Letter to the Editor
Persistent lactate deshydrogenase elevation of uncertain etiology in Graves’ Disease
Elevación persistente de lactato deshidrogenasa de causa desconocida en enfermedad de Graves
Inés Jiménez Varas
, Ane Miren Azkutia, Martín Cuesta
Corresponding author
Servicio de Endocrinología y Nutrición, Hospital Clínico San Carlos, Madrid, Spain
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Source: proprietary.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Ascension Lupiañez-Barbero, Cintia González Blanco, Alberto de Leiva Hidalgo" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Ascension" "apellidos" => "Lupiañez-Barbero" ] 1 => array:2 [ "nombre" => "Cintia" "apellidos" => "González Blanco" ] 2 => array:2 [ "nombre" => "Alberto" "apellidos" => "de Leiva Hidalgo" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S2530016418301046" "doi" => "10.1016/j.endinu.2018.05.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2530016418301046?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2530018018300982?idApp=UINPBA00004N" "url" => "/25300180/0000006500000006/v1_201807250425/S2530018018300982/v1_201807250425/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Letter to the Editor</span>" "titulo" => "Persistent lactate deshydrogenase elevation of uncertain etiology in Graves’ Disease" "tieneTextoCompleto" => true "saludo" => "<span class="elsevierStyleItalic">Dear Sir</span>," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "374" "paginaFinal" => "375" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Inés Jiménez Varas, Ane Miren Azkutia, Martín Cuesta" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Inés" "apellidos" => "Jiménez Varas" "email" => array:1 [ 0 => "i.jimenez.varas@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Ane" "apellidos" => "Miren Azkutia" ] 2 => array:2 [ "nombre" => "Martín" "apellidos" => "Cuesta" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Endocrinología y Nutrición, Hospital Clínico San Carlos, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Elevación persistente de lactato deshidrogenasa de causa desconocida en enfermedad de Graves" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1651 "Ancho" => 1230 "Tamanyo" => 101244 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Lactate dehydrogenase (LDH) isoforms identified by serum agarose electrophoresis of the patient and control.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Elevated plasma lactate dehydrogenase (LDH) levels can be found in a great variety of conditions, including systemic infections or inflammation, muscle injury, hemolysis, thromboembolism, or malignancy. An uncommon and benign cause of such elevation is the presence of immune complexes called macroenzymes. A firm diagnosis of the underlying cause is therefore essential. However, the diagnosis is not always obvious, and other manifestations of the disorder need to be considered.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We report the case of a 50-year-old woman with no prior history of interest and diagnosed with primary hyperthyroidism (undetectable TSH, FT3 15.41<span class="elsevierStyleHsp" style=""></span>pg/mL [normal range 2.5–3.9], FT4 39.9<span class="elsevierStyleHsp" style=""></span>pg/mL [5.8–16.4]), for which antithyroid treatment was started (methimazole 20<span class="elsevierStyleHsp" style=""></span>mg/day). The results of the complementary tests were consistent with Graves–Basedow disease (anti-TSH receptor antibodies [TRab] 23<span class="elsevierStyleHsp" style=""></span>mIU/mL [0–1.5]; a significant increase in vascularization in both thyroid lobes as revealed by ultrasound). During follow-up (16 weeks after starting methimazole), the patient developed multiple joint pain in the hips and ankles, with LDH 1175<span class="elsevierStyleHsp" style=""></span>μ/L (240–480), the remaining biochemical parameters and blood count values being within normal ranges. Her general condition was excellent, and the physical examination yielded no data of interest.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Since treatment with antithyroid drugs may trigger arthralgia and osteoarthritis,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> the patient was evaluated by Rheumatology, which ruled out disease. The subsequent biochemical controls showed persistent LDH elevation (>1000<span class="elsevierStyleHsp" style=""></span>μ/L). The patient reported newly manifesting constipation. Colonoscopy and abdominal ultrasound were thus performed, with normal findings. Evaluation by Gynecology ruled out the presence of a gynecological neoplastic process. Likewise, since several nevi were found, dermatology discarded the presence of melanoma. A peripheral blood smear proved to be normal. Based on all the previous complementary tests, with no pathological findings, and in the presence of sustained high LDH levels, a positron emission tomography (PET) scan was performed and possible neoplastic disease discarded.</p><p id="par0020" class="elsevierStylePara elsevierViewall">In the absence of a diagnosis, electrophoresis (Reference laboratory) was requested to assess the different LDH isoforms. The results showed the presence of high molecular weight isoforms suggesting circulating immune complexes bound to immunoglobulins (macro-LDH, <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">One and a half years after the diagnosis, and 6 months after the discontinuation of antithyroid treatment, the Graves–Basedow disease is in remission (TSH 1.22<span class="elsevierStyleHsp" style=""></span>μIU/mL, FT4 9.75<span class="elsevierStyleHsp" style=""></span>pg/mL, TRab 0.9<span class="elsevierStyleHsp" style=""></span>mIU/mL), with persistent markedly elevated LDH levels (>800<span class="elsevierStyleHsp" style=""></span>μ/L).</p><p id="par0030" class="elsevierStylePara elsevierViewall">Macroenzymes are complexes resulting from the binding of serum enzymes to a plasma protein such as circulating immunoglobulins (Igs), the most common being IgG. The macroenzymes most commonly reported in the literature are macro-creatine kinase (CK)<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> and macro-amylase,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> with a reported macro-CK prevalence of 2% in hospitalized patients when systematic screening is performed.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> The diagnosis of macro-LDH is established by electrophoresis,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> which shows the presence of an abnormal high molecular weight band, with a half-life that increases as a result of decreased elimination through the kidneys. No association between autoimmune thyroid disease and macro-LDH has been established to date. However, some studies have suggested a possible relationship between these enzyme complexes and other autoimmune diseases such as rheumatoid arthritis or lupus erythematosus.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6,7</span></a> The physiopathology of macroenzyme formation has not been established. It has been suggested that the release of LDH into plasma and its exposure to proteolytic activity may lead to conformational change in the enzyme, increasing its immunogenicity.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">8,9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">On the other hand, the existence of these complexes has future repercussions for the patient, since enzyme determination cannot be used for diagnostic or for follow-up purposes, i.e., its clinical usefulness is lost.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Our review of the literature has yielded only one previous case of macro-LDH associated with Graves–Basedow disease.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> A lack of awareness of this relationship and the scant link between the two disorders caused us to perform multiple complementary tests. Greater initial diagnostic suspicion could have reduced the patient risks associated with invasive tests, as well as the uncertainty related to the lack of a definitive diagnosis.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Given the limited understanding of this disorder in the medical community,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> we believe that our clinical experience may encourage other specialists to include screening for macroproteins in patients with high enzyme or protein levels, in which no firm diagnosis is apparent and few clinical repercussions are observed. This could contribute to limiting the number of complementary tests performed and to optimizing the time to diagnosis.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In any case, further studies are needed to establish the mechanism whereby these complexes are formed and the risk factors involved, as well as their natural history.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Jiménez Varas I, Miren Azkutia A, Cuesta M. Elevación persistente de lactato deshidrogenasa de causa desconocida en enfermedad de Graves. Endocrinol Diabetes Nutr. 2018;65:374–375.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1651 "Ancho" => 1230 "Tamanyo" => 101244 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Lactate dehydrogenase (LDH) isoforms identified by serum agarose electrophoresis of the patient and control.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available from: <a class="elsevierStyleInterRef" target="_blank" id="intr0010" href="http://www.ncbi.nlm.nih.gov/pubmed/15745981">http://www.ncbi.nlm.nih.gov/pubmed/15745981</a>" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antithyroid drugs" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "D.S. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 33 | 6 | 39 |
| 2024 September | 62 | 26 | 88 |
| 2024 August | 49 | 20 | 69 |
| 2024 July | 60 | 28 | 88 |
| 2024 June | 32 | 22 | 54 |
| 2024 May | 24 | 15 | 39 |
| 2024 April | 35 | 30 | 65 |
| 2024 March | 37 | 24 | 61 |
| 2024 February | 43 | 23 | 66 |
| 2024 January | 38 | 7 | 45 |
| 2023 December | 41 | 2 | 43 |
| 2023 November | 34 | 6 | 40 |
| 2023 October | 67 | 8 | 75 |
| 2023 September | 21 | 0 | 21 |
| 2023 August | 36 | 4 | 40 |
| 2023 July | 84 | 5 | 89 |
| 2023 June | 58 | 4 | 62 |
| 2023 May | 86 | 7 | 93 |
| 2023 April | 70 | 9 | 79 |
| 2023 March | 64 | 5 | 69 |
| 2023 February | 36 | 15 | 51 |
| 2023 January | 26 | 16 | 42 |
| 2022 December | 41 | 9 | 50 |
| 2022 November | 46 | 11 | 57 |
| 2022 October | 26 | 11 | 37 |
| 2022 September | 35 | 30 | 65 |
| 2022 August | 50 | 29 | 79 |
| 2022 July | 37 | 10 | 47 |
| 2022 June | 38 | 5 | 43 |
| 2022 May | 44 | 12 | 56 |
| 2022 April | 56 | 27 | 83 |
| 2022 March | 46 | 18 | 64 |
| 2022 February | 45 | 7 | 52 |
| 2022 January | 81 | 7 | 88 |
| 2021 December | 57 | 18 | 75 |
| 2021 November | 34 | 7 | 41 |
| 2021 October | 58 | 16 | 74 |
| 2021 September | 38 | 23 | 61 |
| 2021 August | 54 | 22 | 76 |
| 2021 July | 54 | 9 | 63 |
| 2021 June | 64 | 7 | 71 |
| 2021 May | 89 | 11 | 100 |
| 2021 April | 235 | 26 | 261 |
| 2021 March | 169 | 16 | 185 |
| 2021 February | 112 | 30 | 142 |
| 2021 January | 112 | 13 | 125 |
| 2020 December | 81 | 8 | 89 |
| 2020 November | 73 | 12 | 85 |
| 2020 October | 69 | 6 | 75 |
| 2020 September | 63 | 16 | 79 |
| 2020 August | 91 | 10 | 101 |
| 2020 July | 77 | 11 | 88 |
| 2020 June | 65 | 5 | 70 |
| 2020 May | 52 | 12 | 64 |
| 2020 April | 63 | 2 | 65 |
| 2020 March | 58 | 12 | 70 |
| 2020 February | 49 | 1 | 50 |
| 2020 January | 50 | 3 | 53 |
| 2019 December | 31 | 5 | 36 |
| 2019 November | 28 | 9 | 37 |
| 2019 October | 13 | 9 | 22 |
| 2019 September | 20 | 5 | 25 |
| 2019 August | 6 | 2 | 8 |
| 2019 July | 7 | 11 | 18 |
| 2019 June | 9 | 7 | 16 |
| 2019 May | 43 | 20 | 63 |
| 2019 April | 25 | 6 | 31 |
| 2019 March | 2 | 0 | 2 |
| 2019 February | 3 | 0 | 3 |
| 2019 January | 0 | 1 | 1 |
| 2018 December | 3 | 1 | 4 |
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