Case Report
Protein-losing Enteropathy Associated With Refractory Systemic Lupus Erythematosus With a Good Response to Rituximab
Enteropatía perdedora de proteínas asociada a lupus eritematoso sistémico refractaria con buena respuesta a rituximab
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Nonspecific symptoms such as anorexia, nausea, vomiting and diarrhea are observed in up to one third of the patients with active disease. Ascites, peptic ulcer disease and dysphagia develop in 8–12%, 6% and 1–7.3% of the cases, respectively. Abdominal pain, present in 8–37% of the patients, may be a sign of a complication, such as mesenteric vasculitis, or may be attributable to causes unrelated to lupus, such as irritable bowel syndrome.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">1</span></a> Protein-losing enteropathy (PLE) is an uncommon clinical manifestation associated with SLE but, in some cases, is the presenting sign.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a> The prevalence is around 2–3%.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">3,4</span></a> It is characterized by the presence of hypoalbuminemia secondary to gastrointestinal protein loss. We present the case of a patient with SLE associated with PLE refractory to conventional immunosuppressive therapy with a satisfactory response to rituximab (RTX).</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Case Report</span><p id="par0010" class="elsevierStylePara elsevierViewall">The patient was a 17-year-old woman, who was admitted to the hospital for the study of recent-onset ascites. She had a 3-year history of episodes of chronic abdominal pain and diarrhea. The physical examination revealed malar rash, polyarthritis, alopecia, oral ulcers, anasarca and pleural effusion. The most notable analytical findings were: hemoglobin 11<span class="elsevierStyleHsp" style=""></span>g/dl, platelets 67<span class="elsevierStyleHsp" style=""></span>000/mm<span class="elsevierStyleSup">3</span>, total protein concentration 35<span class="elsevierStyleHsp" style=""></span>g/l, albumin 17<span class="elsevierStyleHsp" style=""></span>g/l, triglycerides 800<span class="elsevierStyleHsp" style=""></span>mg/dl, erythrocyte sedimentation rate 120<span class="elsevierStyleHsp" style=""></span>mm/1<span class="elsevierStyleHsp" style=""></span>h, C3: 58<span class="elsevierStyleHsp" style=""></span>mg/dl (90–180<span class="elsevierStyleHsp" style=""></span>mg/dl), C4: 13<span class="elsevierStyleHsp" style=""></span>mg/dl (10–40<span class="elsevierStyleHsp" style=""></span>mg/dl), normal urinary sediment and negative test for 24-h urinary protein excretion. Antinuclear antibodies (1/640 dense fine speckled pattern), anti-DNA, anti-Sm, anti-Ro and anti-La were negative; IgM anticardiolipin antibodies, at 36<span class="elsevierStyleHsp" style=""></span>MPL units/ml (reference values [RV] 15–20<span class="elsevierStyleHsp" style=""></span>MPL units/ml), and lupus anticoagulant were positive. Systemic lupus erythematosus was diagnosed on the basis of the 1982 criteria of the American College of Rheumatology. Renal and hepatic compromise were ruled out as the cause of hypoproteinemia. Coproculture, examination of stool for parasites and tests for IgA and IgG antibodies to transglutaminase, IgA and IgG antibodies to deamidated gliadin peptide and IgA antibodies to endomysium were negative. In the study of fecal material, alpha-1 antitrypsin (A1AT) clearance was 1040<span class="elsevierStyleHsp" style=""></span>ml/24<span class="elsevierStyleHsp" style=""></span>h (RV<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ml/24<span class="elsevierStyleHsp" style=""></span>h). Upper gastrointestinal video endoscopy revealed marked edema in the second segment of the duodenum, which resulted in the swelling of the duodenal flexures. Duodenal biopsies disclosed chronic nonspecific duodenitis with a conserved crypt:villus ratio and chorionic edema. Video colonoscopy provided no evidence of lesions and the biopsies showed nonspecific changes. Protein-losing enteropathy associated with SLE was diagnosed, and treatment was begun with methylprednisolone (MP) in intravenous (iv) pulses of 1<span class="elsevierStyleHsp" style=""></span>g/day for 3 days and 6 doses of 500<span class="elsevierStyleHsp" style=""></span>mg of cyclophosphamide (CY) at 2-week intervals, followed by 150<span class="elsevierStyleHsp" style=""></span>mg/day of azathioprine (AZA) and 400<span class="elsevierStyleHsp" style=""></span>mg/day of hydroxychloroquine; the doses of corticosteroids were tapered to 20<span class="elsevierStyleHsp" style=""></span>mg/day. Two months after the start of treatment, remission was achieved and the patient remained asymptomatic for 24 months, during which she continued to take 150<span class="elsevierStyleHsp" style=""></span>mg/day of AZA as maintenance treatment. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the laboratory parameters and response to treatment.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">At 24 months, she had her first relapse, presenting with ascites and edema, and no other clinical manifestations of SLE activity. An analysis revealed low C3 levels and, again, treatment consisted of iv pulses of 1<span class="elsevierStyleHsp" style=""></span>g/day of MP administered on 3 consecutive days, as well as iv CY at a dose of 1<span class="elsevierStyleHsp" style=""></span>g/month. She continued with 200<span class="elsevierStyleHsp" style=""></span>mg/day of cyclosporine as maintenance therapy. The latter had to be discontinued because of gastrointestinal intolerance. The patient's symptoms were reactivated after the prednisone dose was reduced to less than 30<span class="elsevierStyleHsp" style=""></span>mg/day. As a complication of the prolonged corticosteroid therapy, she developed avascular osteonecrosis in both knees.</p><p id="par0020" class="elsevierStylePara elsevierViewall">One year later, the patient had a second relapse, with ascites and edema, but no other symptoms of SLE activity. Once again, treatment consisted of 6 doses of 500<span class="elsevierStyleHsp" style=""></span>mg of CY at 2-week intervals. Fifteen months later, she had a new recurrence, with a marked deterioration of her nutritional status; she was taking corticosteroids at a dose of 20<span class="elsevierStyleHsp" style=""></span>mg/day. Parenteral nutrition was started and she underwent treatment with mycophenolate mofetil (MMF) at a dose of 3<span class="elsevierStyleHsp" style=""></span>g/day for 3 months. As there was no improvement in her clinical status or analytical results, her treatment was changed to RTX at a dose of 375<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span> weekly for 4 weeks, associated with 2<span class="elsevierStyleHsp" style=""></span>g of MMF, and complete remission was achieved 5 months later.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Given the severity of the disease and its refractoriness to different immunosuppressive agents, the decision was made to administer a new dose of RTX 6 months later. CD19 lymphocytes were not monitored. At the present time, the patient's SLE and PLE have been in remission for 2 years and she continues to take 2<span class="elsevierStyleHsp" style=""></span>mg/day of prednisone and 1<span class="elsevierStyleHsp" style=""></span>g/day of MMF. During the follow-up period, there has been no evidence of any adverse effect related to RTX.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0030" class="elsevierStylePara elsevierViewall">Protein-losing enteropathy is a condition associated with the loss of proteins via the gastrointestinal tract. The clinical signs are abdominal pain, diarrhea of varying severity and peripheral edema. Hypoalbuminemia with no evidence of proteinuria is the most common finding.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">5</span></a> It can be associated with a wide variety of disorders such as inflammatory bowel disease, tuberculosis, lymphoma, lymphangiectasia, Whipple's disease, celiac disease, amyloidosis and autoimmune diseases.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Protein-losing enteropathy is an uncommon manifestation in SLE. In a series of 15 SLE patients at the Peking Union Medical College Hospital in Beijing, China, PLE was the presenting sign of SLE in 53%; only 40% complained of diarrhea and abdominal pain. The majority had some degree of peripheral edema: ascites (73%), pleural effusion (60%) and pericardial effusion (47%). All the patients had hypoalbuminemia, and 80% had hypocomplementemia, 67% had dyslipidemia and 40% had hypocalcemia.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">6</span></a> Although the cause is unknown, several pathogenic mechanisms have been proposed: complement-mediated vascular injury, non-necrotizing mesenteric vasculitis, acquired lymphangiectasia and increased permeability of the intestinal microvasculature mediated by interferon gamma, interleukin 6, tumor necrosis factor-α and other cytokines.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">7–11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The diagnosis of PLE is based on the combination of the clinical signs, demonstration of the loss of proteins into the gastrointestinal tract by means of <span class="elsevierStyleSup">99m</span>Tc-labeled serum albumin scintigraphy, fecal A1AT clearance, response to treatment and the exclusion of other causes of hypoalbuminemia.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">99m</span>Tc scintigraphy is the diagnostic study of choice over A1AT clearance as it has a higher sensitivity (100% vs 46%) and negative predictive value (100% vs 63%). On the other hand, it makes it possible to trace the origin of the enteric protein loss.<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">12,13</span></a> In the case reported here, <span class="elsevierStyleSup">99m</span>Tc scintigraphy was not performed as it was not available. We used A1AT clearance, which enabled us to follow the patient's course and evaluate the response to treatment.</p><p id="par0045" class="elsevierStylePara elsevierViewall">In a systematic review of 112 patients with PLE associated with SLE, 42% responded to steroid therapy and 66% required another immunosuppressive drug, which included CY in 46%, AZA in 33% and the combination of AZA and CY in 7%.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">5</span></a> With respect to the indication for RTX, to date, only one case of PLE associated with Sjögren's syndrome has been reported, and the response to this monoclonal antibody was good.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">14</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Rutiximab is a monoclonal antibody against the B lymphocyte antigen CD20. Although there are no randomized controlled clinical trials showing the benefits of RTX in SLE, evidence of its efficacy has been shown in observational studies and case reports. At any rate, its use has been indicated for the treatment of patients with refractory forms, defined as individuals who did not achieve remission or had relapsing disease, despite an optimal corticosteroid dose, and the failure of at least 2 immunosuppressive agents. Ramos-Casals et al. analyzed the efficacy of the off-label use of RTX in patients with SLE and found a response of over 80% among patients with proliferative nephritis and neurological and hematological compromise (hemolytic disease and thrombocytopenia); in contrast, the response rate was lower than 50% in those with signs of cutaneous and joint involvement. On the other hand, it made it possible to reduce steroid doses in 79% and discontinue steroid therapy altogether in 14%.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">15,16</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In conclusion, PLE is an uncommon complication of lupus that should be suspected in patients with persistent hypoalbuminemia, peripheral edema, pleural effusion and ascites, once other diseases, mainly kidney and liver disease, have been ruled out. Treatment with RTX should be considered as soon as therapy with a second immunosuppressive agent fails. This approach would probably prevent the development of irreversible damage related to corticosteroid therapy.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Ethical Disclosure</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Protection of human and animal subjects</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Confidentiality of data</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Right to privacy and informed consent</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of Interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres599030" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec613498" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres599029" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec613499" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case Report" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Ethical Disclosure" "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" => "Conflict of Interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-09-06" "fechaAceptado" => "2015-01-23" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec613498" "palabras" => array:4 [ 0 => "Systemic lupus erythematosus" 1 => "Protein-losing enteropathy" 2 => "Rituximab" 3 => "Refractory" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec613499" "palabras" => array:4 [ 0 => "Lupus eritematoso sistémico" 1 => "Enteropatía perdedora de proteínas" 2 => "Rituximab" 3 => "Refractario" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A case is presented of a protein-losing enteropathy (PLE) as the initial manifestation of systemic lupus erythematosus (SLE) in a 17 year-old female patient, who presented with ascites, edema and hypoalbuminemia. The diagnosis of SLE was based on the presence of: malar rash, oral ulcers, thrombocytopenia, antinuclear antibodies, IgM anticardiolipin antibody, and lupus anticoagulant. Renal and liver diseases were ruled out. The PLE diagnosis was confirmed with fecal alpha 1-antitrypsin clearance. The PLE was refractory to different lines of immunosuppressive agents like glucocorticoids, cyclophosphamide, azathioprine, and cyclosporine, showing a satisfactory and sustained response with rituximab, allowing steroid sparing and long term remission.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se presenta un caso de enteropatía perdedora de proteínas (EPP)como manifestación inicial del lupus eritematoso sistémico (LES). Se trata de una paciente de sexo femenino, de 17 años de edad, que consulta por síndrome ascítico edematoso e hipoalbuminemia. El diagnóstico de LES se estableció por la presencia de: rash malar, úlceras orales, trombocitopenia, anticuerpos antinucleares, anticardiolipinas IgM y anticoagulante lúpico positivos. Se descartó el compromiso renal y hepático como causa de hipoproteinemia. El diagnóstico de la pérdida enteral de proteínas se realizó con el Clearance de alfa 1 antitripsina. La EPP fue refractaria a distintas líneas de inmunosupresores, como corticoides, ciclofosfamida, azatioprina y ciclosporina, presentando respuesta satisfactoria y sostenida a rituximab, lo que posibilitó la reducción de corticoides y la remisión de la enfermedad por tiempo prolongado.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Sansinanea P, Carrica SA, Marcos J, García MA. Enteropatía perdedora de proteínas asociada a lupus eritematoso sistémico refractaria con buena respuesta a rituximab. Reumatol Clin. 2016;12:47–49.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A1AT: alpha-1 antitrypsin; AZA: azathioprine; CsA: cyclosporine; CY: cyclophosphamide; MMF: mycophenolate mofetil; MP: methylprednisolone pulse therapy; PD: prednisone; RTX: rituximab; TP: total proteins (normal range: 60–80<span class="elsevierStyleHsp" style=""></span>g/l).</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">At time of diagnosis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">MP<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>CY<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>AZA \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">MP<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>CY<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>CsA \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">CY<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MMF \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">5 months after 1st RTX infusion \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">2 years after 2nd RTX infusion \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">A1AT clearance (ml/24<span class="elsevierStyleHsp" style=""></span>h) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1040 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">177 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">400 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.03 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">TP (g/l) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Albumin (g/l) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">PD (mg/day) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab979992.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Changes in Laboratory Parameters and Treatment.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0085" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gastrointestinal and hepatic manifestations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D.S. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 3 | 10 |
| 2024 October | 89 | 32 | 121 |
| 2024 September | 81 | 16 | 97 |
| 2024 August | 127 | 37 | 164 |
| 2024 July | 112 | 43 | 155 |
| 2024 June | 87 | 34 | 121 |
| 2024 May | 94 | 36 | 130 |
| 2024 April | 73 | 23 | 96 |
| 2024 March | 87 | 33 | 120 |
| 2024 February | 61 | 30 | 91 |
| 2024 January | 53 | 20 | 73 |
| 2023 December | 63 | 29 | 92 |
| 2023 November | 74 | 35 | 109 |
| 2023 October | 73 | 32 | 105 |
| 2023 September | 111 | 46 | 157 |
| 2023 August | 60 | 22 | 82 |
| 2023 July | 74 | 33 | 107 |
| 2023 June | 75 | 24 | 99 |
| 2023 May | 75 | 29 | 104 |
| 2023 April | 60 | 14 | 74 |
| 2023 March | 76 | 30 | 106 |
| 2023 February | 79 | 38 | 117 |
| 2023 January | 97 | 67 | 164 |
| 2022 December | 82 | 28 | 110 |
| 2022 November | 85 | 46 | 131 |
| 2022 October | 63 | 29 | 92 |
| 2022 September | 58 | 71 | 129 |
| 2022 August | 71 | 58 | 129 |
| 2022 July | 73 | 47 | 120 |
| 2022 June | 75 | 30 | 105 |
| 2022 May | 82 | 38 | 120 |
| 2022 April | 68 | 46 | 114 |
| 2022 March | 99 | 60 | 159 |
| 2022 February | 68 | 34 | 102 |
| 2022 January | 77 | 50 | 127 |
| 2021 December | 54 | 44 | 98 |
| 2021 November | 83 | 43 | 126 |
| 2021 October | 100 | 63 | 163 |
| 2021 September | 69 | 47 | 116 |
| 2021 August | 34 | 34 | 68 |
| 2021 July | 51 | 25 | 76 |
| 2021 June | 48 | 32 | 80 |
| 2021 May | 44 | 55 | 99 |
| 2021 April | 155 | 73 | 228 |
| 2021 March | 83 | 34 | 117 |
| 2021 February | 75 | 38 | 113 |
| 2021 January | 59 | 20 | 79 |
| 2020 December | 68 | 28 | 96 |
| 2020 November | 66 | 32 | 98 |
| 2020 October | 77 | 21 | 98 |
| 2020 September | 85 | 35 | 120 |
| 2020 August | 67 | 38 | 105 |
| 2020 July | 48 | 29 | 77 |
| 2020 June | 42 | 23 | 65 |
| 2020 May | 42 | 32 | 74 |
| 2020 April | 20 | 21 | 41 |
| 2020 March | 11 | 7 | 18 |
| 2020 February | 1 | 0 | 1 |
| 2018 May | 4 | 0 | 4 |
| 2018 April | 56 | 17 | 73 |
| 2018 March | 59 | 16 | 75 |
| 2018 February | 44 | 9 | 53 |
| 2018 January | 35 | 8 | 43 |
| 2017 December | 33 | 3 | 36 |
| 2017 November | 45 | 5 | 50 |
| 2017 October | 32 | 9 | 41 |
| 2017 September | 27 | 14 | 41 |
| 2017 August | 25 | 8 | 33 |
| 2017 July | 30 | 26 | 56 |
| 2017 June | 49 | 17 | 66 |
| 2017 May | 59 | 12 | 71 |
| 2017 April | 45 | 9 | 54 |
| 2017 March | 29 | 8 | 37 |
| 2017 February | 25 | 13 | 38 |
| 2017 January | 17 | 12 | 29 |
| 2016 December | 67 | 24 | 91 |
| 2016 November | 63 | 32 | 95 |
| 2016 October | 70 | 29 | 99 |
| 2016 September | 69 | 11 | 80 |
| 2016 August | 60 | 11 | 71 |
| 2016 July | 44 | 9 | 53 |
| 2016 March | 1 | 0 | 1 |
| 2016 February | 3 | 45 | 48 |
| 2016 January | 1 | 21 | 22 |
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