT3 should be administered in small (LT4:LT3 ratio, 10:1 to 20:1) divided daily doses. Combined therapy should be avoided in elderly patients or those with cardiac risk factors and in pregnancy.Conclusion: LT4 therapy should be aimed at resolution of symptoms of hypothyroidism, normalization of serum TSH, and improvement of quality of life. In selected cases, the use of liquid LT4 formulations or combined LT4/LT3 treatment may be considered to improve adherence to treatment or patient well-being.Abbreviations:AACE = American Association of Clinical EndocrinologistsFT3 = free triiodothyronineFT4 = free thyroxineLT3 = levotriiodothyronineLT4 = levothyroxineMeSH = medicine medical subject headingsQoL = quality of lifeTSH = thyroid-stimulating hormone     

Reducing Inappropriate Serum T3 Laboratory Test Ordering in Patients with Treated Hypothyroidism

Objective: Choosing Wisely is a campaign of the American Board of Internal Medicine that aims to promote evidence-based practices to reduce unnecessary ordering of tests or procedures. As part of this campaign, the Endocrine Society advises against ordering a serum total or free triiodothyronine (T3) level when assessing levothyroxine dosing in hypothyroid patients. This study was performed to assess and reduce inappropriate laboratory ordering practices among providers who manage patients with hypothyroidism within a large U.S. academic health system.Methods: A best practice alert (BPA) in the health record was developed and implemented following the collection of baseline data. This alert consisted of a popup window that was triggered when a serum T3 laboratory test was ordered for patients prescribed levothyroxine. The alert required user acknowledgement before the serum T3 laboratory test could be ordered.Results: During the 6-week period prior to launching the BPA, serum T3 tests were ordered a mean of 162.3 ± 15.4 (standard deviation) occurrences per 10,000 patients per week. Over a 15-week period following implementation of the BPA, the frequency of serum T3 orders steadily decreased and resulted in >44% fewer inappropriate tests being ordered.Conclusion: Although national societal guidelines recommend against ordering serum T3 concentrations while monitoring patients with hypothyroidism managed with levothyroxine, these laboratory tests are frequently ordered. Development of a triggered alert in the health record may reduce inappropriate monitoring practices, decrease costs, and improve utilization of limited health-care resources for this common clinical condition.Abbreviations: ATA = American Thyroid Association; BPA = best practice alert; T3 = triiodothyronine; TSH = thyroid-stimulating hormone     

Baseline TSH Level is Associated with Risk of Anti–PD-1–Induced Thyroid Dysfunction

Objective: To characterize anti–programmed cell death 1 (PD-1)–induced thyroid immune-related adverse events (irAEs) in metastatic melanoma patients treated at our institution and to identify risk factors associated with their development.Methods: We reviewed the files of 154 patients with metastatic melanoma treated with PD-1 inhibitors at a single institution from November 1, 2011, to February 28, 2017. The association of thyroid irAEs within 120 days posttreatment initiation with age, gender, melanoma characteristics, treatment protocol, and baseline thyroid-stimulating hormone (TSH) was examined.Results: Overall, 42.4% developed thyroid dysfunction following treatment, including 20.2% (20/99) subclinical thyroid dysfunction, 13.1% (13/99) overt hypothyroidism, and 9.1% (9/99) overt hyperthyroidism. Of those that developed overt hyperthyroidism, 8 progressed to overt hypothyroidism, consistent with thyroiditis. Age, gender, melanoma characteristics, or treatment protocol did not modify the risk of developing thyroid irAEs. Higher baseline TSH was observed in patients who developed overt hypothyroidism versus hyperthyroidism versus those who remained euthyroid (P = .05). A pretreatment TSH >2.19 mIU/mL was associated with an increased risk of overt thyroid dysfunction (odds ratio, 3.46; 95% confidence interval, 1.2 to 9.8).Conclusion: Thyroid dysfunction following treatment with PD-1 inhibitors is common, and patients with a higher baseline TSH appear to be at increased risk. Such patients may benefit from closer monitoring of their thyroid function following initiation of anti PD-1 agents.Abbreviations: CTLA-4 = cytotoxic T-lymphocyte antigen 4; FT3 = free triiodothyronine; FT4 = free thyroxine; irAE = immune-related adverse event; PD-1 = programmed cell death 1; TFT = thyroid function test; TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone     

Thyroid-stimulating Hormone Levels Are Inversely Associated With Serum Total Bile Acid Levels: a Cross-Sectional Study

Objective: Bile acids (BAs) synthesized from cholesterol play a critical role in eliminating excess cholesterol to maintain cholesterol homeostasis. BAs are also signaling molecules that are involved in the regulation of lipid, glucose, and energy metabolism. Thyroid-stimulating hormone (TSH) has been found to decrease liver BA synthesis via a sterol regulatory element-binding protein 2/hepatocyte nuclear factor 4 alpha/cholesterol 7α-hydroxylase (SREBP-2/HNF-4α/CYP7A1) pathway in vivo and in vitro. However, the relationship between serum TSH and total BA levels in humans is still unclear.Methods: This was a single-center cross-sectional study of 339 subclinical hypothyroidism (SCH) patients and an equal number of controls matched by age and sex from 11,000 subjects.Results: Serum total BA levels significantly decreased (3.11 ± 2.05 vs. 5.87 ± 2.39, P<.01), while total cholesterol (TC) levels increased (5.02 ± 0.65 vs. 4.88 ± 0.63, P<.01) in subclinical hypothyroidism (SCH) patients compared to control subjects. Serum TSH and BA levels were significantly and negatively correlated in subclinical hypothyroid patients who were also hypercholesterolemic (r_s = -0.189, P = .004). Each 1 μIU/mL increase in TSH level was associated with a decrease in log-transformed values of total BAs (logTBAs) by 0.182 after controlling for confounding factors relevant to BA metabolism. The relationship between TSH and serum total BAs was more significant in subjects younger than 65 years.Conclusion: Our results suggested that TSH is correlated with the total BA level in SCH patients independent of thyroid hormone, which suggests a potential physiological role of TSH and the importance of maintaining normal range TSH in SCH patients.Abbreviations:BA = bile acidCYP7A1 = cholesterol 7α-hydroxylaseFBG = fasting blood glucoseHDL-C = highdensity lipoprotein cholesterolLDL-C = low-density lipoprotein cholesterollogTBAs = log-transformed values of total BAsSCH = subclinical hypothyroidismTC = total cholesterolTG = triglycerideTH = thyroid hormoneTSH = thyroid-stimulating hormone     

Unchanged Serum Adipokine Concentrations in the Setting of Short-Term Thyroidectomy-Induced Hypothyroidism

ObjectiveTo investigate short-term effects of thyroidectomy-induced hypothyroidism on leptin, adiponectin, and resistin concentrations in association with anthropometric data.MethodsThirty premenopausal women with euthyroid nodulargoiter-mean age, 44.0 ± 11.6 years; mean body mass index (BMI), 28.6 ± 5.9 kg/m²; 13 obese, 7 overweight, and 10 normal weight subjects—scheduled for total thyroidectomy were included in the study. Serum leptin, adiponectin, resistin, free triiodothyronine, free thyroxine, thyroid-stimulating hormone, glucose, insulin, and C-reactive protein concentrations, lipid profile, and anthropometric variables were determined in the euthyroid state (preoperatively) and the hypothyroid state (postoper atively, with a thyroid-stimulating hormone concentration > 30 mIU/L).ResultsBody weight, BMI, waist and hip circumferences, body fat mass, and serum lipid concentrations increased significantly after thyroidectomy. No significant difference was found between preoperative and postoperative serum leptin, adiponectin, and resistincon centrations. Fat tissue mass-corrected leptin, adiponectin, and resistin concentrations did not differ significantly between euthyroid and hypothyroid periods. Thyroid hor mone concentrations showed no significant correlations with adipokine levels.ConclusionSerum adipokine concentrations seem not to change significantly during short-term thyroidec tomy-induced hypothyroidism despite significant increases in body weight, BMI, fat mass, and lipid concentrations.(Endocr Pract. 2012;18:887-893)     

Evaluation of Treatment of Central Hypothyroidism Versus Primary Hypothyroidism in Relation to Levothyroxine Replacement Dose

Objective: The aim of this study was to evaluate levothyroxine (LT4) replacement daily doses in patients with central hypothyroidism (CeH) and compare them with those adequate for patients with primary hypothyroidism (P-HYPO).Methods: We included 53 patients with CeH and 57 with P-HYPO, matched by sex, age, weight, and body mass index, in the period of 1 year. At the time of inclusion, all presented a stable and adequate dose of LT4 for at least 3 months, considering as adequate the dose associated with normal thyroid-stimulating hormone (TSH) levels and free thyroxine (T4) in P-HYPO patients, and free T4 levels in CeH patients.Results: The absolute daily dose of LT4 differed significantly between the two groups, 103.0 ± 27.1 μg (CeH) and 89.3 ± 32.0 μg (P-HYPO) (P = .017), even after adjustment for age, gender, and free T4 (P = .04). The LT4 dose adjusted to weight was also higher after adjustment for age, gender and free T4 (P = .04), with an average of 1.3 ± 0.4 μg/kg (CeH) and 1.2 ± 0.4 μg/kg (P-HYPO). Sheehan syndrome patients had a lower absolute daily dose of LT4 (P = .001), and patients who underwent pituitary radiotherapy required higher doses (P = .008). There was no difference in the daily dose of LT4 according to other pituitary hormone deficiencies.Conclusion: The results reinforce the relevance of a careful individualization of LT4 replacement in CeH management and the need for new markers for proper LT4 replacement therapy in such cases.Abbreviations: BMI = body mass index; CeH = central hypothyroidism; GH = growth hormone; LT4 = levothyroxine; P-HYPO = primary hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone     

Arterial Wall Stiffness and the Risk of Atherosclerosis in Egyptian Patients with Overt and Subclinical Hypothyroidism

Objective: Hypothyroidism is associated with an increased risk of atherosclerosis. Pulse wave velocity (PWV) is an index of arterial wall stiffness widely used for noninvasive assessment of early atherosclerosis. We assessed PWV in Egyptian patients with hypothyroidism.Methods: The study included 100 Egyptian females aged 18 to 55 years. They were classified into three groups: group I, 40 women with overt hypothyroidism; group II, 40 women with subclinical hypothyroidism; and group III, 20 euthyroid women as a control group. The three groups were age matched. Doppler ultrasonography was used to calculate the heart-femoral PWV.Results: PWV was significantly higher in women with overt and subclinical hypothyroidism as compared with the control group (9.55 ± 1.81 m/s and 9.30 ± 1.28 m/s, respectively vs. 7.82 ± 2.14 m/s; P<.001 and <.01, respectively). There was a positive correlation between thyroid-stimulating hormone (TSH) and PWV in women with overt hypothyroidism and in those with subclinical hypothyroidism (P<.05 for both). Multivariate regression analysis showed that age and diastolic blood pressure were independent determinants of PWV in women with overt and subclinical hypothyroidism (P<.01 for all). TSH was also an independent determinant of PWV in both groups (P<.05 for both).Conclusion: PWV is significantly higher in Egyptian women with overt and subclinical hypothyroidism as compared with normal control subjects. This denotes early increase in arterial wall stiffness in patients with hypothyroidism, even in the subclinical phase. The positive correlation between PWV and TSH in both groups of patients suggests that the risk of atherosclerosis is proportionate to the severity of hypothyroidism.Abbreviations: ABI = ankle/brachial index; baPWV = brachial-ankle pulse wave velocity; BP = blood pressure; CIMT = carotid intima-media thickness; ECG = electrocardiogram; FT4 = free thyroxine; HDL = high-density lipoprotein; hfPWV = heart-femoral pulse wave velocity; LDL = low-density lipoprotein; PTT = pulse transit time; PWV = pulse wave velocity; SCH = subclinical hypothyroidism; TSH = thyroid-stimulating hormone