Irene Campi
@auxologico.it
Department of Endocrinology and Metabolic Diseases
IRCCS Istituto Auxologico Italiano
RESEARCH, TEACHING, or OTHER INTERESTS
Medicine, Endocrinology, Diabetes and Metabolism
Scopus Publications
Scopus Publications
Irene Campi, Marco Dell’Acqua, Elisa Stellaria Grassi, Maria Cristina Vigone, and Luca Persani
Bioscientifica
The clinical consequences of primary hypothyroidism include cardiovascular morbidity, increased mortality, and poor quality of life; therefore guidelines endorsed by several Scientific Societies recommend measuring circulating thyroid-stimulating hormone (TSH) in patients at risk. The assessment of serum TSH levels is also deemed to be the most robust and accurate biomarker during the management of replacement therapy in patients with a previous diagnosis of primary hypothyroidism. In line with a reflex TSH laboratory strategy, free thyroxine is measured only if the TSH falls outside specific cutoffs, in order to streamline investigations and save unjustified costs. This serum TSH-based approach to both diagnosis and monitoring has been widely accepted by several national and local health services; nevertheless, false-negative or -positive testing may occur, leading to inappropriate management or treatment. This review aims to describe several infrequent causes of increased circulating TSH, including analytical interferences, resistance to TSH, consumptive hypothyroidism, and refractoriness to levothyroxine replacement treatment. We propose a clinical flowchart to aid correct recognition of these various conditions, which represent important potential pitfalls in the diagnosis and treatment of primary hypothyroidism.
Valentina Cirello, Marina Lugaresi, Alessandro Manzo, Eva Balla, Gerardina Fratianni, Francesca Solari, Luca Persani, Laura Fugazzola, and Irene Campi
Springer Science and Business Media LLC
Valentina Cirello, Marina Lugaresi, Alessandro Manzo, Eva Balla, Gerardina Fratianni, Francesca Solari, Luca Persani, Laura Fugazzola, and Irene Campi
Springer Science and Business Media LLC
Abstract Purpose The clinical outcome of COVID-19 disease is worse in males, and the reasons of this gender disparity are currently unclear, though evidences point to a combination of biological and gender-specific factors. A phenomenon unique to the female gender is the fetal cell microchimerism (FCM), defined as the presence of fetal microchimeric cells in maternal organs and in the circulation for years after delivery and usually evaluated by assessing the presence of male cells or DNA in a woman. In the present case–control study, we aimed to evaluate the possible effect of pregnancy and related FCM on the susceptibility to SARS-CoV-2 infection and on the clinical course and outcome of COVID-19. Methods One hundred twenty-three women with a previous male pregnancy, comprising 63 COVID-19 cases and 60 healthy controls were enrolled. The presence of blood male DNA was assessed by the amplification of the Y-chromosome specific gene SRY. Results The prevalence of male DNA of presumed fetal origin was significantly higher in healthy controls than in COVID-19 cases (70 vs 44.4%, P = 0.0044; OR 0.3429, 95% CI 0.1631–0.7207, P = 0.0047). Among women affected with COVID-19, the presence of male FCM did not significantly influence the severity of the disease, though the 8 deceased women studied were all FCM negative. Conclusion This is the first case–control study reporting the prevalence of FCM in COVID-19 and healthy women. Overall, our data seem to suggest a role for FCM in the protection towards the SARS-CoV-2 infection with a possible positive impact on clinical outcome.
Luca Persani, Marco dell’Acqua, Stamatina Ioakim, and Irene Campi
Elsevier BV
Kamil Demircan, Thilo Samson Chillon, Tommy Bracken, Ilaria Bulgarelli, Irene Campi, Gijs Du Laing, Samira Fafi-Kremer, Laura Fugazzola, Alejandro Abner Garcia, Raban Heller,et al.
Frontiers Media SA
IntroductionCertain trace elements are essential for life and affect immune system function, and their intake varies by region and population. Alterations in serum Se, Zn and Cu have been associated with COVID-19 mortality risk. We tested the hypothesis that a disease-specific decline occurs and correlates with mortality risk in different countries in Europe.MethodsSerum samples from 551 COVID-19 patients (including 87 non-survivors) who had participated in observational studies in Europe (Belgium, France, Germany, Ireland, Italy, and Poland) were analyzed for trace elements by total reflection X-ray fluorescence. A subset (n=2069) of the European EPIC study served as reference. Analyses were performed blinded to clinical data in one analytical laboratory.ResultsMedian levels of Se and Zn were lower than in EPIC, except for Zn in Italy. Non-survivors consistently had lower Se and Zn concentrations than survivors and displayed an elevated Cu/Zn ratio. Restricted cubic spline regression models revealed an inverse nonlinear association between Se or Zn and death, and a positive association between Cu/Zn ratio and death. With respect to patient age and sex, Se showed the highest predictive value for death (AUC=0.816), compared with Zn (0.782) or Cu (0.769).DiscussionThe data support the potential relevance of a decrease in serum Se and Zn for survival in COVID-19 across Europe. The observational study design cannot account for residual confounding and reverse causation, but supports the need for intervention trials in COVID-19 patients with severe Se and Zn deficiency to test the potential benefit of correcting their deficits for survival and convalescence.
Irene Campi, Giovanni Battista Perego, Antonella Ravogli, Francesca Santafede, Federica Sileo, Antonella Dubini, Gianfranco Parati, Luca Persani, and Laura Fugazzola
Springer Science and Business Media LLC
Luca Persani and Irene Campi
The Endocrine Society
1Department of Medical Biotechnology and Experimental Medicine, University of Milan, 20100 Milan, Italy and 2Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, 20149 Milan, Italy Correspondence: Luca Persani, MD, PhD, Department of Endocrine and Metabolic Diseases, San Luca Hospital, Istituto Auxologico Italiano IRCCS, Piazzale Brescia 20, 20149 Milan, Italy. Email: Luca.persani@unimi.it.
Sathyadeepak Ramesh
Springer International Publishing
Sathyadeepak Ramesh
Springer International Publishing
Irene Campi, Guia Vannucchi, Ilaria Muller, Elisa Lazzaroni, Nicola Currò, Martina Dainese, Benedetta Montacchini, Danila Covelli, Claudio Guastella, Lorenzo Pignataro,et al.
Frontiers Media SA
BackgroundImmunosuppressive therapy of Graves’ orbitopathy (GO) is indicated during the active phase of disease. Intravenous steroids (IVGC) are effective in about 70% of patients, although unresponsiveness or relapse are observed. In previous studies, rituximab (RTX) has been shown to be effective in inactivating moderate-to-severe GO when used early in the disease, but its optimal dosage has never been studied in randomized clinical trials. Aim of this study was to compare the efficacy and safety of different doses of RTX, based on a post-hoc analysis of two open label studies and one prospective trial randomized to IVGC.Methodsof 40 patients (35 women, 5 men), with active moderate-to-severe GO treated with RTX, 14 received a single dose of 100 mg (Group 1), 15 a single dose of 500 mg (Group 2) and 11 two 1000 mg doses, administered one week apart (Group 3). Thyroid function, TSH-receptor antibodies (TRAb) and peripheral CD19+ cells were measured. Primary endpoint was disease inactivation, measured as a decrease of the Clinical Activity Score (CAS) of at least two points. Secondary endpoints were improvement of proptosis, diplopia, quality of life and safety.ResultsBaseline CAS decreased significantly in all groups (P<0.0001), independently of GO duration or whether patients had newly occurring or relapsing GO after IVGC. Proptosis did not significantly change. There was an inverse correlation between the Gorman score for diplopia and RTX dose (P<0.01). The appearance score of the GO-QoL improved in Group 1 (P=0.015), and the visual function score, in Group 2 (P=0.04). A reduction of serum TRAb was observed in Group 1 (P=0.002) and Group 2 (P<0.0002), but not in Group 3. CD19+ cell decreased in all groups (P<0.01), independently of the dose.ConclusionsWe studied the optimal dosage of RTX in the treatment of active moderate-to-severe GO. In this analysis, we considered the efficacy of RTX in inactivating GO, in changing its natural course, its effect on disease severity and on the patients’ quality of life. Based on our clinical findings, and balancing the cost of therapy, a single 500 mg dose regimen is suggested in the majority of patients.
Irene Campi and Laura Fugazzola
Informa UK Limited
GO is an inflammatory process associated with autoimmune thyroid diseases and characterized by increased adipogenesis and enlargement of the extraocular muscles resulting in the expansion of the retro-orbital content. The optimal management of GO relies on the assessment of disease activity and severity, as anti-inflammatory/immunosuppressive treatments are effective on active GO, whereas long-term consequences of inactive GO require rehabilitative surgery, including orbital decompression, squint, and lid surgery [1,2]. GO activity is assessed with the Clinical Activity Score (CAS) (Table 1a) [3], whereas severity is graded, based on the EUGOGO score, as mild, moderate-to-severe, and sightthreatening [4]. This classification mirrors the treatment needs (Table 1b), as milder cases are managed conservatively while moderate-to-severe GO requires immunosuppressive treatments, aimed at inactivating GO, in an attempt to avoid rehabilitative surgery. In Europe, intra-venous methylprednisolone (ivMP) ± sodium mycophenolate for three months, in weekly infusions is the recommended first-line treatment for active GO [5]. To maximize benefits and minimize adverse effects, the ivMP route is modulated based on GO severity: the highest doses (7.5 g) are prescribed to patients with severe forms [5] while intermediate doses (4.5 g) to the milder cases. Sight-threatening GO requires medical decompression, followed by urgent bony orbital decompression, if unresponsive in a few weeks. Medical decompression consists of three ivMP pulses (500–1000 g) given on consecutive or alternate days [6], repeated after one week and followed by weekly infusions not exceeding 8 g. Over the last two decades, the therapeutic toolkit for active GO has been enriched with new biological disease-modifying drugs including rituximab, tocilizumab, and teprotumumab. Currently, these molecules are recommended as second-line treatments alternatively to orbital radiotherapy (OR) or to a second course of ivMP. Nonetheless, randomized controlled trials (RCT), meta-analysis, reviews, and statistical analyses on pooled data suggest that these drugs are effective and will probably enter into clinical practice more and more frequently in the near future. Indeed, in the US, following FDA approval, teprotumumab is now used by several physicians as first-line treatment for GO. Nevertheless, the proportion of relapses after teprotumumab is similar to that reported after ivMP (15–30%) and some safety concerns have been raised following the observation of increased risk of hearing loss with teprotumumab [7–10]. Response to treatment can be objectively measured by scores such as the composite index, which assess changes of lid retraction, inflammatory signs, exophthalmos, and eye muscle ductions (Table 1c) [11]. Unfortunately, available therapies are still inadequate since a successful treatment measured as the change of biological parameters, does not imply per se an improvement of patients’ quality of life (Qol). Indeed, GO patients exhibit long-term visual, appearance, and psychosocial disability and suffer from emotional stress and occupational impairment even many years after being treated with immunosuppressants and surgery [12,13].
Giorgio Radetti, Franco Rigon, Alessandro Salvatoni, Irene Campi, Tiziana De Filippis, Valentina Cirello, Silvia Longhi, Fabiana Guizzardi, Marco Bonomi, and Luca Persani
Bioscientifica
Introduction Patients with congenital hypothyroidism (CH) may transiently show a certain degree of pituitary resistance to levothyroxine (LT4) which, however, normalizes subsequently. However, in some individuals, thyroid-stimulating hormone (TSH) fails to normalize despite adequate LT4 treatment. Methods Nine patients with CH followed in three Academic Centre who developed over time resistance to thyroid hormones underwent extensive biochemical and genetic analyses. These latter were performed by Sanger sequence or targeted next-generation sequencing technique including a panel of candidate genes involved in thyroid hormone actions and congenital hypothyroidism (CH): THRA, THRB, DIO1, DIO2, SLC16A2, SECISBP2, DUOX2, DUOXA2, FOXE1, GLIS3, IYD, JAG1, NKX2-1, NKX2- 5, PAX8, SLC26A4, SLC5A5, TG, TPO, TSHR. Results All patients displayed a normal sensitivity to thyroid hormone (TH) in the first years of life but developed variable degrees of resistance to LT4 treatment at later stages. In all cases, TSH normalized only in the presence of high free thyroxine levels. Tri-iodothyronine suppression test followed by thyrotrophin-releasing hormone stimulation was performed in two cases and was compatible with central resistance to THs. This biochemical feature was present independently on the cause of CH, being observed either in patients with an ectopic (n = 2) or eutopic gland (n = 3) or in case of athyreosis (n = 1). None of the patients had genetic variants in genes involved in the regulation of TH actions, while in two cases, we found two double heterozygous missense variants in TSHR and GLIS3 or in DUOX2 and SLC26A4 genes, respectively. Conclusions We report CH patients who showed an acquired and unexplainable pituitary refractoriness to TH action.
Irene Campi, Luigi Gennari, Daniela Merlotti, Christian Mingiano, Alessandro Frosali, Luca Giovanelli, Camilla Torlasco, Martino F. Pengo, Francesca Heilbron, Davide Soranna,et al.
Springer Science and Business Media LLC
AbstractBackgroundVitamin D deficiency has been suggested to favor a poorer outcome of Coronavirus disease-19 (COVID-19). We aimed to assess if 25-hydroxyvitamin-D (25OHD) levels are associated with interleukin 6 (IL-6) levels and with disease severity and mortality in COVID-19.MethodsWe prospectively studied 103 in-patients admitted to a Northern-Italian hospital (age 66.1 ± 14.1 years, 70 males) for severely-symptomatic COVID-19. Fifty-two subjects with SARS-CoV-2 infection but mild COVID-19 symptoms (mildly-symptomatic COVID-19 patients) and 206 subjects without SARS-CoV-2 infection were controls. We measured 25OHD and IL-6 levels at admission and focused on respiratory outcome during hospitalization.ResultsSeverely-symptomatic COVID-19 patients had lower 25OHD levels (18.2 ± 11.4 ng/mL) than mildly-symptomatic COVID-19 patients and non-SARS-CoV-2-infected controls (30.3 ± 8.5 ng/mL and 25.4 ± 9.4 ng/mL, respectively,p < 0.0001 for both comparisons). 25OHD and IL-6 levels were respectively lower and higher in severely-symptomatic COVID-19 patients admitted to intensive care Unit [(ICU), 14.4 ± 8.6 ng/mL and 43.0 (19.0–56.0) pg/mL, respectively], than in those not requiring ICU admission [22.4 ± 1.4 ng/mL,p = 0.0001 and 16.0 (8.0–32.0) pg/mL,p = 0.0002, respectively]. Similar differences were found when comparing COVID-19 patients who died in hospital [13.2 ± 6.4 ng/mL and 45.0 (28.0–99.0) pg/mL] with survivors [19.3 ± 12.0 ng/mL,p = 0.035 and 21.0 (10.5–45.9) pg/mL,p = 0.018, respectively). 25OHD levels inversely correlated with: i) IL-6 levels (ρ − 0.284,p = 0.004); ii) the subsequent need of the ICU admission [relative risk, RR 0.99, 95% confidence interval (95%CI) 0.98–1.00,p = 0.011] regardless of age, gender, presence of at least 1 comorbidity among obesity, diabetes, arterial hypertension, creatinine, IL-6 and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count; iii) mortality (RR 0.97, 95%CI, 0.95–0.99, p = 0.011) regardless of age, gender, presence of diabetes, IL-6 and C-reactive protein and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count.ConclusionIn our COVID-19 patients, low 25OHD levels were inversely correlated with high IL-6 levels and were independent predictors of COVID-19 severity and mortality.
Irene Campi, Maura Agostini, Federica Marelli, Tiziana de Filippis, Beatriz Romartinez-Alonso, Odelia Rajanayagam, Giuditta Rurale, Ilaria Gentile, Federica Spagnolo, Massimiliano Andreasi,et al.
Bioscientifica
<b><i>Introduction:</i></b> Resistance to thyroid hormone β (RTHβ) is an inherited syndrome caused by dominant negative variants in the <i>THRB</i> gene (NM_000461.5). The clinical picture of RTHβ is variable, and patients harboring the same variant may display different degrees of disease severity. <b><i>Case Presentation:</i></b> A 30-year-old man presented with thyrotoxicosis and central hyperthyroidism and was found to have a novel variant in the exon 10 of <i>THRB</i> gene (c.C1282G, p.L428V), located within the third hot spot region of the C-terminal of the receptor. Surprisingly, the same variant was found in two other relatives with an apparent normal thyroid function at initial screening. After exclusion of a TSH-secreting adenoma and serum interference in the proband, and the finding that exogenous levothyroxine failed to suppress the TSH in the brother affected by nodular goiter, relatives’ thyroid function tests (TFTs) were reassessed with additional analytical method revealing biochemical features consistent with RTHβ in all carriers of the p.L428V variant. Functional studies showed a slightly impaired in vitro transcriptional activity of p.L428V. Interestingly‚ the expression of the human p.L428V thyroid hormone receptor beta in the zebrafish embryo background generated a phenotype consistent with RTHβ. <b><i>Conclusion:</i></b> Variable results of TFTs on some immunoassays can be a cause of RTHβ diagnostic delay, but the genotype-phenotype correlation in this family and functional studies support p.L428V as a novel <i>THRB</i> variant expanding the spectrum of gene variants causing RTHβ. In vivo, rather than in vitro, functional assays may be required to demonstrate the dominant negative action of <i>THRB</i> variants.
Guia Vannucchi, Irene Campi, Danila Covelli, Nicola Currò, Elisa Lazzaroni, Andrea Palomba, Davide Soranna, Antonella Zambon, Laura Fugazzola, Ilaria Muller,et al.
Mary Ann Liebert Inc
BACKGROUND
Rituximab (RTX), a chimeric human-murine anti-CD20 monoclonal antibody, has been used for treatment of active moderate-severe Graves' orbitopathy (GO) since 2004 as second line therapy in patients unresponsive to intravenous steroids. We conducted an open label, prospective study (EUDRACT 2012-001980-53) in which patients were treated with a single infusion of only 100 mg RTX to analyze the efficacy and safety of this low dose.
METHODS
Seventeen patients, of whom nine had disease that was unresponsive to intravenous methylprednisolone, and eight with newly diagnosed GO were enrolled. Disease activity was assessed with the clinical activity score (CAS) and severity with a composite ophthalmic score. Long term surgical treatment and quality of life were also assessed, as well as treatment-related adverse events.
RESULTS
Mean baseline CAS was 4.56±0.96 and decreased to 1.25±1.14 at 24 weeks (P=0.001). Disease inactivation occurred within 24 weeks in >90% of patients and was unrelated to disease duration. Severity improved in about 60% of patients, with no relapses. All patients showed peripheral depletion of CD20+ and CD19+ cells at the end of the RTX infusion (60 minutes). Two patients required surgical orbital decompression because of optic neuropathy (ON). Among adverse events observed, there was one patient who developed a cytokine release syndrome.
CONCLUSIONS
A dose of 100 mg RTX is effective in patients with active moderate-severe GO. Low doses are better tolerated, expose patients to immune suppression for a shorter period of time and are extremely cost effective, compared to higher doses. This dose, consistently with all other immunosuppressants, does not prevent the progression of GO to dysthyroid optic neuropathy.
Irene Campi, Ilaria Bulgarelli, Antonella Dubini, Giovanni Battista Perego, Elena Tortorici, Camilla Torlasco, Erminio Torresani, Lorenzo Rocco, Luca Persani, and Laura Fugazzola
Oxford University Press (OUP)
Objective Alterations in thyroid function tests (TFTs) have been recorded during SARS-CoV-2 infection as associated to either a destructive thyroiditis or a non-thyroidal illness. Methods We studied 144 consecutive COVID-19 patients admitted to a single center in intensive or subintensive care units. Those with previous thyroid dysfunctions or taking interfering drugs were excluded. Differently from previous reports, TSH, FT3, FT4, thyroglobulin (Tg), anti-Tg autoantibodies (TgAb) were measured at baseline and every 3–7 days. C-reacting protein (CRP), cortisol and IL-6 were also assayed. Results The majority of patients had a normal TSH at admission, usually with normal FT4 and FT3. Low TSH levels were found either at admission or during hospitalization in 39% of patients, associated with low FT3 in half of the cases. FT4 and Tg levels were normal, and TgAb-negative. TSH and FT3 were invariably restored at the time of discharge in survivors, whereas were permanently low in most deceased cases, but only FT3 levels were predictors of mortality. Cortisol, CRP and IL-6 levels were higher in patients with low TSH and FT3 levels. Conclusions Almost half of our COVID-19 patients without interfering drugs had normal TFTs both at admission and during follow-up. In this series, the transient finding of low TSH with normal FT4 and low FT3 levels, inversely correlated with CRP, cortisol and IL-6 and associated with normal Tg levels, is likely due to the cytokine storm induced by SARS-Cov-2 with a direct or mediated impact on TSH secretion and deiodinase activity, and likely not to a destructive thyroiditis.
Roberta D'Ambrosio, Irene Campi, Marco Maggioni, Riccardo Perbellini, Enza Giammona, Roberta Stucchi, Marta Borghi, Elisabetta Degasperi, Annalisa De Silvestri, Luca Persani,et al.
Public Library of Science (PLoS)
Background Data on the role of hypothyroidism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis are conflicting, although selective Thyroid Hormone Receptor (THR)-β agonists have been identified as potential therapy in patients with non-alcoholic steatohepatitis (NASH). Therefore, we investigated the association between hypothyroidism and NAFLD histological features potentially associated with progressive liver disease. Methods Between 2014 and 2016, consecutive patients with histologically proven NAFLD and frozen serum available for thyroid function tests assessment were included. NAFLD was staged according to the NAFLD Activity Score (NAS), and fibrosis according to Kleiner. NASH was defined as NAS ≥4, significant fibrosis as F2-F4 and significant steatosis as S2-S3. Thyroid function tests (TFT; TSH, FT3, FT4, rT3), TPO-Ab and Tg-Ab were also assessed. Results Fifty-two patients were analyzed: median age 54 years, 58% females, LSM 7.8 kPa, 27% diabetics, 14% hypothyroid. At histology, NASH was present in 21 (40%), F2-F4 in 28 (54%) and S2-S3 in 30 (58%) patients. Rates of hypothyroidism were similar independently of the presence of NASH (p = 0.11), significant fibrosis (p = 0.21) or steatosis (p = 0.75). However, hypothyroid patients displayed a higher NAS (p = 0.02) and NASH (p = 0.06) prevalence. At multivariate analysis, TFT were not independently associated with histology. Conclusion Hypothyroidism was highly prevalent in NAFLD patients, and was associated with increased NAFLD activity, but not with fibrosis and steatosis severity. Thus, thyroid dysfunction might play a direct and/or indirect in the pathogenesis of NAFLD and NASH.
Luca Persani and Irene Campi
Springer International Publishing
Irene Campi, Nicola Currò, Guia Vannucchi, Danila Covelli, Simona Simonetta, Laura Fugazzola, Davide Dazzi, Lorenzo Pignataro, Claudio Guastella, Elisa Lazzaroni,et al.
Mary Ann Liebert Inc
BACKGROUND
The overall changes of ocular motility in Graves' Orbitopathy (GO), are not easily quantifiable with the methods currently available, especially in clinical studies. The aim of the present study was to calculate parameters that quantify the changes of ocular motility in GO, in relation to the Gorman score for diplopia.
METHODS
We studied 100 GO patients (Group 1) and 100 controls (Group 2). We also included 30 patients treated with intravenous methylprednisolone (iv-MP) and assessed at baseline, after 12 and 24 weeks (Group 3) and 66 patients submitted to squint surgery, assessed at baseline and after 12 weeks (Group 4). Ocular ductions were measured in four gaze directions by a perimeter arc and were used to calculate a Total Motility Score (TMS), as the sum of ductions in each direction; a bi-ocular TMS (b-TMS) as the sum of the TMS of two eyes and an Asymmetry Ratio (AR) as the sum of the differences of the corresponding ductions between the two fellow eyes divided by the mean difference found in controls. Quality of life was accessed by a specific questionnaire (GO-Qol).
RESULTS
TMS and b-TMS were lower, while AR was higher in Group 1 compared to controls (P<0.001). In Group 1, TMS and b-TMS were inversely correlated with the Gorman score (P<0.001) and AR was higher in patients with constant diplopia compared to the others (P<0.001). In Group 3, TMS and b-TMS increased after treatment in responders to iv-MP (P<0.001). In Group 4, TMS and b-TMS improved in all patients after surgery (P<0.01), while AR and GO-Qol improved only in those without residual constant diplopia (P<0.001).
CONCLUSION
We describe a quantitative method to assess the eye motility dysfunction in any stage of GO to be used as an outcome measure in clinical studies.
Michela Del Prete, Fabrizio Muratori, Irene Campi, Gianleone Di Sacco, Federico Vignati, Domenico Pellegrino, and Luca Persani
Bioscientifica
Summary Resistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter. Learning points Resistance to thyroid hormone (RTH) is a rare autosomal dominant hereditary syndrome with impaired tissue responsiveness to thyroid hormones (TH). Diagnosis of RTH is usually based on the clinical finding of discrepant thyroid function tests and confirmed by a genetic test. RTH is a rare condition that must be considered for the management of patients with goiter, elevation of TH and non-suppressed serum TSH levels in order to avoid unnecessary treatments.
Irene Campi, Danila Covelli, Carla Moran, Laura Fugazzola, Chiara Cacciatore, Fabio Orlandi, Gabriella Gallone, Krishna Chatterjee, Paolo Beck-Peccoz, and Luca Persani
Frontiers Media SA
Background: Discrepant thyroid function tests (TFTs) are typical of inappropriate secretion of TSH (IST), a rare entity encompassing TSH-secreting adenomas (TSHoma) and Resistance to Thyroid Hormone (RTHβ) due to THRB mutations. The differential diagnosis remains a clinical challenge in most of the cases. The objective of this study was to share our experience with patients presenting with discrepant TFTs outlining the main pitfalls in the differential diagnosis. Methods: medical records of 100 subjects with discrepant TFTs referred to Thyroid Endocrine Centers at the University of Milan were analyzed, retrospectively. Patients were studied by dynamic testing (TRH test, T3-suppression test, or a short course of long-acting somatostatin analog, when appropriate), THRB sequencing, and pituitary imaging. Results: 88 patients were correctly diagnosed as RTHβ with (n = 59; 16 men, 43 women) or without THRB variants (n = 6; 2 men, 4 female) or TSHoma (n = 23; 9 men, 14 women). We identified 14 representative subjects with an atypical presentation or who were misdiagnosed. Seven patients, with spurious hyperthyroxinemia due to assays interference were erroneously classified as RTHβ (n = 4) or TSHoma (n = 3). Three patients with genuine TSHomas were classified as laboratory artifact (n = 2) or RTHβ (n = 1). Two TSHomas presented atypically due to coexistent primary thyroid diseases. In one RTHβ a drug-induced thyroid dysfunction was primarily assumed. These patients experienced a mean diagnostic delay of 26 ± 14 months. Analysis of the investigations which can differentiate between TSHoma and RTHβ showed highest accuracy for the T3-suppression test (100% specificity with a cut-off of TSH <0.11 μUI/ml). Pituitary MRI was negative in 6/26 TSHomas, while 11/45 RTHβ patients had small pituitary lesions, leading to unnecessary surgery in one case. Conclusions: Diagnostic delay and inappropriate treatments still occur in too many cases with discrepant TFTs suggestive of central hyperthyroidism. The insistent pitfalls lead to a significant waste of resources. We propose a revised flow-chart for the differential diagnosis.
Giulia Lanzolla, Guia Vannucchi, Ilaria Ionni, Irene Campi, Federica Sileo, Elisa Lazzaroni, and Michele Marinò
Frontiers Media SA
Graves' Orbitopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease (GD). Its ultimate cause remains unclear, but it is commonly considered an autoimmune disorder due to self recognition of autoantigens constitutively expressed by orbital fibroblasts (OFs), and thyroid epithelial cells. High dose intravenous glucocorticoids (ivGC) are the most commonly used treatment for moderately severe and active GO. However, based on the complex pathogenesis of GO, a number of factors may have a protective and maybe a therapeutic role. The use of other medications improving the effect of GC may increase the overall effectiveness of the therapy and reduce GC doses, thereby limiting side effects. Recently, a possible protective role of 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, the so-called statins, and perhaps of lowering cholesterol levels, has been proposed. Thus, statins have been reported to be associated with a reduced frequency of GO in GD patients and in recent cross-sectional and retrospective studies a significant correlation was found between the occurrence of GO and both total and LDL-cholesterol in patients with a GD of relatively recent onset, suggesting a role of cholesterol in the development of GO. Moreover, a correlation was found between the GO clinical activity score and total as well as LDL-cholesterol in untreated GO patients, depending on GO duration, indicating a role of cholesterol on GO activity. Therefore, statin treatment may be beneficial for GO. Here we review this subject, which offers new therapeutic perspectives for patients with GO.
Guia Vannucchi, Danila Covelli, Irene Campi, Nicola Currò, Davide Dazzi, Marcello Rodari, Giovanna Pepe, Arturo Chiti, Claudio Guastella, Elisa Lazzaroni,et al.
Mary Ann Liebert Inc
Background: Radioiodine (RAI) is a known risk factor for activation or de novo occurrence of Graves' orbitopathy (GO). Several studies demonstrated that GO can be prevented by glucocorticoids (GCs) in patients with pre-existing GO. We have previously shown that Graves' disease duration (GDd) <5 years is a risk factor for RAI-induced GO. We studied the effect of prophylaxis with either oral GCs (OGCs) or intravenous GCs (IVGCs) on GO activation in patients with GDd. Methods: In total, 99 hyperthyroid patients without GO or with pre-existing inactive GO with GDd <5 years were randomized to receive IVGCs (N = 49) or OGCs (N = 50) before RAI; 22 patients with GDd >5 did not receive steroids and were studied as controls. All patients underwent ophthalmological assessment before and 45, 90, 180 days and for a 5-year follow-up after RAI. Serum thyrotropin (TSH) receptor antibodies (TRAbs), thyroid hormones, and thyroid volume (TV) were also measured in response to RAI therapy and steroid prophylaxis. Results: No patient on prophylaxis developed GO after RAI. One woman of the control group, without steroid prophylaxis, and who had a marked elevation of her TSH, showed transient reactivation of GO, which spontaneously improved after restoring euthyroidism. On follow-up at 12 and 20 months after RAI, two patients developed overt optic neuropathy. A smaller TV was associated with a higher prevalence of RAI-induced hypothyroidism. Serum TRAbs increased significantly after RAI (p < 0.0001) but less in patients receiving steroids than in those without prophylaxis at 45 days (p < 0.01). Conclusions: The risk of RAI-induced GO can be prevented in all patients with GDd <5 years by steroids. Such treatment may not be necessary in patients with GDd >5 years. The blunting of TRAb elevation after RAI may be related to the prophylactic effect of steroids.
Roberta Gualtierotti, Carolina Artusi, Guia Maria Vannucchi, Irene Campi, Luca Persani, and Pier Luigi Meroni
Elsevier
Abstract The etiology of autoimmune diseases is the result of a complex interaction of the immune system with environmental and genetic factors, although the underlying mechanisms are not completely understood. A number of autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a striking female predominance. Sexual dimorphism in autoimmunity can be explained at least in part by the role of sex hormones in the regulation of the immune system, whose cells express estrogen and androgen receptors. Furthermore, other mechanisms such as epigenetics may be involved in this multifaceted scenario. The rupture of this complex balance may contribute to the development of autoimmune diseases. In this chapter, we will focus on the effects of sex hormones and prolactin on the pathogenesis and development of autoimmunity.
Irene Campi, Giovanni B Perego, Antonella Ravogli, Antonella Groppelli, Gianfranco Parati, Luca Persani, and Laura Fugazzola
Oxford University Press (OUP)
Objectives Amiodarone-induced thyrotoxicosis (AIT) affects up to 3% of treated patients. Type 2 AIT (AIT2) is a destructive thyroiditis and is usually treated with medium-high oral doses of prednisone. As AIT may worsen the underlying heart disease, a rapid control of thyroid function is desirable. We aimed to determine whether a combined intravenous methylprednisolone (IVMP) pulses therapy associated to prednisone in the interpulse period can represent an efficient and safe alternative to urgent total thyroidectomy in patients with AIT2 not responsive to prednisone alone. Design and methods Patients presenting with a severe AIT2 studied in a tertiary referral Center from August 2018 to April 2019. We included four patients requiring a rapid improvement of thyroid function for their underlying cardiac disorders. The baseline doses of oral prednisone (range: 5–12.5 mg/day) and IVMP (range: 250–500 twice a week) were determined according to the severity of the thyrotoxicosis and were titrated based on clinical response. Results Combined treatment was effective in all patients in the prompt restoration of euthyroidism and no major adverse events were reported during the follow-up. In all cases, FT4 and FT3 levels normalized at 3–5 weeks of treatment. A permanent hypothyroidism was observed in one patient, 3 months after the discontinuation of treatment. Conclusions We report for the first time that the combined intravenous and oral steroid therapy is effective in patients with AIT2. The treatment is well tolerated and leads to a rapid improvement of thyroid function, avoiding urgent total thyroidectomy and favoring a quick functional recovery and rehabilitation of cardiac patients.