Systemic capillary extravasation syndrome (Clarkson’s syndrome) in a patient with primary hypothyroidism

Blasco, Felipe; Guillamón, Ana Elena; Navarro, María

doi:10.1016/j.medcle.2021.07.004

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The underlying mechanism of this disease is unknown, although 82% of cases exhibit increased levels of immunoglobulin G subclass 1 (IgG1).<a class="elsevierStyleCrossRef" href="#bib0005">1</a>In this case report we describe how an elevation in the levels of vascular endothelial growth factor (VEGF), one of whose effects is to increase capillary permeability, secondary to a sustained stimulus of thyroid stimulating hormone (TSH), may have triggered this process and explain the myxedema described in untreated primary hypothyroidism.We describe the case of a 52-year-old woman with clinical criteria of autoimmune polyglandular syndrome type 4 (type 1 diabetes mellitus, autoimmune hypothyroidism, and pernicious anemia) who visited the Emergency Department with anasarca of abrupt onset. She reported that she had discontinued levothyroxine a few months earlier. Laboratory tests performed on admission revealed TSH levels >150 uIU/ml and thyroxine (T4) levels of 0.38 ng/dl. Because a chest X-ray showed severe bilateral pleural effusion, a thoracocentesis was consequently performed, extracting 900 ml of fluid compatible with transudate. An abdominal ultrasound revealed images of ascites, but no signs of a chronic liver disease. The diagnostic studies were completed with an echocardiogram that showed no valvular nor contractility alterations.Additional blood work revealed albumin levels of 2.4 g/dl and baseline cortisol levels of 14 µg/dl. All other parameters fell within normal limits. Because of the increased extravascular volume, the abrupt onset associated with hypoalbuminemia, but not albuminuria, as well as the study findings ruling out a nephrotic syndrome, liver cirrhosis, or heart failure, a potential diagnosis of SCLS was considered.Both a VEGF level above 1000 pg/ml (normal value: <124 pg/ml) and the existence of an IgG1 monoclonal component were confirmed. After correcting the hypothyroidism and normalizing the TSH levels, the VEGF levels dropped to 250 pg/ml, but no changes were observed in the IgG1 levels. The patient’s symptoms resolved within a few weeks, and she has not experienced a relapse after one year of follow-up.The VEGF comprises a set of proteins synthesized from a single gene that encodes 5 protein isoforms that interact with 3 tyrosine kinase receptors. Activation of VEGF receptor 1 (VEGFR-1) by isoforms VEGF-C or VEGF-D leads to an increase in vascular permeability. In a cohort of 20 patients with the classic form of SCLS, all patients had significantly higher VEGF levels than the controls, and short intervals of elevated VEGF levels coincided with episodes of SCLS.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>This factor is also increased in the context of inflammation induced by interferon beta, interleukins (IL-1 and IL-6), growth factors such as fibroblast growth factor 4 (FFG-4) and insulin-like growth factor 1 (IGF-1), and hypoxia. Increased plasma levels of this factor have also been described with tumors secreting follicle-stimulating hormone (FSH) or luteinizing hormone (LH), as well as with oral contraceptives.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>With respect to the case described herein, experimental studies carried out primarily with thyroid tumors have demonstrated how TSH induces the production of VEGF through increased expression of the gene regulating the synthesis of this protein.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The suppression of this stimulus by means of treatment with levothyroxine and normalization of the TSH levels was followed by a marked decrease in the VEGF levels and resolution of the anasarca, which has not recurred after one year of follow-up.Coinciding with other authors, we conclude that the role of IgG1 in the onset of this disease is debatable and that this parameter seems to be more related to an adaptive clinical response than being a triggering factor in itself. This is supported by data from a case series published by Xie et al.,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> in which the levels of these antibodies showed no differences between active episodes and the remission phase. Thus, we hypothesize that IgG1 acts as a control mechanism in this context. In their study on the angiogenesis suppression effect of humanized IgG1 antibodies, Bogdanovich et al.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> suggest that endogenous antibodies, such as IgG1, may play a homeostatic role in modulating the action of the VEGF. In this context, an increase in IgG1 levels would entail nothing more than a modulatory response to block VEGF activity. This response, once triggered, would persist over time." "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Blasco F, Guillamón AE, Navarro M. Síndrome de extravasación capilar sistémica (síndrome de Clarkson) en una paciente con hipotiroidismo primario. Med Clin (Barc). 2020. https://doi.org/10.1016/j.medcli.2020.05.056" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Idiopathic systemic capillary leak syndrome (Clarkson disease)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K.M. Druey" 1 => "S. 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El papel del Factor de Crecimiendo del endotelio Vascular en la Angiogénesis [Accessed 26 May 2020] Available from: <a target="_blank" href="http://www.siicsalud.com/des/expertoimpreso.php/90129/;2009">http://www.siicsalud.com/des/expertoimpreso.php/90129/;2009</a>." ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thyrotropin (TSH) induced production of vascular endothelial growth factor in thyroid cancer cells in vitro: evaluation of TSH signal transduction and of angiogenesis-stimulating growth factors" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "S. Hoffmann" 1 => "L.C. Hofbauer" 2 => "V. Scharrenbacj" 3 => "A. Wunderlich" 4 => "I. Hassan" 5 => "S. Lingelbach" 6 => "A. Zielke" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2004-1260" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2004" "volumen" => "89" "paginaInicial" => "6139" "paginaFinal" => "6145" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15579770" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human IgG1 antibodies suppress angiogenesis in a target-independent manner" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:5 [ 0 => "S. Bogdanovich" 1 => "Y. Kim" 2 => "T. Mizutani" 3 => "R. Yasuma" 4 => "L. Tudisco" ] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1038/sigtrans.2015.1" "Revista" => array:4 [ "tituloSerie" => "Signal Transduct Targeted Ther" "fecha" => "2016" "volumen" => "1" "paginaInicial" => "15001" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763941/" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015700000004/v2_202201010719/S2387020621003934/v2_202201010719/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015700000004/v2_202201010719/S2387020621003934/v2_202201010719/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020621003934?idApp=UINPBA00004N"]

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