Case Report
Foreign Body Granulomatous Reaction to Silica, Silicone, and Hyaluronic Acid in a Patient With Interferon-Induced Sarcoidosis
Reacción granulomatosa a cuerpo extraño a sílice, silicona y ácido hialurónico, en paciente con sarcoidosis inducida por interferon
a Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
b Servicio de Digestivo, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
c Servicio de Anatomía Patológica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
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Novoa, M.A. Barnadas, X. Torras, R. Curell, A. Alomar" "autores" => array:5 [ 0 => array:3 [ "nombre" => "R." "apellidos" => "Novoa" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:4 [ "nombre" => "M.A." "apellidos" => "Barnadas" "email" => array:1 [ 0 => "MBarnadas@santpau.cat" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 2 => array:3 [ "nombre" => "X." "apellidos" => "Torras" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "R." "apellidos" => "Curell" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "A." "apellidos" => "Alomar" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Digestivo, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Reacción granulomatosa a cuerpo extraño a sílice, silicona y ácido hialurónico, en paciente con sarcoidosis inducida por interferon" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 645 "Ancho" => 1750 "Tamanyo" => 337580 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A, Histopathology of the left axillary lymph node showing widespread sarcoid granulomas (hematoxylin and eosin, original magnification, ×200). B, The center of the node contains clear vacuoles in the extracellular space and in the cytoplasm of multinucleated giant cells. Note the refractile material within these vacuoles (hematoxylin and eosin, original magnification, ×400).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Sarcoidosis is more prevalent in patients receiving interferon than in the general population.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Furthermore, the appearance of granulomas in the skin is known to be related to the presence of foreign bodies.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> We describe the case of a patient with chronic hepatitis C who developed sarcoidosis while receiving treatment with pegylated interferon alfa combined with ribavirin. The sarcoid granulomas were located in the skin and were associated with 3 different foreign bodies: silica, hyaluronic acid, and silicone within a lymph node.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Case Description</span><p id="par0010" class="elsevierStylePara elsevierViewall">The patient was a 54-year-old woman who was referred to the dermatology department in September 2009 with erythematous-violaceous nodules on her face.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Important findings in her past history included silicone gel implants to both breasts 19 years previously (these implants had not been replaced) and chronic infection by hepatitis C virus (HCV), genotype 1b, which had been detected 11 years earlier, giving rise to severe liver fibrosis. In September 2008 she started treatment with subcutaneous interferon alfa 2a (180<span class="elsevierStyleHsp" style=""></span>μg weekly) combined with oral ribavirin (1000<span class="elsevierStyleHsp" style=""></span>mg/d), which led to a partial early virologic response. Erythropoietin (40 000<span class="elsevierStyleHsp" style=""></span>IU) was added at week 4 owing to anemia secondary to antiviral treatment.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Physical examination revealed erythematous-violaceous nodules in the interciliary sulci and nasolabial folds (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, A and B). The patient reported that she had had hyaluronic acid injections at these sites 1 year earlier. She had received treatment with intralesional corticosteroids but had shown no signs of improvement. In addition, she presented nodules covered by skin of normal appearance on both sides of her forehead in areas where she denied having had injections of hyaluronic acid. She also presented brownish papules in a linear distribution on her left shoulder (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B), elbows, knees, and in the proximity of old scars, and the axillary lymph nodes were palpable bilaterally. The patient reported having had dry cough and fever (38<span class="elsevierStyleHsp" style=""></span>°C) during the previous month. Laboratory tests revealed the following important results: hemoglobin, 10.1<span class="elsevierStyleHsp" style=""></span>g/dL; white cell count, 2330 μL; and angiotensin-converting enzyme, 80<span class="elsevierStyleHsp" style=""></span>U/L (reference range, 20-60 U/L). The results of the other laboratory tests—including renal and liver function and blood and urinary calcium and phosphate—were within the normal range.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Computed tomography of the chest and abdomen revealed changes in the breast implants, which had acquired a nodular morphology, and bilateral axillary lymphadenopathies, as well as a 1-cm nodule in segment IV of the liver, together with 2 other hepatic lesions measuring <1<span class="elsevierStyleHsp" style=""></span>cm that were suggestive of cysts. Magnetic resonance of the breasts revealed an intracapsular rupture of the implant on the left side.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Biopsy of a papule on the left shoulder showed epithelioid granulomas with no central necrosis in the papillary and upper reticular dermis, surrounded by sparse lymphocytes (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A). Shiny particles were observed in the cytoplasm of some histiocytes and of some multinucleated giant cells (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B). These particles were birefringent with polarized light and were interpreted to be silica.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Histopathology of an axillary lymph node revealed numerous nonnecrotizing sarcoid epithelioid granulomas (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A). In addition, clear extracellular vacuoles of different sizes were present in the center of the node and there were abundant multinucleated giant cells with cytoplasmic vacuoles. Nonbirefringent refractile material was observed inside some vacuoles. Given that the patient had silicone breast implants, this finding was compatible with silicone from the implants (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>B), thus indicating silicone lymphadenopathy.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">A diagnosis of sarcoidosis was made. As no visceral involvement was observed, the same antiviral treatment was maintained. However, in November 2009, hepatic cholestasis was detected (alkaline phosphatase 245<span class="elsevierStyleHsp" style=""></span>U/L [reference range, 35-110 U/L] and gamma-glutamyltransferase 469<span class="elsevierStyleHsp" style=""></span>U/L [reference value,<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>43 U/L]) and treatment with pegylated interferon alfa 2a and ribavirin was stopped. The results of the laboratory tests subsequently returned to normal values, the size of the cutaneous lesions gradually decreased, and the cough and fever resolved. In addition, the virologic response was maintained 1 year after completing 60 weeks of antiviral treatment.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0045" class="elsevierStylePara elsevierViewall">Sarcoidosis is a multisystem granulomatous disease of unknown etiology that is sometimes associated with interferon administered to treat other diseases.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–7</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Sarcoidosis is detected more frequently in HCV-infected patients than in the general population. In their 2010 study, Faurie et al.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> found a prevalence of 0.12% in a series of HCV-infected patients; in the general population, prevalence has been estimated to be between 1 and 40 cases per 100 000.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In 2005, Ramos-Casals et al.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> reviewed 68 cases of sarcoidosis associated with chronic HCV infection and compared their findings with a control group of non–HCV-infected patients. Those authors found that skin involvement in sarcoidosis was more frequent in HCV-infected patients (56%) than in non–HCV-infected patients (22%). In 4 cases, the granulomas were adjacent to old scars and tattoos. Faurie et al. considered that sarcoidosis had been triggered by antiviral treatment in most cases (79.4%). The potential role of interferon could arise from the induction of a type 1 helper T-cell response, which is thought to affect the formation of granulomas in patients with sarcoidosis.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Both pegylated and nonpegylated interferon alfa, whether in monotherapy or in combination with ribavirin, have been cited as possible triggers of sarcoidosis. Prognosis is generally good in these cases, and sarcoidosis can resolve spontaneously in 85% of cases if antiviral treatment is stopped.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In the case we report, antiviral treatment was maintained until the onset of systemic manifestations. At that time, antiviral therapy was discontinued, even though the 72-week regimen had not been completed.</p><p id="par0055" class="elsevierStylePara elsevierViewall">In the present case, we think that sarcoidosis was probably induced by interferon and ribavirin for 2 reasons: first, the lesions appeared 11 months after starting treatment, and second, the skin and liver lesions, the liver function tests, angiotensin-converting enzyme levels, and changes in the breast implants returned to normal once interferon was discontinued.</p><p id="par0060" class="elsevierStylePara elsevierViewall">We believe that the case we report is unusual, as the sites of the sarcoid granulomas were associated with the presence of 3 foreign bodies (silica, hyaluronic acid, and silicone). The simultaneous onset of cutaneous sarcoid granulomas associated with 2 foreign bodies (silica and silicone) has been described elsewhere.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Of note, Marcoval et al.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> demonstrated the presence of foreign bodies in cutaneous granulomatous lesions in 22% of 65 patients with systemic sarcoidosis and skin involvement and suggested that these foreign bodies could induce the formation of granulomas in patients with sarcoidosis.</p><p id="par0065" class="elsevierStylePara elsevierViewall">There have been reports of systemic sarcoidosis associated with tattoos<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> and fillers (permanent and reabsorbable).<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10–12</span></a> Two studies<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> have reported sarcoid granulomas associated with injection of hyaluronic acid in 2 women: one of those patients had hepatitis C treated with interferon.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">We report the first case of sarcoid granulomas developing in a silicone-induced lymphadenopathy. This complication of breast implants is caused by migration of silicone to the lymph nodes.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Sarcoidosis has been reported in patients with breast implants.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a> The condition improved spontaneously in 1 case,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> and in the other, the patient's condition improved dramatically after removal of the implants.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">We believe that sarcoidosis associated with HCV infection is of special interest for the dermatologist, since it frequently affects the skin (56% of cases). In addition, cosmetic procedures such as tattoos and the use of fillers may induce the appearance of sarcoid granulomas in patients who develop sarcoidosis. It has been suggested that the informed consent signed before cosmetic microimplant procedures should include the risk of severe interaction between the injected material and interferon or other immunostimulants, were the patient to need such treatments in the future.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> This warning should be given even before injection of reabsorbable material.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Any changes in the areas where cosmetic materials have been injected should alert the dermatologist and cosmetic surgeon to a possible diagnosis of sarcoidosis, especially in patients with HCV infection. Furthermore, before receiving cosmetic injections, patients should be warned of the risk of developing or reactivating sarcoidosis in the future.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Ethical Disclosures</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Protection of human and animal subjects</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this investigation.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Confidentiality of data</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare that they followed their hospital's regulations regarding the publication of patient information and that written informed consent for voluntary participation was obtained for all patients.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Right to privacy and informed consent</span><p id="par0095" class="elsevierStylePara elsevierViewall">The authors declare that no private patient data are disclosed in this article.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of Interest</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:2 [ "identificador" => "xres295315" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec279236" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres295314" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec279235" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case Description" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Ethical Disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Right to privacy and informed consent" ] ] ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of Interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-03-05" "fechaAceptado" => "2012-07-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec279236" "palabras" => array:8 [ 0 => "Sarcoidosis" 1 => "Hepatitis C" 2 => "Foreign-body granulomas" 3 => "Silica" 4 => "Silicone" 5 => "Hyaluronic acid" 6 => "Interferon" 7 => "Silicone lymphadenopathy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec279235" "palabras" => array:8 [ 0 => "Sarcoidosis" 1 => "Hepatitis C" 2 => "Granulomas a cuerpo extraño" 3 => "Sílice" 4 => "Silicona" 5 => "Ácido hialurónico" 6 => "Interferón" 7 => "Linfadenopatía por silicona" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">We report the case of a patient who developed sarcoid granulomas 11 months after starting treatment with pegylated interferon alfa and ribavirin for chronic hepatitis C. The sites of the lesions were related to 3 different foreign bodies: silica in old scars on the skin, hyaluronic acid that had been injected into facial tissues, and silicone in an axillary lymph node draining the area of a breast implant. Systemic sarcoidosis was diagnosed on the basis of a history of dry cough and fever and blood tests that revealed elevated angiotensin converting enzyme and liver enzymes. Interruption of the antiviral therapy led to normalization of liver function tests and disappearance of the skin lesions and lymphadenopathies. Dermatologists and cosmetic surgeons should be aware of the risk of sarcoid lesions related to cosmetic implants in patients who may require treatment with interferon in the future.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se describe el caso de una paciente que desarrolló granulomas sarcoideos 11 meses después de haber iniciado interferón α pegilado y ribavirina, como tratamiento de la hepatitis crónica C. Las lesiones se localizaban en relación a 3 cuerpos extraños diferentes: sílice en cicatrices cutáneas antiguas, ácido hialurónico que se había inyectado previamente en la cara, y silicona que se detectó en una adenopatía axilar donde había drenado de un implante mamario previo. La paciente también aquejaba tos seca, fiebre y en la analítica se detectó un incremento de la enzima convertidora de angiotensina y de las enzimas hepáticas. A partir de estos hallazgos se diagnosticó de sarcoidosis sistémica y se suspendió el tratamiento antiviral con posterior normalización de las pruebas hepáticas, desaparición de las lesiones cutáneas y de las adenopatías.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Los dermatólogos y cosmetólogos deben ser conscientes del riesgo de aparición de manifestaciones sarcoideas en las áreas donde se han realizado implantes estéticos, en los sujetos que en un futuro requieran tratamiento con interferón.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Novoa R, Barnadas MA, Torras X, Curell R, Alomar A. Reacción granulomatosa a cuerpo extraño a sílice, silicona y ácido hialurónico, en paciente con sarcoidosis inducida por interferon. Actas Dermosifiliogr. 2013;104:920–923.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 653 "Ancho" => 1000 "Tamanyo" => 118369 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A, Clinical appearance of nodules in a nasolabial fold. B, Clinical appearance of linear papules on an old scar.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 648 "Ancho" => 1750 "Tamanyo" => 326248 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A, Histopathology of a papule from the shoulder. Sarcoid granulomas are visible in the reticular dermis (hematoxylin and eosin, original magnification, ×200). B, Detail of shiny particles in the cytoplasm of multinucleated giant cells (hematoxylin and eosin, original magnification, ×400).</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 645 "Ancho" => 1750 "Tamanyo" => 337580 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A, Histopathology of the left axillary lymph node showing widespread sarcoid granulomas (hematoxylin and eosin, original magnification, ×200). B, The center of the node contains clear vacuoles in the extracellular space and in the cytoplasm of multinucleated giant cells. Note the refractile material within these vacuoles (hematoxylin and eosin, original magnification, ×400).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sarcoidosis in patients with chronic hepatitis C virus infection: analysis of 68 cases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Ramos-Casals" 1 => "J. Mañá" 2 => "N. Nardi" 3 => "P. Brito-Zerón" 4 => "A. Xaubet" 5 => "J.M. 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| 2024 Enero | 77 | 38 | 115 |
| 2023 Diciembre | 70 | 24 | 94 |
| 2023 Noviembre | 89 | 38 | 127 |
| 2023 Octubre | 106 | 33 | 139 |
| 2023 Septiembre | 97 | 34 | 131 |
| 2023 Agosto | 61 | 34 | 95 |
| 2023 Julio | 74 | 36 | 110 |
| 2023 Junio | 64 | 29 | 93 |
| 2023 Mayo | 85 | 41 | 126 |
| 2023 Abril | 72 | 44 | 116 |
| 2023 Marzo | 68 | 36 | 104 |
| 2023 Febrero | 50 | 28 | 78 |
| 2023 Enero | 70 | 43 | 113 |
| 2022 Diciembre | 72 | 36 | 108 |
| 2022 Noviembre | 48 | 25 | 73 |
| 2022 Octubre | 59 | 35 | 94 |
| 2022 Septiembre | 40 | 46 | 86 |
| 2022 Agosto | 18 | 60 | 78 |
| 2022 Julio | 36 | 47 | 83 |
| 2022 Junio | 61 | 36 | 97 |
| 2022 Mayo | 82 | 63 | 145 |
| 2022 Abril | 107 | 69 | 176 |
| 2022 Marzo | 83 | 71 | 154 |
| 2022 Febrero | 64 | 36 | 100 |
| 2022 Enero | 76 | 54 | 130 |
| 2021 Diciembre | 45 | 53 | 98 |
| 2021 Noviembre | 81 | 57 | 138 |
| 2021 Octubre | 126 | 76 | 202 |
| 2021 Septiembre | 373 | 54 | 427 |
| 2021 Agosto | 112 | 32 | 144 |
| 2021 Julio | 86 | 39 | 125 |
| 2021 Junio | 79 | 61 | 140 |
| 2021 Mayo | 69 | 55 | 124 |
| 2021 Abril | 104 | 95 | 199 |
| 2021 Marzo | 69 | 39 | 108 |
| 2021 Febrero | 56 | 38 | 94 |
| 2021 Enero | 35 | 44 | 79 |
| 2020 Diciembre | 57 | 46 | 103 |
| 2020 Noviembre | 31 | 25 | 56 |
| 2020 Octubre | 41 | 21 | 62 |
| 2020 Septiembre | 43 | 20 | 63 |
| 2020 Agosto | 33 | 49 | 82 |
| 2020 Julio | 47 | 29 | 76 |
| 2020 Junio | 36 | 42 | 78 |
| 2020 Mayo | 31 | 43 | 74 |
| 2020 Abril | 33 | 30 | 63 |
| 2020 Marzo | 24 | 27 | 51 |
| 2020 Febrero | 1 | 7 | 8 |
| 2020 Enero | 4 | 18 | 22 |
| 2019 Diciembre | 6 | 10 | 16 |
| 2019 Noviembre | 4 | 20 | 24 |
| 2019 Octubre | 0 | 8 | 8 |
| 2019 Septiembre | 0 | 14 | 14 |
| 2019 Agosto | 6 | 14 | 20 |
| 2019 Julio | 4 | 16 | 20 |
| 2019 Junio | 4 | 19 | 23 |
| 2019 Mayo | 4 | 69 | 73 |
| 2019 Abril | 2 | 60 | 62 |
| 2019 Marzo | 3 | 19 | 22 |
| 2019 Febrero | 0 | 21 | 21 |
| 2019 Enero | 3 | 12 | 15 |
| 2018 Diciembre | 1 | 11 | 12 |
| 2018 Noviembre | 1 | 6 | 7 |
| 2018 Octubre | 2 | 8 | 10 |
| 2018 Septiembre | 3 | 2 | 5 |
| 2018 Agosto | 0 | 7 | 7 |
| 2018 Julio | 0 | 24 | 24 |
| 2018 Junio | 0 | 15 | 15 |
| 2018 Mayo | 0 | 12 | 12 |
| 2018 Abril | 0 | 11 | 11 |
| 2018 Marzo | 6 | 25 | 31 |
| 2018 Febrero | 76 | 10 | 86 |
| 2018 Enero | 85 | 11 | 96 |
| 2017 Diciembre | 91 | 12 | 103 |
| 2017 Noviembre | 69 | 16 | 85 |
| 2017 Octubre | 64 | 12 | 76 |
| 2017 Septiembre | 77 | 17 | 94 |
| 2017 Agosto | 87 | 29 | 116 |
| 2017 Julio | 81 | 19 | 100 |
| 2017 Junio | 87 | 28 | 115 |
| 2017 Mayo | 74 | 24 | 98 |
| 2017 Abril | 92 | 21 | 113 |
| 2017 Marzo | 69 | 41 | 110 |
| 2017 Febrero | 53 | 15 | 68 |
| 2017 Enero | 54 | 14 | 68 |
| 2016 Diciembre | 54 | 14 | 68 |
| 2016 Noviembre | 93 | 29 | 122 |
| 2016 Octubre | 138 | 25 | 163 |
| 2016 Septiembre | 189 | 17 | 206 |
| 2016 Agosto | 87 | 13 | 100 |
| 2016 Julio | 43 | 9 | 52 |
| 2016 Junio | 8 | 6 | 14 |
| 2016 Mayo | 14 | 10 | 24 |
| 2016 Abril | 8 | 10 | 18 |
| 2016 Marzo | 12 | 1 | 13 |
| 2016 Febrero | 10 | 1 | 11 |
| 2016 Enero | 12 | 2 | 14 |
| 2015 Diciembre | 8 | 2 | 10 |
| 2015 Noviembre | 7 | 10 | 17 |
| 2015 Octubre | 6 | 3 | 9 |
| 2015 Septiembre | 3 | 1 | 4 |
| 2015 Agosto | 6 | 1 | 7 |
| 2015 Julio | 72 | 5 | 77 |
| 2015 Junio | 70 | 9 | 79 |
| 2015 Mayo | 76 | 9 | 85 |
| 2015 Abril | 51 | 8 | 59 |
| 2015 Marzo | 54 | 10 | 64 |
| 2015 Febrero | 67 | 14 | 81 |
| 2015 Enero | 60 | 5 | 65 |
| 2014 Diciembre | 51 | 5 | 56 |
| 2014 Noviembre | 58 | 7 | 65 |
| 2014 Octubre | 52 | 10 | 62 |
| 2014 Septiembre | 36 | 7 | 43 |
| 2014 Agosto | 37 | 7 | 44 |
| 2014 Julio | 37 | 8 | 45 |
| 2014 Junio | 62 | 9 | 71 |
| 2014 Mayo | 45 | 8 | 53 |
| 2014 Abril | 54 | 6 | 60 |
| 2014 Marzo | 50 | 9 | 59 |
| 2014 Febrero | 45 | 6 | 51 |
| 2014 Enero | 36 | 5 | 41 |
| 2013 Diciembre | 35 | 10 | 45 |
| 2013 Noviembre | 1 | 2 | 3 |
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