T4 Replacement Therapy Research Articles

Van Wyk Grumbach Syndrome and Ovarian Hyperstimulation in Juvenile Primary Hypothyroidism: Lessons From a 30-Case Cohort.

Prolonged hypothyroidism in children commonly causes short stature with delayed bone maturation, and delayed puberty. However, a paradoxical occurrence of peripheral precocious puberty and pituitary enlargement in chronically untreated juvenile hypothyroidism was first reported by Van Wyk and Grumbach in 1960. To create increased awareness and a better understanding of this clinical entity among emergency room physicians, pediatricians, surgeons, gynecologists and oncologists. Case records of children diagnosed with Van Wyk-Grumbach syndrome (VWGS) were analyzed retrospectively. Twenty-six girls and 4 boys were identified (2005-2020). All had profound primary hypothyroidism (total thyroxine [T4]: 2.5-33.5 nmol/L, thyrotropin: > 75-3744μIU/mL). Hypothyroidism was not the referral diagnosis in any of the girls. Among them, 17 were referred for precocious puberty, 5 with a diagnosis of pituitary tumor on magnetic resonance imaging, and others for acute surgical abdomen in 7 girls (painful abdominal mass-2, ovarian tumor-2, ovarian torsion-2, ruptured ovarian cyst-1), acute myelopathy in 1, and menorrhagia with headache in another. All girls were successfully managed with levothyroxine replacement alone, except for the 2 with ovarian torsion, who required surgery. Menstruation ceased promptly with T4 therapy in all girls, occurring at an age-appropriate later date. All boys had testicular enlargement at presentation that regressed partially after T4treatment. Catch-up growth was remarkable during the first treatment year, but the final height was compromised in all. Increased awareness of varied presentations of VWGS is vital among pediatricians to facilitate early diagnosis and targeted investigations, and to help in the initiation of the simple yet highly rewarding T4 replacement therapy to avoid all possible complications.

Thyroxine Replacement Therapy during Ramadan Fasting: Physicians' and Patients' Perceptions and Practices

Abstract Objective Thyroxine (T4) therapy is taken on an empty stomach and no food is taken for a short period. During Ramadan fasting (RF), Muslim patients may face difficulties taking levothyroxine as recommended. Materials and Methods We performed a mixed methods study of an online survey of 218 physicians to explore their perceptions and practices. Also, we interviewed a sample of 172 hypothyroid patients to establish their practices and source of information. Their median age was 46 (17–90) years; they had hypothyroidism for a median of 5 years and took a median thyroxine dose of 100 µg daily. Furthermore, we attempted to explore the effects of RF on available thyroid function tests. Results Consultants were 58.4%, and the most represented specialty was endocrinology, 46.1%. Regarding the impact of RF on T4 therapy, 52.3% thought the RF was not clinically relevant in most patients on T4 replacement. However, 27.5% thought RF affects T4 replacement therapy in a clinically relevant manner. About 77.1% of respondents reported giving advice routinely to all patients on T4 replacement during RF. One hundred sixty-four respondents were split between recommending taking the medications with Iftar, Suhour, or other times. Most respondents (73.9%) do not repeat measurements of thyroid hormone levels after Ramadan unless needed during their scheduled clinic visit. On the other hand, 50.3% of the patients confirmed that their physician advised them to take their thyroxine during Ramadan, whereas 40.4% could not recall receiving any advice. About 59.9% of the patients took thyroxine with Iftar, 23.8% with Suhour, and 16.3% at different times. In those patients where thyroid function tests were available before and after RF, serum thyroid-stimulating hormone and serum-free T4 did not show a specific pattern in the group as a whole and with subgroups. Conclusion There is variation in the advice that hypothyroid patients receive on taking thyroxine during Ramadan and in their practices. Further studies are needed to determine the best timing for thyroxine replacement.

Hypothyroidism Prevalence in the United States: A Retrospective Study Combining National Health and Nutrition Examination Survey and Claims Data, 2009-2019.

Previous estimates determined prevalence of hypothyroidism (HT) to be 4.6% of the US population. This study aimed to update estimates of HT prevalence in the United States by retrospective analysis of 2 datasets. Data on HT type (overt or subclinical HT) and treatment were collected from the 2009-2010 and 2011-2012 National Health and Nutrition Examination Survey (NHANES) cycles. From the Optum administrative claims database, medical and pharmacy claims were collected between January 1, 2012, and December 31, 2019. Patients were defined as having HT if, per given year, they had >1 prescription for HT treatment, >1 claim indicating an HT diagnosis, or thyroid-stimulating hormone levels >4.0 mIU/L (NHANES arm). For both studies, treatment was defined as any evidence of synthetic or natural thyroid hormone replacement, identified by pharmacy claims or patient surveys. Data are reported as percentage of patients with HT and treatments received. Between 2009 and 2012, HT prevalence remained around 9.6% of the US population. The administrative claims dataset showed that HT prevalence grew from 9.5% in 2012 to 11.7% in 2019 and that >78% of patients received thyroxine (T4) monotherapy. Similarly, the NHANES dataset showed that T4 replacement therapy was the most common treatment for HT. From 2012-2019, patients with untreated HT grew from 11.8% to 14.4%. The prevalence of HT in the United States has steadily increased since 2009. Likewise, the percentage of hypothyroid-diagnosed patients not receiving treatment also increased, suggesting that the increased prevalence may be due to increased cases of subclinical HT.

COVID-19 Induced Myxedema Madness

Background: Corona Virus Disease 2019 (COVID-19) pandemic was first reported in December 31st, 2019 in Wuhan, China. The clinical presentation is variable, including a variety of neuropsychiatric related symptoms. Myxedema Madness is a rare and severe neuropsychiatric complication of hypothyroidism manifested as psychosis. Case Presentation: A 25-year-old female with past medical history significant for treated Papillary Thyroid Cancer, presented with near syncopal event associated with weakness, lower extremity swelling, constipation, cold intolerance and dry skin. The patient was not compliant with her thyroid replacement therapy. Upon collateral history taken from the patient’s mother; the patient became dysphoric and tearful. On examination, patient had slightly decreased blood pressure and non-pitting edema on lower extremities. On neurological evaluation she exhibited forgetfulness and retardation of speech and motoric activity. Lab was remarkable for TSH greater than 100 uU/mL (reference range 0.30-4.20 uU/mL), FT4 0.4 ng/dL (reference range 0.6-1.5 ng/dL), and FT3 0.7 pg/mL (reference range 2.3-4.2 pg/mL). Patient tested negative for COVID-19 PCR. She was started on her home dose of Levothyroxine 150 mcg daily. Patient was discharged home after she was assessed by a psychiatrist, with no further interventions. Three days later, the patient was readmitted for confusion, disorientation and memory loss. Patient was found to be positive for COVID-19 PCR and negative for SARS-CoV-2 antibodies. She was found to be disoriented with paranoid delusions. Laboratory studies showed negative urine drug screen, syphilis and NMDA antibodies. CSF analysis were within normal ranges. Brain Magnetic resonance imaging was only positive for pituitary hyperplasia. Patient was started on T4 and T3 replacement therapy (Levothyroxine 50 mcq Intravenous, Liothyronine 5 mcg daily orally, respectively) followed by Risperdal 1 mg nightly. Aftersignificant improvement in her mood and delusions, patient was discharged home on Levothyroxine 150 mg daily and Risperdal 1mg for two weeks. Patient and family members were counseled on medications compliance. In a two-week follow-up visit, patient reported to be compliant with medications and improvement of mood. She denied hallucination or delusions. Her lab work was significant for TSH 5.57 uU/mL, FT4 1.3 ng/dL and FT3 3.2 pg/mL. Conclusion: Both psychosis secondary to COVID-19 and Myxedema Madness are rare conditions. Appropriate and timely supplementation of thyroid hormone facilitated speedy return of patient’s cognitive and psychiatric functions to appropriate baseline. This case report may increase physician’s awareness for potentially increased susceptibility of patients with severe hypothyroidism to neuropsychiatric manifestations of COVID-19.

Effect of hypothyrodism’s medication (T4) on implant osstointegration: A case series and literature search

IntroductionHypothyroidism reduces the recruitment, maturation, and activity of bone cells, decreasing bone resorption and formation. Several investigations have reported that T4 replacement therapy is associated with a significant decrease in bone mineral density in various skeletal parts, while others have failed to corroborate these results. The present study describes both a literature review and our own experience with dental implants in patients with hypothyroidism undergoing T4 replacement therapy. Case presentationThe study included two parts: a literature review and case series. The literature review included 12 articles documenting the success rate of osseointegrated dental implants in patients with hypothyroidism. The clinical cases were chosen from King Saud University Dental College, Riyadh. The patients’ identity was only available to the main researcher. The inclusion criteria for the clinical cases were: T4-treated hypothyroidism, age 20–60 years, and use of dental implants with a follow-up period of 6–12 months after loading. The exclusion criteria were: any other medical condition alongside hypothyroidism, syndromic hypothyroidism, pregnancy, current smoking, bruxism, and hypothyroidism caused by surgical excision combined with radiotherapy. The following parameters were assessed: insertion torque (IT), crestal bone height (CBH), mesial bone width (MBW), and distal bone width (DBW) at different time points, probing depth, and signs of infection. DiscussionSeventeen dental implants placed in patients with T4-treated hypothyroidism showed median IT success (42.4 N⋅cm; range: 35–45 N⋅cm). The median crestal bone loss was measured at 6–12 months after loading was 0.6 mm (range: 0.5–0.7. mm). Conversely, the median bone loss differences in MBW and DBW at 6–12 months after loading were 0.3 mm and 0.2 mm, respectively. ConclusionAfter a 1-year follow-up, patients with T4-treated hypothyroidism who had received dental implants fulfilled the criteria for successful implants.

Effect of thyroxine on the expression of HIF-1α after aneurysmal subarachnoid hemorrhage in rat brain and its mechanism

Objective: To investigate the effect of thyroxine (T4) on the expression of hypoxia inducible factor-1α (HIF-1α) in rat brain after aneurysmal subarachnoid hemorrhage (SAH) and its mechanism. Methods: Seventy-two adult male SD rats were randomly divided into the following 4 groups: subarachnoid hemorrhage model group(SAH), subarachnoid hemorrhage model and T4 group (SAH with T4), subarachnoid hemorrhage model with normal saline group (SAH with vehicle), and sham-operation group, 18 rats in each group. The model of subarachnoid hemorrhage group was established by internal carotid artery puncture. CT plain scan was performed after the modeling immediately, T4 was administrated by intraabdominal injection of 3 μg/100 g every 24 hours for 3 days. SAH with T4 group was treated with thyroxine. SAH with vehicle group was treated with equal volume vehicle, all of them were killed 72 hours after modeling. The brain water content was determined to evaluate the brain edema, the apoptosis of cerebral cortex cells was detected by TUNEL method, and HIF-1α protein and p-Akt protein in cerebral cortex were detected by immunohistochemistry in six SD rats of each group. Results: After the modeling, the brain tissues of SAH group, SAH + T4 group and SAH +vehicle group were swollen obviously, and blood clots were observed in subarachnoid space. The neurobehavioral score,the brain water content, apoptosis index, HIF-1α protein and p-Akt protein in SAH group were significantly higher than those in sham-operation group(P＜0.05).The neurobehavioral score,HIF-1α protein and p-Akt protein in SAH with T4 group were significantly higher than those in SAH group, and the brain water content, apoptosis index were significantly lower than those in SAH group (P＜0.05). Conclusion: The expression of HIF-1α protein in the brain of rats after aneurysm subarachnoid hemorrhage can be upregulated by T4 replacement therapy, which may by activating the signal pathway of inositol triphosphate kinase / protein kinase B (PI3K/Akt). Finally, apoptosis index was decreased, the rat behavior was improved and the brain was protected.

3,5-T2-A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action.

Over the last decades, thyroid hormone metabolites (THMs) received marked attention as it has been demonstrated that they are bioactive compounds. Their concentrations were determined by immunoassay or mass-spectrometry methods. Among those metabolites, 3,5-diiodothyronine (3,5-T2), occurs at low nanomolar concentrations in human serum, but might reach tissue concentrations similar to those of T4 and T3, at least based on data from rodent models. However, the immunoassay-based measurements in human sera revealed remarkable variations depending on antibodies used in the assays and thus need to be interpreted with caution. In clinical experimental approaches in euthyroid volunteers and hypothyroid patients using the immunoassay as the analytical tool no evidence of formation of 3,5-T2 from its putative precursors T4 or T3 was found, nor was any support found for the assumption that 3,5-T2 might represent a direct precursor for serum 3-T1-AM generated by combined deiodination and decarboxylation from 3,5-T2, as previously documented for mouse intestinal mucosa. We hypothesized that lowered endogenous production of 3,5-T2 in patients requiring T4 replacement therapy after thyroidectomy or for treatment of autoimmune thyroid disease, compared to production of 3,5-T2 in individuals with intact thyroid glands might contribute to the discontent seen in a subset of patients with this therapeutic regimen. So far, our observations do not support this assumption. However, the unexpected association between high serum 3,5-T2 and elevated urinary concentrations of metabolites related to coffee consumption requires further studies for an explanation. Elevated 3,5-T2 serum concentrations were found in several situations including impaired renal function, chronic dialysis, sepsis, non-survival in the ICU as well as post-operative atrial fibrillation (POAF) in studies using a monoclonal antibody-based chemoluminescence immunoassay. Pilot analysis of human sera using LC-linear-ion-trap-mass-spectrometry yielded 3,5-T2 concentrations below the limit of quantification in the majority of cases, thus the divergent results of both methods need to be reconciliated by further studies. Although positive anti-steatotic effects have been observed in rodent models, use of 3,5-T2 as a muscle anabolic, slimming or fitness drug, easily obtained without medical prescription, must be advised against, considering its potency in suppressing the HPT axis and causing adverse cardiac side effects. 3,5-T2 escapes regular detection by commercially available clinical routine assays used for thyroid function tests, which may be seriously disrupted in individuals self-administering 3,5-T2 obtained over-the counter or from other sources.

Thyroid Dysfunction and Atherosclerosis: A Systematic Review.

Thyroid dysfunction, both hypo- and hyperthyroidism, has been associated with cardiovascular disease. The aim of this study was to evaluate the association between thyroid dysfunction and atherosclerosis measured mostly by carotid intima-media thickness, as well as discuss whether L-T4 replacement is able to reverse or slow down the progression of atherosclerosis. The review was conducted according the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We performed on PubMed a literature search from May 2004 to January 2020, using the search terms 'subclinical hypothyroidism' or 'thyroid disorders' and 'carotid artery', 'carotid intima-media thickness (IMT)', 'levothyroxine', and 'atherosclerosis'. Twenty-six studies were eligible and included in the analysis. Overall, the studies encompassed a total of 36.434 patients included in this review. Most studies indicated a proportional correlation between IMT and thyroid dysfunction. Levothyroxine (L-T4) replacement led to significant decrease of IMT after 1 year in most studies. Most studies have concluded that thyroid dysfunction is associated with arterial wall remodeling and, thus, with increased cardiovascular risk. However, the exact mechanistic background of pathological structural changes in the arterial wall is still unsettled. Large randomized controlled studies are required to definitively address the extent to which T4 replacement therapy might benefit patients with subclinical thyroid disorders.

P4.40: Severe hypothyroidism and metabolic encephalopathy in a child receiving long-term home parenteral nutrition without selenium

Introduction: Selenium is essential in the protection against oxidative stress, for optimum immune response and for thyroid hormone biosynthesis and metabolism. We describe a case of chronic selenium deficiency with severe hypothyroidism and metabolic encephalopathy in a child with ultra-short bowel syndrome receiving long-term home parenteral nutrition (PN) without selenium supplementation. Methods: The patient is a 4-year-old girl, born prematurely at 26 weeks of gestation, birth weight 670g. At the 13th day of life she was diagnosed with necrotizing enterocolitis and required exploratory laparotomy. There was necrosis of the small bowel and need of extensive resection, with 3 cm of small bowel and half of colon remaining. After the surgery, she was started on exclusive PN containing a fixed dose of multi-trace element solution but lacking selenium, probably due to drug shortage. After a one-year hospitalization, she was discharged and continued to receive PN at home. At 3 years old she presented with converging strabismus and regression of motor development. Initially she had inability to ambulate, which worsened until she couldn’t walk, sit and talk. At that time, she was diagnosed with decompensated hypothyroidism, requiring T3 and T4 replacement therapy. Results: At the age of 3 years 8 months, she was referred to our intestinal rehabilitation center for investigation. On examination she had an edematous face, muscle weakness, irritability and depigmented hair. Plasma selenium levels were undetectable. The diagnosis of encephalopathy and myxedema secondary to severe selenium deficiency was made. Intravenous selenium repletion therapy was initiated (4 µg/kg/day), followed by 2 µg/kg/day as maintenance and, as selenium plasma levels normalized, the need of T3 replacement was reduced until it was discontinued and maintenance treatment with levothyroxine isolated was initiated. She was discharged from hospital to home care four months later at the age of 4. After selenium levels restored to normal, neurological signs improved progressively and growing hair was repigmented. She continues to receive physio, speech and occupational therapy and she is progressing well. Conclusion: Chronic selenium deficiency caused severe hypothyroidism and metabolic encephalopathy in a child receiving exclusive long-term home PN without selenium. Patients on long-term PN need selenium supplementation to avoid serious clinical manifestations of deficiency.

THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect?

About 5%-10% of hypothyroid patients on T4 replacement therapy have persistent symptoms, despite normal TSH levels. It was hoped that T4 + T3 combination therapy might provide better outcomes, but that was not observed according to a meta-analysis of 11 randomized clinical trials comparing T4 monotherapy with T4 + T3 combination therapy. However, the issue is still subject of much research because normal thyroid function tests in serum may not necessarily indicate an euthyroid state in all peripheral tissues. This review evaluates recent developments in the field of T4 + T3 combination therapy. T4 monotherapy is associated with higher serum FT4 levels than in healthy subjects, and subnormal serum FT3 and FT3/FT4 ratios are observed in about 15% and 30% respectively. T4 + T3 combination therapy may mimic more closely thyroid function tests of healthy subjects, but it has not been demonstrated that relatively low serum FT3 or FT3/FT4 ratios are linked to persistent symptoms. One study reports polymorphism Thr92Ala in DIO2 is related to lower serum FT3 levels after thyroidectomy, and that the D2-Ala mutant reduces T4 to T3 conversion in cell cultures. Peripheral tissue function tests such as serum cholesterol reflect thyroid hormone action in target tissues. Using such biochemical markers, patients who had a normal serum TSH during postoperative T4 monotherapy, were mildly hypothyroid, whereas those with a TSH 0.03-≤0.3 mU/L were closest to euthyroidism. Peripheral tissue function tests suggest euthyroidism more often in patients randomized to T4 + T3 rather than that to T4. Preference for T4 + T3 combination over T4 monotherapy was dose-dependently related to the presence of two polymorphisms in MCT10 and DIO2 in one small study. It is not known if persistent symptoms during T4 monotherapy disappear by switching to T4 + T3 combination therapy. The number of patients on T4 + T3 therapy has multiplied in the last decade, likely induced by indiscriminate statements on the internet. Patients are sometimes not just asking but rather demanding this treatment modality. It creates tensions between patients and physicians. Only continued research will answer the question whether or not T4 + T3 combination therapy has true benefits in some patients.

Dynamics of immune-mediated thyroid dysfunction in patients with advanced renal cell carcinoma receiving checkpoint inhibitor therapy.

e16071 Background: Checkpoint inhibitors (CPI) are quickly gaining relevance in the management of metastatic renal cell carcinoma (RCC). Treatment is generally well tolerated, but immune-induced thyroid dysfunction (TD) is reported in up to 10% of patients (pts) across trials. The dynamics of this phenomenon are undefined; hence there are no proposed standards for endocrine surveillance on therapy. Here we report on a cohort of RCC pts treated with CPI at Memorial Sloan Kettering Cancer Center with serial prospective assessment of thyroid function on therapy. Methods: Thyroid function tests (TFT) were assessed at baseline and serially on therapy. We recorded trends for hyper- and hypothyroidism and determined median time to development of TD by standard statistical methods. T4 replacement therapy was investigated by individual chart review. The association of TD with outcomes on CPI therapy was assessed by non-parametric tests. Results: Of 59 pts with serial TFT assessment, 20 were hypothyroid and 39 were euthyroid at baseline. 50% of previously hypothyroid pts required adjustment of T4 dosage. Thirteen of 39 euthyroid pts (36%) developed new TD requiring thyroid replacement. TD occurred early (median time to onset: 1.4 months, range 0.9-9.6), and in six of the 13 pts (46%), transient thyroiditis preceded hypothyroidism. None of the pts with thyroiditis required treatment, and the median duration from onset of thyroiditis to development of hypothyroidism was 1.5 months (range 0.7-2.8). All pts with hypothyroidism required replacement therapy; none required discontinuation of immunotherapy due to TD. TD was not associated with difference in objective response rate (fisher’s exact, p = 0.163), regression in target lesions (wilcoxon rank-sum, p = 0.135), or PFS (log rank p = 0.8214). Conclusions: TD is common in RCC pts receiving CPI therapy. In this cohort, onset of TD was early, thyroiditis was always transient, and no new cases were detected beyond 10 months. Confirming these findings in larger cohorts will provide meaningful data to guide management of TD when using this new class of agents outside of clinical trials.

Original Research: Metabolic alterations from early life thyroxine replacement therapy in male Ames dwarf mice are transient.

Ames dwarf mice are exceptionally long-lived due to a Prop1 loss of function mutation resulting in deficiency of growth hormone, thyroid-stimulating hormone and prolactin. Deficiency in thyroid-stimulating hormone and growth hormone leads to greatly reduced levels of circulating thyroid hormones and insulin-like growth factor 1, as well as a reduction in insulin secretion. Early life growth hormone replacement therapy in Ames dwarf mice significantly shortens their longevity, while early life thyroxine (T4) replacement therapy does not. Possible mechanisms by which early life growth hormone replacement therapy shortens longevity include deleterious effects on glucose homeostasis and energy metabolism, which are long lasting. A mechanism explaining why early life T4 replacement therapy does not shorten longevity remains elusive. Here, we look for a possible explanation as to why early life T4 replacement therapy does not impact longevity of Ames dwarf mice. We found that early life T4 replacement therapy increased body weight and advanced the age of sexual maturation. We also find that early life T4 replacement therapy does not impact glucose tolerance or insulin sensitivity, and any deleterious effects on oxygen consumption, respiratory quotient and heat production are transient. Lastly, we find that early life T4 replacement therapy has long-lasting effects on bone mineral density and bone mineral content. We suggest that the transient effects on energy metabolism and lack of effects on glucose homeostasis are the reasons why there is no shortening of longevity after early life T4 replacement therapy in Ames dwarf mice.

Subclinical Hypothyroidism Might Increase the Risk of Postoperative Atrial Fibrillation after Aortic Valve Replacement.

Background To evaluate the influence of subclinical hypothyroidism (SCH) on the development of postoperative atrial fibrillation (AF) in patients undergoing aortic valve replacement surgery with extracorporeal circulation. Methods A prospective study in a tertiary hospital between July 2005 and December 2013 in which all patients undergoing aortic valve replacement with no other valve surgery were consecutively included. Patients who were in preoperative sinus rhythm were selected and they underwent thyroxine (T4) and thyroid-stimulating hormone determination in the month before surgery. Postoperative AF was defined as the development of AF during hospital admittance. Descriptive analysis and binary logistic regression were performed for the target variable. Results A total of 467 patients were studied, with 35 cases of SCH. The incidence of postoperative AF was 57% in the group with SCH versus 30.3% (p = 0.001) in the group without hypothyroidism, without significant differences in other postoperative complications. In the logistic regression analysis, the independent predictors of postoperative AF were SCH, age, and aortic clamping time. SCH multiplies the odds ratio of postoperative AF by 3.14 (95% confidence interval: 1.24-7.96). Conclusion SCH behaves like a risk factor for the development of postoperative AF in patients undergoing aortic valve replacement with extracorporeal circulation. Other studies are needed to determine whether preoperative T4 replacement therapy and/or more aggressive AF prophylaxis can prevent this complication in patients undergoing aortic valve replacement.

Laparoscopic Sleeve Gastrectomy Leads to Reduction in Thyroxine Requirement in Morbidly Obese Patients With Hypothyroidism

The impact of laparoscopic sleeve gastrectomy (LSG) on various co-morbidities including type II diabetes mellitus, hypertension, and sleep apnea is well established. However, its effect on hypothyroidism has not been given due attention evidenced by the scant literature on the subject. The purpose of this report is to assess the change in thyroxine (T4) requirement in morbidly obese patients with clinical hypothyroidism after LSG. We conducted a retrospective review of morbidly obese patients on T4 replacement therapy for clinical hypothyroidism who underwent LSG from August 2009 to July 2012 at our institution. Of the 200 patients who underwent LSG during this period, 21 (10.5 %) were on T4 replacement therapy preoperatively for clinical hypothyroidism. Two patients were lost to follow-up. The remaining 19 patients were categorized into two groups. Group 1 comprised 13 patients with decreased T4 requirements after LSG. Group 2 comprised six patients in whom the T4 dose remained unaltered. The mean change in T4 requirement in group 1 was 42.07 % (12-100 %). Group 1 patients had a significantly higher mean preoperative body mass index (48.7 vs. 43.0 kg/m(2); p = 0.03) than the group 2 patients. There was a significant correlation between the percentage excess weight loss and the percentage change in T4 requirement in group 1 (r = 0.607, p = 0.028). Sleeve gastrectomy has a favorable impact on hypothyroid status as seen by a reduction in T4 requirement in the majority of morbidly obese patients with overt hypothyroidism.

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. …

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.

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.

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 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.