Understanding the Pathogenesis of Gestational Hypothyroidism

Pregnancy is a complex state with many endocrinological challenges to a woman’s physiology. Gestational Hypothyroidism (GHT) is an emerging condition where insufficiency of the thyroid gland has developed during pregnancy in a previously euthyroid woman. It is different to overt hypothyroidism, where marked elevation of thyroid-stimulating hormone with corresponding reduction in free thyroxine levels, is well known to cause detrimental effects to both the mother and the baby. During the past couple of decades, it has been shown that GHT is associated with multiple adverse maternal and fetal outcomes such as miscarriage, pre-eclampsia, placental abruption, fetal loss, premature delivery, neurocognitive and neurobehavioral development. However, three randomized controlled trials and a prospective cohort study performed within the last decade, show that there is no neurodevelopmental improvement in the offspring of mothers who received levothyroxine treatment for GHT. Thus, the benefit of initiating treatment for GHT is highly debated within the clinical community as there may also be risks associated with over-treatment. In addition, regulatory mechanisms that could possibly lead to GHT during pregnancy are not well elucidated. This review aims to unravel pregnancy induced physiological challenges that could provide basis for the development of GHT. During pregnancy, there is increased renal clearance of iodine leading to low iodine state. Also, an elevated estrogen level leading to an increase in circulating thyroglobulin level and a decrease in free thyroxine level. Moreover, placenta secretes compounds such as human chorionic gonadotropin (hCG), placental growth factor (PIGF) and soluble FMS-like tyrosine kinase-1 (s-Flt1) that could affect the thyroid function. In turn, the passage of thyroid hormones and iodine to the fetus is highly regulated within the placental barrier. Together, these mechanisms are hypothesized to contribute to the development of intolerance of thyroid function leading to GHT in a vulnerable individual.

THYROTOXIC PERIODIC PARALYSIS IN A COMPETITIVE BODYBUILDER WITH THYROTOXICOSIS FACTITIA

Objective: We report a case of thyrotoxic periodic paralysis (TPP) in a bodybuilder who developed paralysis secondary to thyrotoxicosis factitia after taking a supplement containing thyroid hormone. Interestingly, the patient had no intrinsic thyroid disease. Prompt recognition of thyrotoxicosis is critical to avoid progression of paralysis and subsequent complications. Methods: We discuss a 27-year-old body builder who presented after a 3-day bodybuilding competition with sudden upper and lower extremity paralysis. He admitted to taking anabolic steroids, a supplement containing an unknown amount of thyroid hormone for 2 weeks, and furosemide 40 mg twice daily with near-complete fluid restriction for 3 days. Results: Laboratory results showed a thyroid-stimulating hormone (TSH) level of <0.010 μIU/mL (normal, 0.3 to 5.8 μIU/mL), normal total triiodothyronine level, elevated free thyroxine level of 3.6 ng/dL (normal, 0.8 to 1.9 ng/dL), and potassium level of 1.9 mEq/L (normal, 3.7 to 5.2 mEq/L). Thyroid peroxidase antibody, thyroid-stimulating immunoglobulin, and thyroglobulin antibody levels were normal. Thyroid uptake was 1% (normal, 8 to 25%) after administration of I-123 and thyroglobulin level was 9 ng/mL (normal, 1.4 to 29.2 ng/mL). The patient was treated with normal saline infusion, magnesium supplementation and a total of 230 mEq of potassium within 12 hours of hospitalization. Muscle weakness resolved within this time period and potassium level normalized. By the third day of hospitalization free thyroxine level also normalized and TSH improved to 0.1 mIU/L. Conclusion: TPP is a rare complication of thyrotoxicosis that should be considered in bodybuilders who are presenting with acute muscle weakness.

Permanent Decompensated Congenital Hypothyroidism in Newborns with Whole-Blood Thyroid-Stimulating Hormone Concentrations between 8 and 10 mU/L: The Case for Lowering the Threshold

Background: Congenital hypothyroidism (CHT) has a reported incidence of approximately 1 in 2,000–4,000 births. There is no consensus on the optimal cut-off whole-blood thyroid-stimulating hormone (TSH) concentration that should be used for newborn screening (NBS). The NBS programme in the Republic of Ireland has used a cut-off of 8 mU/L since 1979. The aim of this study was to determine if raising the cut-off to 10 mU/L would have resulted in undetected cases of permanent or decompensated CHT. Methods: All cases of CHT with a screening whole-blood TSH concentration between 8.0 and 9.9 mU/L were identified from the Republic of Ireland’s NBS programme. Baseline demographics and imaging results were recorded. All cases over 3 years of age were evaluated to determine if CHT was permanent or transient. Results: Of 2,361,174 infants screened in the Republic of Ireland between July 1979 and December 2016, a total of 1,063 babies were diagnosed with CHT and treated with levothyroxine. This included 33 (3.5%) infants with a whole-blood TSH concentration between 8 and 9.9 mU/L. Thirteen of these 33 infants had decompensated hypothyroidism with low plasma free thyroxine level at diagnosis and 9 (41%) of the 21 evaluable cases have confirmed permanent CHT. Conclusion: Although lowering screening TSH cut-offs can increase the cost of NBS, as well as anxiety for families, many infants with borderline increases in whole-blood TSH concentrations on NBS have persistent CHT and low thyroxine concentrations in infancy. We recommend that this is considered when developing and reviewing NBS protocols for identifying infants with CHT.

Alteration in Lipid Profile Levels in Women with Subclinical Hypothyroidism

Thyroid hormones play an important role in regulating energy balance and metabolism of glucose and lipids. A relationship between dyslipidemia and atherosclerosis is well established in clinical hypothyroidism. Whether subclinical hypothyroidism (SCH) is associated with lipid profile alteration, is the main concept behind the study. SCH is defined as an elevated thyroid stimulating hormone (TSH>5mIU/l) and normal free thyroxine level (FT4 9.5- 25.0 pmol/l). It is highly prevalent in elderly subjects, especially in women but it is frequently overlooked. We examined 40 women with SCH and 50 healthy controls (TSH 0.5-5.0 mIU/l and FT4 9.5- 25.0 pmol/l). None of the patients had been previously treated with thyroxine. In all participants we measured blood pressure, BMI, TSH, FT4 and fasting serum lipid profile. We conclude that SCH in middle aged women is associated with hypertension and significant increase of TC (p<0.001), LDL-C (p<0.001), TG (p<0.001) and decreased level of HDLC p<0.001) in comparison to euthyroid Controls. SCH patients showed significant positive correlation between TSH and total cholesterol (r=.492, p<0.01), LDL-C (r=.355, p<0.05) and TG (r=.274, p<0.05) and negative but nonsignificant corelationship with HDL-C (r = - .058,p=0.361). Dyslipidemia is one of the established risk factors of cardiovascular diseases. Therefore, this study indicates that monitoring of lipid level in SCH patients would be helpful in preventing cardiovascular diseases.Bangladesh J Med Biochem 2015; 8(1): 10-15

Euthyroid athyroxinemia – a novel endocrine syndrome

Summary A 55-year-old female was referred with abnormal thyroid function tests (TFTs); the free thyroxine level (FT4) was undetectable <3.3 pmol/L (normal: 7.9–14.4), while her FT3, TSH and urinary iodine levels were normal. She was clinically euthyroid with a large soft lobulated goitre that had been present for more than thirty years. She received an injection of recombinant human TSH (rhTSH) following which there was a progressive rise of the FT3 and TSH levels to 23 pmol/L and >100 mIU/L respectively at 24 h, The FT4 however remained undetectable throughout. Being on thyroxine 100 µg/day for one month, her FT4 level increased to 15 pmol/L and TSH fell to 0.08 mIU/L. Four years earlier at another hospital, her FT4 level had been low (6.8 pmol/L) with a normal TSH and a raised Tc-99 uptake of 20% (normal<4%). We checked the TFTs and Tc-99 scans in 3 of her children; one was completely normal and 2 had euthyroid with soft lobulated goitres. Their Tc-99 scan uptakes were raised at 17% and 15%, with normal TFTs apart from a low FT4 7.2 pmol/L in the son with the largest thyroid nodule. This is a previously unreported form of dyshormonogenesis in which, with time, patients gradually lose their ability to synthesize thyroxine (T4) but not triiodothyroxine (T3). Learning points: This is a previously unreported form of dyshormonogenetic goitre. This goitre progressively loses its ability to synthesize T4 but not T3. The inability to synthesize T4 was demonstrated by giving rhTSH.

Thyrotoxic Atrial Fibrillation: Factors Associated with Persistence and Risk of Ischemic Stroke

Background. Atrial fibrillation (AF) is one of the commonest cardiovascular manifestations of thyrotoxicosis. A significant proportion of patients have persistent AF which may have long term consequences, for example, ischemic stroke. Methods. We performed a retrospective cohort study in a regional hospital from January 2004 to June 2016 to examine the clinical characteristics and outcomes of thyrotoxic patients who presented with atrial fibrillation and to investigate possible factors associated with persistent atrial fibrillation and ischemic stoke. Results. Among 1918 patients who had a diagnosis of thyrotoxicosis, 133 (6.9%) patients presented with AF. Spontaneous sinus conversion occurred in 89 (66.9%) patients in which 85 (94%) patients developed sinus conversion before or within 6 months after having achieved euthyroidism. The remaining 44 (33.1%) had persistent AF. The rate of ischemic stroke was numerically higher among patients who had persistent AF than those with spontaneous sinus conversion (15.9% versus 10.1%; log-rank 0.442, p=0.506). Patients who sustained an ischemic stroke were older (71 ± 11 years versus 62 ± 16 years, p=0.023) and had a trend towards higher CHA2DS2-VASc score (2.9 ± 1.7 versus 2.3 ± 1.7, p=0.153). History of smoking (adjusted odds ratio 4.9, 95% CI [1.8,14.0], p=0.002), a larger left atrial diameter (adjusted odd ratio 2.6, 95% CI [1.2,5.5], p=0.014), and a relatively lower free thyroxine level at diagnosis (adjusted odd ratio 2.1, 95% CI [1.2,3.5], p=0.008) were associated with persistence of AF on multivariate analysis. Conclusion. Persistence of thyrotoxic AF occurred in one-third of patients and spontaneous sinus conversion was unlikely after six months of euthyroidism. High rate of ischemic stroke was observed among patients with persistent thyrotoxic AF and older age. Patients with factors associated with persistent AF, especially older people, should be closely monitored beyond 6 months so that anticoagulation can be initiated in a timely manner to reduce risk of ischemic stroke.

Lateralized exanthem mimicking figurate inflammatory dermatosis of infancy after methimazole therapy

We reported a case of an 11-year-old girl admitted to our hospital for goiter, tachycardia, sweating, and visible and palpable thyroid. Thyroid function tests revealed a low thyrotropin level (<0.004 mIU/L) and elevated free thyroxine level (3.4 ng/ dL) diagnosed with Graves’ disease and treated with methimazole. This anti-thyroid drug is recommended as first-line treatment in children with Graves’ disease because it produces minor adverse effects with respect to propylthiouracil. She developed a lateralized exanthem mimicking figurate inflammatory dermatosis of infancy after methimazole therapy. The symptoms resolved after discontinuation of methimazole and treatment with an antihistamine and a corticosteroid. Furthermore, the treatment was changed to propylthiouracil without any adverse effects. According to current literature this is the first case of cutaneous figurate erythema related to methimazole, different from other well-known reactions such as skin eruption or urticaria.

Diplopia, Convergent Strabismus, and Eye Abduction Palsy in a 12-Year-Old Boy with Autoimmune Thyroiditis

Pseudotumor cerebri (PTC) is defined by clinical criteria of increased intracranial pressure, elevated intracranial pressure with normal cerebrospinal fluid (CSF) composition, and exclusion of other causes such tumors, vascular abnormalities, or infections. The association of PTC with levothyroxine (LT4) has been reported. A 12-year-old boy has been followed up for autoimmune thyroiditis under LT4. Family history was irrelevant for endocrine or autoimmune diseases. A TSH level of 4.43 μUI/mL (0.39–3.10) motivated a LT4 adjustment from 75 to 88 μg/day. Five weeks later, he developed horizontal diplopia, convergent strabismus with left eye abduction palsy, and papilledema. Laboratorial evaluation revealed elevated free thyroxine level (1.05 ng/dL [0.65–1.01]) and low TSH, without other alterations. Lumbar puncture was performed and CSF opening pressure was 24 cm H2O with normal composition. Blood and CSF cultures were sterile. Brain MRI was normal. LT4 was temporarily discontinued and progressive improvement was observed, with a normal fundoscopy at day 10 and reversion of diplopia one month later. LT4 was restarted at lower dose and gradually titrated. The boy is currently asymptomatic. This case discloses the potential role of LT4 in inducing PTC. Despite its rarity and unclear association, PTC must be seen as a potential complication of LT4, after excluding all other intracranial hypertension causes.

Case report: clues to the diagnosis of an unsuspected massive levothyroxine overdose

There is currently little literature pertaining to levothyroxine overdose apart from minor or accidental overdoses in the pediatric population. In particular, there is little information available on how to confidently differentiate levothyroxine overdose from endogenous causes of thyrotoxicosis when there is no history available at the time of assessment.We report a levothyroxine (15,800 mcg) and citalopram (2,460 mg) overdose in a 55-year-old woman presenting with seizure and tachycardia in which the diagnosis was not initially suspected. Clinical data, including a long history of treated hypothyroidism and lack of a goiter; and biochemical findings, such as an incompletely suppressed thyroid-stimulating hormone (TSH) level, despite a markedly elevated free thyroxine level (FT4), a normal sex hormone-binding globulin level at baseline, and an undetectable thyroglobulin, supported the diagnosis of thyrotoxicosis due to a massive exogenous thyroid hormone overdose. Treatment was given to decrease free triiodothyronine (FT3) conversion and increase thyroid hormone clearance with dexamethasone and cholestyramine. The patient made a full recovery.Levothyroxine overdose can result in subtle symptoms and signs clinically, even when in massive quantities. This can make diagnosis challenging. Biochemical features, such as the pattern of thyroid hormone elevation and thyroglobulin levels, help differentiate exogenous thyroid hormone overdose from endogenous causes of thyrotoxicosis.