T4 Replacement Research Articles

Creatine Treatment to Relieve Muscle Pain Caused by Thyroxine Replacement Therapy

To the Editor: The impact of thyroid deficiency and its reversal by T4 replacement therapy on glucose metabolism remained controversial [1–4]. Small doses of thyroxine (1 µg/kg) normalized most of the intermediary metabolic parameters of thyroidectomized rats [5], while 20-times-higher doses would be needed to depress the high rates of thyroid-stimulating hormone (TSH) release of pituitary via feedback inhibition [6]. Thyroxine levels can be brought up to normal with oral thyroxine pills from 25 to 200 µg/day. Under constant balanced conditions, low levels of thyroid hormones maintain normal intermediary metabolism; insufficient thyroxine administration results in hypothyroidism; and high thyroxine doses cause swinging to hyperthyreoidic symptoms. The regulatory functions of adenohypophysis and pituitary-dependent glands are to smooth out oscillations. In thyroidectomized patients, the negative feedback loop does not function, and the development of hypothyreoidic symptoms are prevented by thyroxine replacement therapy. This letter presents a hypothyroid case where the muscular side effects following thyroxine replacement therapy manifested as muscle pain. Long-term protection against thyroxine replacement therapy-induced muscle pain has been provided by low doses (2 g/day) of creatine monohydrate administration. In 1993, our male patient was 49 years old when his hyperthyreosis was diagnosed. In 2001, the patient had 7–8 kg loss in weight in 6 months and hyperthyreosis recidiva was diagnosed. A single dose of p.o. administered radioisotope 131I (240 MBq) was applied in a capsular form. Three months later (December 2001), laboratory parameters showed high creatine kinase (894 U/L) and transaminase (GOT 65 IU/L, GPT 61 IU/L) activities. Elevated creatine kinase levels may reflect injury in myocardial infarction, muscle breakdown, muscular dystrophy, myositis, reduced adenosine triphosphate (ATP) level in muscle, and acute renal failure. Upon the radioactive destruction of thyroid function, the patient experienced excessive muscle pain and involuntary defecation of stool for several days. …

Mice Deficient in Dual Oxidase Maturation Factors Are Severely Hypothyroid

Dual oxidases (DUOX1 and DUOX2) are evolutionary conserved reduced nicotinamide adenine dinucleotide phosphate oxidases responsible for regulated hydrogen peroxide (H(2)O(2)) release of epithelial cells. Specific maturation factors (DUOXA1 and DUOXA2) are required for targeting of functional DUOX enzymes to the cell surface. Mutations in the single-copy Duox and Duoxa genes of invertebrates cause developmental defects with reduced survival, whereas knockdown in later life impairs intestinal epithelial immune homeostasis. In humans, mutations in both DUOX2 and DUOXA2 can cause congenital hypothyroidism with partial iodide organification defects compatible with a role of DUOX2-generated H(2)O(2) in driving thyroid peroxidase activity. The DUOX1/DUOXA1 system may account for residual iodide organification in patients with loss of DUOX2, but its physiological function is less clear. To provide a murine model recapitulating complete DUOX deficiency, we simultaneously targeted both Duoxa genes by homologous recombination. Knockout of Duoxa genes (Duoxa(-/-) mice) led to a maturation defect of DUOX proteins lacking Golgi processing of N-glycans and to loss of H(2)O(2) release from thyroid tissue. Postnatally, Duoxa(-/-) mice developed severe goitreous congenital hypothyroidism with undetectable serum T4 and maximally disinhibited TSH levels. Heterozygous mice had normal thyroid function parameters. (125)I uptake and discharge studies and probing of iodinated TG epitopes corroborated the iodide organification defect in Duoxa(-/-) mice. Duoxa(-/-) mice on continuous T4 replacement from P6 showed normal growth without an overt phenotype. Our results confirm in vivo the requirement of DUOXA for functional expression of DUOX-based reduced nicotinamide adenine dinucleotide phosphate oxidases and the role of DUOX isoenzymes as sole source of hormonogenic H(2)O(2).

Atypical Celiac Disease as Cause of Increased Need for Thyroxine: A Systematic Study

Replacement T4 dose in hypothyroid patients bearing both chronic autoimmune thyroiditis and atypical celiac disease (CD) has been analyzed. Replacement T4 dose has been analyzed in 35 hypothyroid patients with Hashimoto's thyroiditis (HT) and atypical CD, as defined by the American Gastroenterological Association. We have evaluated the ability of the same dose of T4 to reach target TSH in 21 patients before and during gluten-free diet (GFD). In the remaining 14 patients, noncompliant with GFD, we analyzed replacement T4 dose and compared it with that in a similar group consisting of 68 patients with hypothyroid HT but no evidence of celiac sprue or other conditions interfering with T4 absorption. In patients with isolated HT, the desired serum TSH (median=1.02 mU/liter) was reached in all patients after 5±2 months of treatment at a median T4 dose of 1.31 μg/kg·d. After a similar period and dose of T4, higher levels of TSH (median=4.20 mU/liter) were observed in patients with HT and CD. In 21 CD patients, target TSH (median TSH=1.25 mU/liter) has been attained after 11±3 months of GFD without increasing T4 dose (1.32 μg/kg·d). In the remaining 14 patients, who were noncompliant with GFD, target TSH has also been achieved but at a higher T4 dose (median=1.96 μg/kg·d; +49%; P=0.0002) than in hypothyroid patients without CD. Atypical CD increases the need for T4. The effect was reversed by GFD or by increasing T4 dose. Malabsorption of T4 may provide the opportunity to detect CD that was overlooked until the patients were put under T4 therapy.

Comparison of the therapeutic effects of tri-iodothyronine and methylprednisolone during early sepsis in laboratory animals

Despite major advances, the treatment of sepsis is still a challenging problem for surgeons. This study was aimed to compare the therapeutic effects of methylprednisolone and tri-iodothyronine replacement therapy during an early sepsis. Forty male Wistar albino rats weighing 300-340 g were divided into the Control, CLP, CLP/MP, CLP/T3 and CLP/MP/T3 groups. The Control group underwent a sham operation. Only cecal ligation and puncture was performed in the CLP group. The CLP/MP groups received an intramuscular injection of (MP) methylprednisolone (30 mg/kg) at one and half hour before CLP. The CLP/T3 group was given an intraperitoneal (IP) injection of tyroid hormone (T3) 0.4 µg/100 g immediately after CLP. The CLP/MP/T3 group was given IM injection of MP 30 mg/kg before CLP and IP injection of T3 0.4 µg/100 g after CLP. Hemavet changes, blood cultures, peritoneal bacteria content, hormonal alterations and histopathologic changes of intestinal, lung and liver tissue were used to asses the possible therapeutic effects of MP and T3 during early sepsis. A septic insult resulted in significant alterations on hemavet values, free T3, free T4 and cortisol levels, peritoneal bacteria content and intestinal lung and liver tissue samples of the CLP group. Hemavet changes and peritoneal inflammation findings were significantly limited in the CLP/T3 and CLP/MP/T3 groups. Histopathologic changes had no significant difference between the groups during an early sepsis. Compared to the MP replacement therapy, therapeutic effects of T3 replacement therapy have been found significantly more promising (Tab. 1, Fig. 10, Ref. 49).

Simulation of Post-thyroidectomy Treatment Alternatives for T3 or T4 Replacement in Pediatric Thyroid Cancer Patients

Abstract Background: As with adults, thyroidectomy of pediatric patients with differentiated thyroid cancer is often followed by 131I remnant ablation. A standard protocol is to give normalizing oral T4 or T3 after surgery and then withdraw it for 2 to 6 weeks. Thyroid remnants or metastases are treated most effectively when serum TSH is high, but prolonged withdrawals should be avoided to minimize hypothyroid morbidity. Methods: A published feedback control system model of adult human thyroid hormone regulation was modified for children using pediatric T4 kinetic data. The child model was developed from data for patients ranging from 3-9 years old. We simulated a range of T4 and T3 replacement protocols for children, exploring alternative regimens for minimizing the withdrawal period, while maintaining normal or suppressed TSH during replacement. The results are presented with the intent of providing a quantitative basis to guide further studies of pediatric treatment options. Replacement was simulated for up to 3 weeks post-thyroidectomy, followed by various withdrawal periods. T4 vs. T3 replacement, remnant size, dose size and dose frequency were tested for effects on the time for TSH to reach 25 mU/L (withdrawal period). Results: For both T3 and T4 replacement, higher doses were associated with longer withdrawal periods. T3 replacement yielded shorter withdrawal periods than T4¬ replacement (up to 3.5 days versus 7-10 days). Higher than normal serum T3 concentrations were required to normalize or suppress TSH during T3 monotherapy, but not T4 monotherapy. Larger remnant sizes resulted in longer withdrawal periods if T4 replacement was used, but had little effect for T3 replacement. Conclusions: T3 replacement yielded withdrawal periods about half those for T4¬ replacement. Higher than normal hormone levels under T3 monotherapy can be partially alleviated by more frequent, smaller doses (e.g. twice a day). L-T4 may be the preferred option for most children, given the convenience of single daily dosing and familiarity of pediatric endocrinologists with its administration. Remnant effects on withdrawal period highlight the importance of minimizing remnant size.

Hypothyroidism caused by phenobarbital affects patterns of estrous cyclicity in rats

We found that repeated treatment with phenobarbital (PB), a thyroid modulator, resulted in a persistent estrous stage in the present study. Although the effects of PB in blocking the surge release of luteinizing hormone (LH), inducing anovulation and prolonging the diestrous period has been well established, there is still no research describing the appearance of persistent estrous states in normal cycling rats dosed with PB. To further study this phenomenon, female rats exhibiting regular estrous cycle were administered an oral dose of PB for 14 consecutive days. Consecutively, vaginal smears were observed and rats from all the groups were sacrificed and serum hormone levels for prolactin, progesterone, estradiol, triiodothyronin (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) were measured. Pituitary, thyroid, liver, uteri and ovaries were excised, weighed and further subjected to histological observations. We found that PB induced irregular estrous cycles, especially persistent estrus in rats. Histopathologically, the persistent estrous stages are characterized by persistent vaginal cornification in the vagina, cystic follicles and anovulation in the ovaries. Endocrinologically, serum T3 and T4 levels were significantly lower, and TSH was higher in treated-female rats compared to control females. The serum estradiol level and the estradiol/progesterone ratio tend to increase in treated-females. Furthermore, PB-treated animals with irregular estrous cycle were reduced by T4 replacement. Our data indicate that treatment with PB resulted in hypothyroidism and irregular estrous cycle, particularly a persistent estrous stage in normal cycling female rats.

Thyroid Replacement Therapy and Heart Failure

Heart failure (HF) is a major public health and economic problem in Western countries and is one of the most common causes of hospitalization and death. Coronary artery disease is the underlying cause in more than two thirds of chronic HF patients. By 2020, the World Health Organization projects that ischemic heart disease alone will be the most important global cause of morbidity and mortality. The estimated increases in HF-related morbidity and mortality suggest that our understanding of the pathophysiological mechanisms of this syndrome is inadequate. Interest in the role of thyroid hormones (THs) in HF has increased in recent years. The driving considerations can be summarized as follows: (1) the known effects of THs on contractile and relaxation properties of the heart; (2) experimental findings offering strong support for the hypothesis that TH signaling is critical in preserving cardiac structure and performance under normal conditions and after cardiac injury; and (3) evidence that mildly altered TH function is strongly associated with a worsening prognosis in cardiac patients in general and in HF patients in particular. Diastolic function and systolic function are clearly influenced by THs.1 Ventricular contractile function is also influenced by changes in hemodynamic conditions secondary to TH effects on peripheral vascular tone.1 TH homeostasis preserves positive ventricular-arterial coupling, leading to a favorable balance for cardiac work. A study in rats demonstrated that chronic hypothyroidism alone can eventually lead to HF.2 Other studies suggest reduced cardiac tissue triiodothyronine (T3) levels after myocardial infarction (MI) or with development of hypertension by upregulating type 3 deiodinase (D3), which leads to deactivation of T3 and T4 (thyroxine).3–6 This review highlights a growing body of evidence from animal studies and small-scale clinical trials suggesting that low cellular thyroid activity at the cardiac tissue level may adversely affect HF …

A Randomized Controlled Trial of the Effect of Thyroxine Replacement on Cognitive Function in Community-Living Elderly Subjects with Subclinical Hypothyroidism: The Birmingham Elderly Thyroid Study

Subclinical hypothyroidism (SCH) and cognitive dysfunction are both common in the elderly and have been linked. It is important to determine whether T4 replacement therapy in SCH confers cognitive benefit. Our objective was to determine whether administration of T4 replacement to achieve biochemical euthyroidism in subjects with SCH improves cognitive function. We conducted a double-blind placebo-controlled randomized controlled trial in the context of United Kingdom primary care. Ninety-four subjects aged 65 yr and over (57 females, 37 males) with SCH were recruited from a population of 147 identified by screening. T4 or placebo was given at an initial dosage of one tablet of either placebo or 25 microg T4 per day for 12 months. Thyroid function tests were performed at 8-weekly intervals with dosage adjusted in one-tablet increments to achieve TSH within the reference range for subjects in treatment arm. Fifty-two subjects received T4 (31 females, 21 males; mean age 73.5 yr, range 65-94 yr); 42 subjects received placebo (26 females, 16 males; mean age 74.2 yr, 66-84 yr). Mini-Mental State Examination, Middlesex Elderly Assessment of Mental State (covering orientation, learning, memory, numeracy, perception, attention, and language skills), and Trail-Making A and B were administered. Eighty-two percent and 84% in the T4 group achieved euthyroidism at 6- and 12-month intervals, respectively. Cognitive function scores at baseline and 6 and 12 months were as follows: Mini-Mental State Examination T4 group, 28.26, 28.9, and 28.28, and placebo group, 28.17, 27.82, and 28.25 [not significant (NS)]; Middlesex Elderly Assessment of Mental State T4 group, 11.72, 11.67, and 11.78, and placebo group, 11.21, 11.47, and 11.44 (NS); Trail-Making A T4 group, 45.72, 47.65, and 44.52, and placebo group, 50.29, 49.00, and 46.97 (NS); and Trail-Making B T4 group, 110.57, 106.61, and 96.67, and placebo group, 131.46, 119.13, and 108.38 (NS). Linear mixed-model analysis demonstrated no significant changes in any of the measures of cognitive function over time and no between-group difference in cognitive scores at 6 and 12 months. This RCT provides no evidence for treating elderly subjects with SCH with T4 replacement therapy to improve cognitive function.

Hypothyroidism and survival during sunitinib therapy in metastatic renal cell carcinoma (mRCC): A prospective observational analysis.

e15013 Background: Sunitinib is currently a standard of care for the treatment of mRCC. Hypothyroidism was frequently observed with sunitinib therapy. This study was conducted to determine the thyroid function and progression-free survival (PFS) of patients (pts) treated for mRCC. Methods: Between October 2005 and March 2009 111 pts treated by sunitinib (50 mg/day, 4 weeks followed by 2 weeks rest) for advanced or mRCC were evaluated for serum TSH, T3 and T4 levels before treatment and every 6 weeks during treatment. Survival was analyzed according to the Landmark method with a day 180 cut off; excluding pts presenting an early progression or censored before day 180. Significance was evaluated with a Log rank test. Results: Median age was 61.7 years. Out of 58 patients (52.3%) developing an alteration of thyroid function, 55 presented a hypothyroidism. Median time to TSH alteration was 294 days and PFS was 342 days for the whole population. Of the 55 hypothyroidism pts, 51 (92.7%) received L-Thyroxin replacement with a median dose of 75 mg/day (range 25-250). The group with abnormal thyroid function at day 180 had a median PFS of 575 days versus 481 days for the group without thyroid abnormality (p=0.94, HR=1.024 (95 CI= [0.544-1.930])). Conclusions: As it was previously described, more than half of our population developed a dysthyroidism under sunitinib therapy. Dysthyroid patients with systematic T4 replacement do not have a significant different PFS (p=0.94) compare to patients without dysthyroidism. Dysthyroidism with systematic hormonal substitution does not influence outcome in sunitinib treated hypothyroidism suffering pts. Nevertheless these conclusions have to be validated by larger comparative studies and biological mechanisms connecting sunitinib and thyroid dysfunction need to be deeply explored. No significant financial relationships to disclose.

Comparison between different methods of adjustment of thyroxin replacement dose after total thyroidectomy for bengin thyroid disease

Introduction: Levothyroxin (T4) is commonly employed to correct thyroid hormone deficiency from various causes, and as total thyroidectomy is increasingly used to treat benign thyroid conditions, lifelong treatment with optimal dose of thyroxin (T4) is required which is difficult to predict. This study investigated factors that might predict the ideal T4 dose, and testing the body mass index as predictive factor with the aim of reducing delays in achieving normal thyroid function after surgery. Methods: This study was conducted on 52 patients presented with benign thyroid disease and operated upon with total thyroidectomy. The patients were prospectively randomized into two comparable groups of patients. One group of patients was given the routinely used titration method of thyroid replacement therapy, while the other used an algorithm for T4 dosage based on patient weight (postoperative weight) which was subsequently applied in previous published literatures. Patient and operative variables that might predict time to achieve normal thyroid function and optimal T4 replacement dose were examined. Results: The median time to achieve normal thyroid function was 16 (range 8–33) weeks in the first group in which the traditional titration method was used and large changes in T4 dose needed. But it was only 8 (range 4-17) weeks in the second group in which the weight algorithm was used. In multivariate analysis, the best predictor of optimal T4 dose was body weight. The use of a weight-related algorithm improved time to achieve normal thyroid function. There was a much stronger association between the L-T4 dosage and body mass. Conclusion: The T4 replacement dosage after total thyroidectomy is largely influenced by body weight particularly in subjects with high BMI values. Use of a weight-related algorithm shortens the time required to attain a stable dose of L-T4 compared with use of standard T4 dose-titration methods

Lipid Profiles in the Untreated Patients with Hashimoto Thyroiditis and the Effects of Thyroxine Treatment on Subclinical Hypothyroidism with Hashimoto Thyroiditis

To evaluate the prevalence of dyslipidemia in the population of Hashimoto thyroiditis, we reviewed medical records on the consecutive 1181 cases with adult Hashimoto thyroiditis and 830 cases were adopted for the study. First, the serum TSH level increased and serum free T4 level decreased, slightly but significantly, with increasing age. There were significant positive correlations between serum TSH levels and lipid parameters such as total cholesterol (TC), triglyceride (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), non-HDL-C and LDL-C/HDL-C ratio (L/H). In contrast, there were significant negative correlations between serum free T4 levels and all of these lipid parameters. According to the thyroid function, the cases were classified into 4 groups such as thyrotoxicosis (TT), euthyroidism (EU), subclinical hypothyroidism (SH) and overt hypothyroidism (OH). TC, HDL-C, non-HDL-C and LDL-C of TT were significantly lower than those in EU. In contrast, TC, TG, non-HDL-C, LDL-C, L/H and age of OH were significantly higher than those in EU. Interestingly, LDL-C and L/H of SH were significantly higher compared with EU. Thirty-two of SH patients were treated with small doses of levothyroxine and the effects on the lipid profile were examined. The TC, non-HDL-C, LDL-C and L/H were significantly decreased after treatment. In conclusion, the prevalence of dyslipidemia increases along with hypofunction of the thyroid and T4 replacement therapy may improve lipid profile in the cases of SH with Hashimoto thyroiditis.

Thyroxine alone or thyroxine plus triiodothyronine replacement therapy for hypothyroidism

Standard therapy for patients with hypothyroidism is replacement with synthetic thyroxine (T4). However, thyroxine plus triiodothyronine (T3) replacement therapy resulted in marked improvements in several items of the Profile of Mood States and in a few indices of psychometric function and quality of life. The adequacy of thyroxine alone versus thyroxine plus triiodothyronine to treat hypothyroidism has yielded conflicting results. Therefore, we conducted a systematic review of all included published, randomized controlled trials to evaluate the effects of thyroxine alone or thyroxine plus triiodothyronine replacement therapy for hypothyroidism. We electronically searched Medline, Embase, the Cochrane Library, and China National Infrastructure. We also manually searched the Chinese Journal of Isotopes, Radiologia pratica, and the Chinese Journal of Endocrinology and Metabolism. A total of 10 randomized, double-blind trials (six crossovers, four parallel trials) were identified. Pooled analyses were suggestive of a statistically significant increase of free and total triiodothyronine, significant decrease of serum-free and total thyroxine in patients treated with thyroxine plus triiodothyronine, weighted mean difference (WMD) 0.03, -31.25, 2.19, 3.00; 95% confidence interval (CI) -0.14 to 0.20, -47.04 to -15.47, 0.46-3.92, 1.64-4.36, respectively. Thyroxin alone indicated significant benefits for psychological or physical well-being in terms of the General Health Questionnaire-28 (WMD: -2.90; 95% CI: -3.18 to -2.63), general health (WMD: -0.38; 95% CI: -0.71 to -0.05), physical component summary (WMD: 0.7; 95% CI: 0.53-0.87), and mental component summary (WMD: 0.58; 95% CI: 0.25-0.75); physical functioning (WMD: 1.60; 95% CI: 1.29-1.90), role-physical test (WMD: 3.60; 95% CI: 2.66-4.54), bodily pain (WMD: 2.50; 95% CI: 2.11-2.88), role-emotional (WMD: 2.08; 95% CI: 1.17-2.99), mental health (WMD: 1.30; 95% CI: 0.97-1.64) in items of the Short Form-36 Health Survey; general well-being in items of the Thyroid Symptom Questionnaire (WMD: -1.90; 95% CI: -2.48 to -1.32); better performance in the Letter Number Sequencing-working memory test in items of cognitive performance scores (WMD: 1.10; 95% CI: 0.08-2.13), significant treatment effect for blurred vision, aches, and pain (WMD: -4.66, -0.80; 95% CI: -5.339 to -4.00, -1.34 to -0.26, respectively). However, T4 plus T3 replacement improved cognitive performance (WMD: -0.49; 95% CI: -0.90 to -0.08). No significant statistical differences were found in biochemical variables, mood states clinical variables, adverse effects, and drop-out. In subgroup analysis, two included studies examined the relationship between mental improvement and causes of hypothyroidism, autoimmune, and nonautoimmune hypothyroidism, respectively. T4 alone suggested significantly higher total T4 (autoimmune and nonautoimmune thyroid, WMD: 4.5, 3.7; 95% CI: 2.24-6.76, 1.66-5.74, respectively), and significantly decreased thyroid-stimulating hormone (WMD: -0.05; 95% CI: -0.09 to -0.01). Statistically significant improvement occurred in pairs correctly recalled in the Digit Symbol Test for T4 plus T3 replacement (WMD: -1.60; 95% CI: -2.97 to -0.23) for nonautoimmune thyroid. In conclusion, on the basis of data from recent studies, we conclude that combined T4 and T3 treatment does not improve well-being, cognitive function, or quality of life compared with T4 alone. T4 alone may be beneficial in improving psychological or physical well-being. According to the current evidence, T4 alone replacement may remain the drug of choice for hypothyroid patients.

Hypothyroidism complicated by low T3 state: An issue in intensive care unit

A variety of severe clinical situations, such as organ failure, can determine low serum T3 state in euthyroid patients. Recently various low triiodothyronine (T3) states have been correlated with a poor prognosis in cardiac and respiratory patients. These conditions could have an important impact especially in hypothyroidism. We described one case admitted to our respiratory intensive care unit (RICU) in comatose state, suffering from acute respiratory failure due to pneumonia with untreated subclinical hypothyroidism complicated by low T3 state. In this patient the treatment with levothyroxin alone was ineffective while replacement therapy with synthetic sodic liothyronine proved effective and lead to clinical improvement. The low T3 state is common in RICU patients and this finding could be very important in clinical practice especially when hypothyroidism might be complicated by low T3 state. This report suggest that in this case only the addition of T3 to T4 replacement therapy may improve clinical status.

Effects of 18 months of l‐T4 replacement in women with subclinical hypothyroidism

Some of the cardiovascular and renal abnormalities seen in overt hypothyroidism have also been reported in subclinical hypothyroidism (SCH). Short-term L-T4 replacement in SCH improves cardiovascular risk markers and reduces carotid intima-media thickness (CIMT), a surrogate marker of atherosclerosis. The haemodynamic and renal effects of L-T4 replacement in SCH are poorly understood. To compare cardiovascular risk factors and renal variables in women with SCH and normal women. To study the effects of L-T4 replacement in SCH subjects on these variables and on structural and functional changes in common carotid and brachial arteries. Fifty-six women with SCH before and after L-T4 replacement for 18 months and 56 normal women of similar age distribution were studied. Blood Pressure (BP), plasma lipids and homocysteine were measured and renal function evaluated [estimation of glomerular filtration rate (eGFR) using standard equations and measurement of serum Cystatin-C] in women with SCH before and after 18 months of l-T4, and in healthy women. CIMT and endothelial function (using brachial artery ultrasound) were studied before and after L-T4 in a subgroup of women with SCH. Systolic and diastolic BP, total cholesterol, triglyceride, LDL-cholesterol, lipoprotein(a) and homocysteine were greater in SCH (P < 0.05), and following L-T4 replacement decreased (P < 0.05) to levels that no longer differed from normal subjects. Estimated GFR was reduced and serum Cystatin-C increased (P < 0.05) in SCH. These variables also normalized following L-T4. Following L-T4 replacement the carotid artery baseline diameter increased by 7.1% and CIMT decreased by a mean value of 13%, while brachial artery diameter increased basally by 12.5% and following endothelium-dependent vasodilatation by 17.5% (P < 0.05). However, the increment following reactive hyperaemia did not differ before or following L-T4 replacement. Normalization of cardiovascular risk factors following L-T4 replacement in SCH potentially explains reduced CIMT. Increased carotid and brachial artery diameters and normalized eGFR indicates a haemodynamic effect of L-T4 replacement, the importance of which requires further investigation.

Effects of thyroxine replacement on serum creatinine and cystatin C in patients with primary and central hypothyroidism.

Serum cystatin C (CysC) is a marker for kidney function, possibly superior to serum creatinine (Cr). Cr is increased and CysC decreased in primary hypothyroidism; these changes are reversed upon thyroxine (T4) replacement therapy. This (pilot) study was performed to see whether these opposing changes of CysC and Cr could be confirmed in patients with central hypothyroidism. Prospective case series of consecutively referred patients with primary and central hypothyroidism. CysC and Cr were determined at the time of diagnosis and following T4 replacement therapy. 32 patients with newly diagnosed hypothyroidism were included. In 16 patients with primary hypothyroidism, mean fT4 was 4.4 +/- 2.5 pmol/l (normal range 12 to 22) at diagnosis and increased to 20.1 +/- 5.2 pmol/l (p <0.001) following T4 replacement. CysC increased from 0.79 +/- 0.27 mg/l (normal range 0.63 to 1.33) to 1.03 +/- 0.42 mg/l (p = 0.007) whereas Cr declined from 104 +/- 21 micromol/l to 90 +/- 19 micromol/l (p <0.001). In 16 patients with central hypothyroidism, mean fT4 was 6.5 +/- 1.6 pmol/l at diagnosis and increased to 15.7 +/- 3.3 pmol/l (p <0.001) following T4 replacement. CysC increased from 0.74 +/- 0.27 mg/l to 0.83 +/- 0.30 mg/l (p = 0.01) whereas Cr was not elevated at baseline (83 +/- 11 micromol/l) and did not decrease following treatment (84 +/- 10 micromol/l). CysC was low at diagnosis of hypothyroidism and significantly increased following T4 replacement in patients with primary as well as central hypothyroidism. T4 replacement decreased Cr levels in patients with primary hypothyroidism whereas Cr remained unchanged in;patients with central hypothyroidism. CysC may not accurately reflect kidney function in patients with primary and central thyroid dysfunction.

Effects of thyroxine replacement on serum creatinine and cystatin C in patients with primary and central hypothyroidism.

Serum cystatin C (CysC) is a marker for kidney function, possibly superior to serum creatinine (Cr). Cr is increased and CysC decreased in primary hypothyroidism; these changes are reversed upon thyroxine (T4) replacement therapy. This (pilot) study was performed to see whether these opposing changes of CysC and Cr could be confirmed in patients with central hypothyroidism. Prospective case series of consecutively referred patients with primary and central hypothyroidism. CysC and Cr were determined at the time of diagnosis and following T4 replacement therapy. 32 patients with newly diagnosed hypothyroidism were included. In 16 patients with primary hypothyroidism, mean fT4 was 4.4 +/- 2.5 pmol/l (normal range 12 to 22) at diagnosis and increased to 20.1 +/- 5.2 pmol/l (p <0.001) following T4 replacement. CysC increased from 0.79 +/- 0.27 mg/l (normal range 0.63 to 1.33) to 1.03 +/- 0.42 mg/l (p = 0.007) whereas Cr declined from 104 +/- 21 micromol/l to 90 +/- 19 micromol/l (p <0.001). In 16 patients with central hypothyroidism, mean fT4 was 6.5 +/- 1.6 pmol/l at diagnosis and increased to 15.7 +/- 3.3 pmol/l (p <0.001) following T4 replacement. CysC increased from 0.74 +/- 0.27 mg/l to 0.83 +/- 0.30 mg/l (p = 0.01) whereas Cr was not elevated at baseline (83 +/- 11 micromol/l) and did not decrease following treatment (84 +/- 10 micromol/l). CysC was low at diagnosis of hypothyroidism and significantly increased following T4 replacement in patients with primary as well as central hypothyroidism. T4 replacement decreased Cr levels in patients with primary hypothyroidism whereas Cr remained unchanged in;patients with central hypothyroidism. CysC may not accurately reflect kidney function in patients with primary and central thyroid dysfunction.

Type 2 Iodothyronine Deiodinase in Skeletal Muscle: Effects of Hypothyroidism and Fasting

The iodothyronine deiodinases D1, D2, and D3 enable tissue-specific adaptation of thyroid hormone levels in response to various conditions, such as hypothyroidism or fasting. The possible expression of D2 mRNA in skeletal muscle is intriguing because this enzyme could play a role in systemic as well as local T3 production. We determined D2 activity and D2 mRNA expression in human skeletal muscle biopsies under control conditions and during hypothyroidism, fasting, and hyperinsulinemia. This was a prospective study. The study was conducted at a university hospital. We studied 11 thyroidectomized patients with differentiated thyroid carcinoma (DTC) on and after 4 wk off T4( replacement and six healthy lean subjects in the fasting state and during hyperinsulinemia after both 14 and 62 h of fasting. D2 activity and D2 mRNA levels were measured in skeletal muscle samples. No differences were observed in muscle D2 mRNA levels in DTC patients on and off T4 replacement therapy. In healthy subjects, muscle D2 mRNA levels were lower after 62 h compared to 14 h of fasting. Insulin increased mRNA expression after 62 h, but not after 14 h of fasting. Skeletal muscle D2 activities were very low and not influenced by hypothyroidism and fasting. Human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism. The lack of a clear effect of D2 mRNA modulation on the observed low D2 activities questions the physiological relevance of D2 activity in human skeletal muscle.

Effects of T4 replacement therapy on glucose metabolism in subjects with subclinical (SH) and overt hypothyroidism (OH)

Effects of T4 replacement therapy on glucose metabolism in subjects with subclinical (SH) and overt hypothyroidism (OH)

Effects of T4 replacement therapy on glucose metabolism in subjects with subclinical (SH) and overt hypothyroidism (OH)

Effects of T4 replacement therapy on glucose metabolism in subjects with subclinical (SH) and overt hypothyroidism (OH)

Effects of T4 replacement therapy on glucose metabolism in subjects with subclinical (SH) and overt hypothyroidism (OH)

To evaluate beta-cell function and insulin sensitivity in subjects with overt (OH) and subclinical hypothyroidism (SH) before and after T4 replacement therapy. Disturbances in glucose metabolism have been observed in hypothyroid states. However, the clinical significance and potential reversibility of these alterations by T4 replacement therapy remain to be elucidated especially in patients with SH. Parameters of glucose metabolism have been investigated in subjects with OH (n = 12) and SH (n = 11). Insulin sensitivity has been assessed by the euglycaemic-hyperinsulinaemic clamp technique and beta-cell function by mathematical modelling of data derived from an oral glucose tolerance test. Fasting and dynamic glycaemia as assessed by the AUC(Glucose) remained unaltered following substitution therapy (P > 0.05). Insulin sensitivity significantly improved only in subjects with OH (P < 0.05). Fasting insulin and proinsulin concentrations increased proportionally in both groups (P < 0.05) with the proinsulin : insulin ratio remaining unchanged (P > 0.05). Total insulin secretion was higher in OH before initiation of therapy (P < 0.05). In both groups, dynamic parameters including total insulin secretion, hepatic insulin extraction and the adaptation index were significantly attenuated (P < 0.05) after restoration of thyroid function, whereas the disposition index and the basal insulin secretion rate remained unaltered (P > 0.05). In summary, SH and OH are characterized by attenuated basal plasma insulin levels and increased glucose-induced insulin secretion. T4 replacement therapy partially ameliorates the insulin secretion profile and reduces the demand on pancreatic beta-cells after glucose challenge to an extent that exceeds any effect attributable to the improvement in insulin sensitivity.