Management of Severe Graves' Hyperthyroidism in Pregnancy Following Immune Reconstitution Therapy in Multiple Sclerosis.

CONTEXT: Alemtuzumab (ALZ), a CD52 monoclonal antibody, is highly efficacious in multiple sclerosis; however, side effects are common. Autoimmune thyroid disease (Graves' disease and Hashimoto thyroiditis) is a well-known complication of ALZ. Treatment of ALZ-induced Graves' disease can be challenging, and even more difficult during pregnancy. CASE DESCRIPTION: We present a case of severe ALZ-induced Graves' disease with a rapid increase in thyrotropin receptor antibodies (TRAb 240 IU/L) and thyrotoxicosis in early pregnancy. Treatment with high doses of antithyroid medication was needed. There was high risk of both fetal and neonatal thyrotoxicosis. Serial fetal sonography showed normal development. The newborn baby presented high levels of TRAb (240 IU/L) and developed neonatal thyrotoxicosis on day 8. Adequate monitoring, treatment, and follow-up of the newborn baby ensured normal thyroid function until disappearance of TRAb 6 weeks after birth. CONCLUSION: Multiple sclerosis patients treated with ALZ may develop severe Graves' disease with an increased risk of both fetal and neonatal thyrotoxicosis. Close follow-up with a multidisciplinary approach is needed to ensure a healthy outcome.

Case report: a patient with thyroid storm, refractory cardiogenic shock, and cardiac arrest treated with Lugol's iodine solution and veno-arterial extra corporal membrane oxygenation support.

BACKGROUND: Thyroid storm is a life-threatening condition. Refractory cardiogenic shock and cardiac arrest are rare complications of thyroid storm and the treatment options are limited. CASE SUMMARY: A 35-year- old woman treated for Grave's disease was admitted with thyrotoxicosis complicated by infection and neutropenia caused by thionamide treatment. After treatment including beta-blockers, steroids, and Lugol's iodine solution, she went into cardiac arrest. Echocardiography after resuscitation demonstrated severe biventricular heart failure. The patient was in refractory cardiogenic shock with recurrent cardiac arrest and mechanical circulatory support with a veno-arterial extra corporal membrane oxygenation (V-A ECMO) circuit was established. After 2 days on V-A ECMO and supportive treatment with iodine solution, glucocorticosteroids, and levosimendan, her myocardial function recovered and thyroid hormone levels were normalized. Veno-arterial extra corporal membrane oxygenation was discontinued, and the patient was treated with early total thyroidectomy. The patient made a full recovery with no neurological/cognitive impairment, as assessed after 4 weeks. DISCUSSION: Adverse reactions to standard treatment of hyperthyroidism contributed to this patient's development of thyroid storm and the following refractory cardiogenic shock. When she was critically unstable, levosimendan improved myocardial function while inotropic support with dobutamine was ineffective, likely due to prolonged beta-antagonist administration. Temporary support with V-A ECMO, until effective lowering of thyroid hormone levels and improvement in myocardial function were obtained, was life-saving in this young patient and may be considered in refractory cardiogenic shock caused by thyroid storm.

Thyroid nodules - investigation and follow-up. / Knuter i tyreoidea ­ utredning og oppfølging.

Thyroid nodules are common. As a result of increased use of diagnostic imaging, more nodules are detected as incidental findings. The great majority of them are benign and need no treatment. Systematic ultrasonography performed by a skilled doctor, possibly combined with cytology sampling, will to a large extent determine which nodules require follow-up.

Establishment of a tear protein biomarker panel differentiating between Graves' disease with or without orbitopathy.

BACKGROUND: Graves' orbitopathy (GO) is an autoimmune inflammatory ocular complication and one of the most frequent manifestations of Graves' disease (GD). Clinical judgment of GO is subjective sometimes leading to clinical and therapeutic challenges. Better tools to diagnose this severe complication are warranted. PATIENTS AND METHODS: The aim of the present study was to evaluate tear levels of LYZ, LACRT and AZGP1 in GD patients with or without GO, as possible biomarkers for GO. Tear samples were collected from GD patients with moderate-to-severe GO (n = 21) and no clinical signs of GO (n = 21). Additionally, 18 GD patients with mild GO and 9 patients without GO were included in a further part of the study. RESULTS: Tear levels of LYZ (p < 0.001), LACRT (p = 0.004) and AZGP1 (p = 0.001) were significantly elevated in GD patients with moderate-to-severe GO compared to GD patients without GO. The discriminatory power of the three biomarkers, combined in a panel was confirmed by ROC plot analysis, with an AUC value of 0.93 (sensitivity of 95%; specificity of 80%). Since LYZ showed the best performance in discriminating between GD patients with (moderate-to-severe) and without GO (in combination with limited sample volume available), LYZ levels were also measured in tears from GD patients with mild GO and without GO. Significantly higher levels of LYZ were measured in GD patients with mild GO compared to those without GO (p = 0.003). CONCLUSIONS: We have established a novel three-protein biomarker panel that is able to discriminate between GD patients with and without GO, which might aid in diagnostic evaluation of GO as well as an indicator for disease activity.

Thyroid Function among Breastfed Children with Chronically Excessive Iodine Intakes.

Iodine excess may impair thyroid function and trigger adverse health consequences for children. This study aims to describe iodine status among breastfed infants with high iodine exposure in the Saharawi refugee camps Algeria, and further assess thyroid function and iodine status among the children three years later. In 2010, a cross-sectional study among 111 breastfed children aged 0-6 months was performed (baseline study). In 2013, a second cross-sectional study (follow-up study) was conducted among 289 children; 213 newly selected and 76 children retrieved from baseline. Urinary iodine concentration (UIC) and breast milk iodine concentration (BMIC) were measured at baseline. UIC, thyroid hormones and serum thyroglobulin (Tg) were measured at follow-up. At baseline and follow-up, 88% and 72% had excessive iodine intakes (UIC ≥ 300 µg/L), respectively. At follow-up, 24% had a thyroid hormone disturbance and/or elevated serum Tg, including 9% with subclinical hypothyroidism (SCH), 4% with elevated fT3 and 14% with elevated Tg. Children with SCH had poorer linear growth and were more likely to be underweight than the children without SCH. Excessive iodine intakes and thyroid disturbances were common among children below four years of age in our study. Further, SCH seemed to be associated with poor growth and weight.

Development of thyroid dysfunction among women with excessive iodine intake--A 3-year follow-up.

OBJECTIVES: Thyroid dysfunction can be a result of excessive iodine intake, which may have adverse health consequences, particularly for women in fertile age. In 2010, we conducted a cross-sectional study among lactating women with excessive iodine intake in the Saharawi refugee camps in Algeria and found a high prevalence of thyroid dysfunction. Three years later, we conducted a follow-up study to monitor the iodine situation and explore whether thyroid dysfunction still was highly prevalent when the women no longer were post-partum. None of the women were treated for hyper- or hypothyroidism between baseline and follow-up. METHODS: In 2013, we were able to recapture 78 of the 111 women from the baseline. Thyroid hormones and antibodies were measured in serum and thyroid size was assessed by palpation. Urinary iodine concentration (UIC) and drinking water iodine concentration were measured. RESULTS: The overall prevalence of thyroid dysfunction and/or positive antibodies was 34.3% and was not significantly changed from baseline. Of the non-pregnant women we reexamined, 17 had hypo- or hyperthyroidism in 2010; among these, 12 women still had abnormal thyroid function at follow-up. In addition, we found 9 new cases with marginally abnormal thyroid function. Women with thyroid dysfunction and/or positive antibodies had significantly higher BMI and thyroglobulin than women with normal thyroid function. We also found that women with high breast milk iodine concentration (BMIC) at baseline had more thyroid dysfunction at follow-up than the women with lower BMIC at baseline. CONCLUSIONS: At follow-up, the prevalence of thyroid dysfunction was still high and had not changed during the 3 years between studies and from a postpartum period. The women still had a high iodine intake indicated by high UIC. Breast milk iodine concentration from baseline predicted thyroid dysfunction at follow-up.

Single unit filter-aided method for fast proteomic analysis of tear fluid.

Human tear fluid is a complex mixture containing high concentrations of proteins and is increasingly becoming an important source for studying protein biomarkers of eye-related diseases such as Graves' ophthalmopathy. Today, the Schirmer tear test is the most widely used technique for tear collection. However, sample handling and protein extraction from these strips have been highly challenging. Cutting and removal of the Schirmer strips after extraction, which may lead to sample loss prior to downstream analysis, are some of the challenges to consider. To address some of these limitations, we have developed a single-unit filter-aided method for both sample handling and protein extraction. In addition, we systematically investigated the most suitable conditions for protein extraction from these strips. Among the different extraction conditions applied, extraction with 100 mM ammonium bicarbonate containing 50 mM NaCl resulted in the highest number of identified proteins using one-dimensional liquid chromatography tandem mass spectrometry (LC-MS/MS). Moreover, 1526 proteins were identified when the optimized extraction method was combined with two-dimensional LC-MS/MS analysis, demonstrating the applicability of this novel approach to the study of the tear proteome. This dataset of identified proteins represents a comprehensive catalogue of the tear proteome and may serve as a list for future biomarker research.

Excessive iodine intake and thyroid dysfunction among lactating Saharawi women.

OBJECTIVES: Excessive iodine intake may lead to thyroid dysfunction, which may be particularly harmful during pregnancy and lactation. The main objective was to describe iodine status and the prevalence of thyroid dysfunction among lactating women in areas with high iodine (HI) and very high iodine (VHI) concentrations in drinking water. DESIGN AND METHODS: A cross-sectional survey was performed among 111 lactating women in the Saharawi refugee camps, Algeria. Breast milk iodine concentration (BMIC), urinary iodine concentration (UIC) and the iodine concentration in the most commonly consumed foods/drinks were measured. A 24-h dietary recall was used to estimate iodine intake. Thyroid hormones and antibodies were measured in serum. RESULTS: Median UIC, BMIC and iodine intake across both areas was 350 µg/L, 479 µg/L and 407 µg/day, respectively. In multiple regression analyses, we discovered that being from VHI area was associated with higher UIC and BMIC. BMIC was also positively associated with iodine intake. Thyroid dysfunction and/or positive thyroid antibodies were found in 33.3% of the women, of which 18.9% had hypothyroidism and 8.1% had hyperthyroidism and 6.3% had positive antibodies with normal thyroid function. Elevated thyroid antibodies were in total found in 17.1%. We found no difference in distribution of thyroid dysfunction or positive antibodies between HI and VHI areas. BMI, BMIC and elevated thyroglobulin (Tg) predicted abnormal thyroid function tests. CONCLUSIONS: The high prevalence of thyroid dysfunction may be caused by excessive iodine intake over several years.

Immunological changes and increased expression of myxovirus resistance protein a in thyroid tissue of patients with recent onset and untreated Graves' disease.

BACKGROUND: Few studies have systematically examined the immune cells that infiltrate thyroid tissue at the time of the onset of Graves' disease (GD). The role of viruses in the pathogenesis of autoimmune thyroid diseases is controversial. The present study analyzed inflammatory responses with respect to signs of virus infection. METHODS: Thyroid tissue was obtained from 22 patients with newly diagnosed and untreated GD, 24 patients with chronic GD, and 24 controls. Inflammation was assessed by immunostaining for CD4+ and CD8+ T cells, plasma cells (CD138+), and plasmacytoid dendritic cells (PDCs). The production of interferon-inducible myxovirus resistance protein A (MxA) was analyzed as a sign of virus infection. RESULTS: The degree of thyroid inflammation and fibrosis was significantly higher in both patient groups compared with that in controls. The number of CD4+ T cells and plasma cells (activated B cells) was significantly higher in both patient groups. CD8+ cells were only present in patients with chronic disease. MxA expression and the number of PDCs increased only in patients with newly diagnosed GD. There was a strong positive correlation between the number of PDCs and the number of MxA+ leucocytes. CONCLUSION: The increase in CD8+ T cells during the chronic stage of GD suggests that they may play a role in progression of the autoimmune process from early to chronic thyroiditis. Upregulation of MxA expression during the early stages of the disease, and the positive correlation between the number of PDCs and the number of MxA+ leucocytes, suggests that activated PDCs secrete type I IFNs at the lesion site, possibly in response to viral infection.

Detection of enterovirus in the thyroid tissue of patients with graves' disease.

The etiology and pathogenesis of Graves' disease (GD) are still unknown, although it is thought that both genetic and environmental factors are important. Some indirect evidence implies that a viral infection may be a possible etiologic factor in autoimmunity. The main objective of this study was to examine direct evidence of the presence of enteroviruses (EVs) in the thyroid tissue of patients with GD. Thyroid tissue from 22 patients with newly diagnosed GD was obtained by core needle biopsy, while tissue from 24 patients with chronic GD and 24 control subjects without any autoimmune thyroid diseases was collected during neck surgery. Formalin-fixed, paraffin-embedded thyroid tissue samples were examined for the presence of enterovirus capsid protein using immunohistochemistry and for enterovirus RNA using in situ hybridization. Enterovirus capsid protein was detected in 17 (37%) patients and in 4 (17%) control subjects (P = 0.103). Enterovirus RNA was identified in thyroid tissue from nine (20%) patients, but in none of the control subjects (P = 0.016). Eight (90%) of the nine virus RNA positive patients were also positive for enterovirus protein. This is the first study to analyze thyroid tissue for EVs, including patients with untreated, newly diagnosed GD. The results suggest that EVs are more frequently present in thyroid tissue of patients than controls. Further studies are indicated to explore this association to find out if a low-grade chronic enteroviral infection might be involved in the pathogenesis of GD and if this could offer new therapeutic and preventive opportunities.

Inflammation and increased myxovirus resistance protein A expression in thyroid tissue in the early stages of Hashimoto's thyroiditis.

BACKGROUND: The role of viruses as environmental triggers for Hashimoto's thyroiditis (HT) is controversial. Thyroid epithelial cells express a variety of molecules involved in antiviral responses. This study combined histological, immunological, and virological tests to describe changes in tissue from patients with newly diagnosed and untreated HT. To study the early events, patients with positive thyroid peroxidase antibodies (TPO-Ab) and normal thyroid function were also included. This stage was defined as "prethyroiditis." METHODS: Thyroid tissue was collected from 47 patients with high titers of TPO-Ab and from 24 controls. Seventeen patients had prethyroiditis, 17 had subclinical hypothyroidism, and 13 had overt hypothyroidism. The interferon (IFN)-α/ß-inducible myxovirus resistance protein 1 (myxovirus resistance protein A; MxA) was used as a surrogate marker for type I IFN expression. Inflammation, expression of MxA, and the presence of the enteroviralcapsid protein (VP1) were characterized by immunohistochemistry. The presence of enterovirus (EV) RNA was examined by in situ hybridization. RESULTS: The density of CD4+ T cells was increased in all three patient groups, while CD8+ T cells were increased only in patients with overt hypothyroidism. The density of plasma cells increased as the disease progressed. The density of plasmacytoid dendritic cells and the expression of MxA were significantly increased in all patient groups compared with controls (p<0.01). EV RNA was present in 11% of HT patients, but in none of the control subjects, whereas the enteroviral protein was detected in 19% and 16%, respectively. CONCLUSION: The inflammatory reaction in the thyroid gland is a very early event in the pathogenesis of HT. The increased expression of MxA in the inflamed tissue suggests that type I IFN plays a role in disease development. Whether this is virus-dependent needs to be explored in further studies.

Excessive decrease in serum magnesium after total thyroidectomy for Graves' disease is related to development of permanent hypocalcemia.

BACKGROUND: Transient postoperative hypocalcemia is one of the most common complications after thyroidectomy. Permanent hypocalcemia, however, is rare, but usually requires life-long treatment and follow-up. The risk of permanent hypocalcemia has been shown to be significantly higher in patients with Graves' disease. In the present study we evaluated short-term and long-term changes in serum calcium, phosphate, magnesium, and parathyroid hormone (PTH) levels in order to characterize subjects at risk of postoperative hypoparathyroidism. METHODS: Forty patients who underwent total thyroidectomy for Graves' disease were included in the study. Calcium, phosphate, magnesium, and PTH were measured before surgery and regularly during the year that followed. RESULTS: Postoperative hypocalcemia was seen in 21/40 (53 %) patients. Undetectable PTH (<0.6 pmol/L) was registered in 11/40 (27 %) patients. All patients with measurable PTH 6-48 h after operation regained normal calcium. Of those with undetectable PTH after 6-48 h, four developed permanent hypocalcemia. We found a significantly lower serum calcium level before operation in patients who developed permanent hypocalcemia compared to those who did not (p < 0.001). We also found a significant correlation between the decrease in serum magnesium from time 0 to 48 h after operation and permanent hypocalcemia (p = 0.015). CONCLUSIONS: Serum calcium prior to operation, serum PTH, and degree of decrease in magnesium levels in serum 48 h after operation may predict development of permanent hypocalcemia. Magnesium plays an important role in calcium homeostasis via stimulation of PTH secretion and modulation of PTH receptor sensitivity. Both mechanisms may have played a role for the findings reported in this article.

Pain and small-fiber neuropathy in patients with hypothyroidism.

OBJECTIVE: To investigate large- and small-fiber function in patients with hypothyroidism and pain. METHODS: The authors studied 38 women treated for hypothyroidism and with painful extremities and 38 healthy controls. All subjects underwent neurologic examination of the extremities, neurophysiologic testing of large myelinated nerves, and thresholds for warmth detection (WDT), cold detection (CDT), heat-pain detection (HPDT), and cold-pain detection (CPDT) in one upper and both lower limbs. RESULTS: Eighteen patients had ongoing or intermittent ongoing distal pain in their limbs. Of these, 8 reported evoked and 10 reported paroxysmal pain. Fifteen patients had only diffuse musculoskeletal pain. A total of 16 patients had "hyperphenomena" (brush-evoked allodynia, punctate hyperalgesia, or cold allodynia or a combination of these, in their feet or hands or both). Eight patients were classified as having large fiber neuropathy, whereas 20 had "hypophenomena" (elevated thermal thresholds in their feet or hands or both). Thermal thresholds at the feet (WDT, CDT, and HPDT) were elevated (p = 0.001, p = 0.007, and p = 0.003, respectively) in the whole group of patients compared with the controls as well as WDT (p = 0.001) and CDT (p = 0.001) being elevated at the thenar eminence. All patients with ongoing, evoked, or paroxysmal pain had either hyperphenomena or hypophenomena or a combination of the two. CONCLUSIONS: Some patients treated for hypothyroidism have symptoms and findings compatible with small-fiber neuropathy or "hyperphenomena" indicating central sensitization.

[Hypothyroidism--a manifold clinical view]. / Hypotyreose--mangfoldig klinisk bilde.

Symptoms of hypothyroidism are often unspecific and numerous. As a doctor you will not get the diagnosis if you do not think of the disease and take the tests necessary to verify it. Doctors have been criticised for not being able to make the correct diagnosis and give proper treatment to these patients. As a consequence, too many patients are treated. Here we describe four patients who illustrate how conventional radiotherapy after cancer mammae surgery gave rise to hypothyroidism, how fine needle aspiration biopsy of the thyroid gland can help in the diagnosis of autoimmune thyroiditis, and a patient without hypothyroidism who was treated with thyroxine and triiodothyronine.