Case report
Vanishing bile duct syndrome related to DILI and Hodgkin lymphoma overlap: A rare and severe case
Raquel D. Grecaa,
, Marlone Cunha-Silvaa, Larissa B.E. Costab, Júlia G.F. Costaa, Daniel F.C. Mazoa,c, Tiago Sevá-Pereiraa, Marlla M.C. Nascimentoa, Isadora E. Pereiraa, Flávia C. Oliveiraa, Guilherme A.S. Fariaa, Fernando L.P. Netoa, Jazon R.S. Almeidaa
Corresponding author
a Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
b Department of Pathology, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
c Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
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"documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2020;19:99-106" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 154 "formatos" => array:3 [ "EPUB" => 25 "HTML" => 90 "PDF" => 39 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "MicroRNA-125a-3p overexpression promotes liver regeneration through targeting proline-rich acidic protein 1" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "99" "paginaFinal" => "106" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1783 "Ancho" => 2508 "Tamanyo" => 200941 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">PRAP1 overexpression reversed the auxo-action of miR-125a-3p in the expressions of cell-cycle-associated genes. Several cell cycle-associated gene (cyclin D1, CDC25A, and CDK2) expressions were examined by qPCR and Western blot. (A and B) MiR-125a-3p overexpression could obviously increase their protein levels, but PRAP1 co-transfection partially reversed the upregulated protein levels of cyclin D1, CDC25A, and CDK2 by miR-125a-3p mimics. (C) The changes in mRNA levels of these three genes were consistent with their protein levels. Each value represents mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SEM (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3). β-Actin was considered as an internal control. *<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05 vs. Control group; <span class="elsevierStyleSup">#</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05 vs. Mimics groups.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Xiaolin Wei, Zhiqing Yang, Hui Liu, Tengqian Tang, Peng Jiang, Xiaowu Li, Xiangde Liu" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Xiaolin" "apellidos" => "Wei" ] 1 => array:2 [ "nombre" => "Zhiqing" "apellidos" => "Yang" ] 2 => array:2 [ "nombre" => "Hui" "apellidos" => "Liu" ] 3 => array:2 [ "nombre" => "Tengqian" "apellidos" => "Tang" ] 4 => array:2 [ "nombre" => "Peng" "apellidos" => "Jiang" ] 5 => array:2 [ "nombre" => "Xiaowu" "apellidos" => "Li" ] 6 => array:2 [ "nombre" => "Xiangde" "apellidos" => "Liu" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S166526811932229X?idApp=UINPBA00004N" "url" => "/16652681/0000001900000001/v2_202001221934/S166526811932229X/v2_202001221934/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Case report</span>" "titulo" => "Vanishing bile duct syndrome related to DILI and Hodgkin lymphoma overlap: A rare and severe case" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "107" "paginaFinal" => "112" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Raquel D. Greca, Marlone Cunha-Silva, Larissa B.E. Costa, Júlia G.F. Costa, Daniel F.C. Mazo, Tiago Sevá-Pereira, Marlla M.C. Nascimento, Isadora E. Pereira, Flávia C. Oliveira, Guilherme A.S. Faria, Fernando L.P. Neto, Jazon R.S. Almeida" "autores" => array:12 [ 0 => array:4 [ "nombre" => "Raquel D." "apellidos" => "Greca" "email" => array:2 [ 0 => "raqueldg@unicamp.br" 1 => "raquelgreca@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Marlone" "apellidos" => "Cunha-Silva" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Larissa B.E." 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"apellidos" => "Nascimento" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 7 => array:3 [ "nombre" => "Isadora E." "apellidos" => "Pereira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 8 => array:3 [ "nombre" => "Flávia C." "apellidos" => "Oliveira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 9 => array:3 [ "nombre" => "Guilherme A.S." "apellidos" => "Faria" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 10 => array:3 [ "nombre" => "Fernando L.P." "apellidos" => "Neto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 11 => array:3 [ "nombre" => "Jazon R.S." "apellidos" => "Almeida" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Pathology, University of Campinas (Unicamp), Campinas, São Paulo, Brazil" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1016 "Ancho" => 1305 "Tamanyo" => 122219 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Axial section thorax and abdomen computed tomography, with contrast in the arterial phase. (A) Splenomegaly and enlarged lymph node in aortic chain (white arrow). (B) Bilateral iliac chain. (C) Large lymph node next to the right bronchus measuring 4<span class="elsevierStyleHsp" style=""></span>cm.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Vanishing bile duct syndrome (VBDS) is a rare acquired condition, characterized by progressive loss of intrahepatic bile ducts, which is evidenced in liver biopsy, and leads to ductopenia and cholestasis <a class="elsevierStyleCrossRefs" href="#bib0110">[1,2]</a>. It represents 0.5% of the small biliary ducts diseases <a class="elsevierStyleCrossRef" href="#bib0120">[3]</a>, and is associated with infections, ischemia, drug adverse reactions, neoplasms, autoimmune disease, and allograft rejection. The prognosis is variable—from complete recovery to biliary cirrhosis, liver failure, and death <a class="elsevierStyleCrossRefs" href="#bib0115">[2,4,5]</a>. We describe an unusual case of VBDS related to Hodgkin lymphoma (HL) and a drug-induced liver injury (DILI) overlap.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0020">Case report</span><p id="par0010" class="elsevierStylePara elsevierViewall">A 25-year-old previously healthy Brazilian female was referred to our center after a hematemesis episode and a complaint of jaundice and intense pruritus. She had no recent trips or family history of liver diseases. The patient had been using manipulated drugs for 45 days, prescribed by an endocrinologist for weight loss and ketoprofen to relieve a dorsal pain. Many substances were in the formulation, such as southern field horsetail (<span class="elsevierStyleItalic">Equisetum arvense</span>), garcinia (<span class="elsevierStyleItalic">Garcinia cambogia</span>), bupropion, sertraline, safflower oil, green mate, sene, bearberry (<span class="elsevierStyleItalic">Arctostaphylos uva-ursi</span>), metformin, orlistat, common bean (<span class="elsevierStyleItalic">Phaseolus vulgaris</span>), devil's tongue (<span class="elsevierStyleItalic">Amorphophallus konjac</span>), dyed broccoli extract, yerba mate (<span class="elsevierStyleItalic">Ilex paraguariensis</span>) and ginger (<span class="elsevierStyleItalic">Kaempferia galanga</span>). She denied the use of alcoholic beverages or illicit drugs.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The initial physical examination revealed jaundice, reactive cervical lymph nodes (measuring nearly 1<span class="elsevierStyleHsp" style=""></span>cm) and tenderness on right hypochondrium palpation, without signs of peritonitis or organomegaly. Laboratory tests showed an increase in liver enzymes, such as aspartate aminotransferase 146<span class="elsevierStyleHsp" style=""></span>U/L (normal value [NV]<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>35) and alanine aminotransferase 199<span class="elsevierStyleHsp" style=""></span>U/L (NV<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>35), gamma-GT 1150<span class="elsevierStyleHsp" style=""></span>U/L (NV<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>64), alkaline phosphatase 1395<span class="elsevierStyleHsp" style=""></span>U/L (NV<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>120), total bilirubin 19.6<span class="elsevierStyleHsp" style=""></span>mg/dL (NV<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>1.2), direct bilirubin 14.0 (NV<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.2) and international normalized ratio 1.34 (NV<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>1.25). The hemogram showed normochromic and normocytic anemia (hemoglobin<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>9.3<span class="elsevierStyleHsp" style=""></span>g/dL), with decreased serum iron (25<span class="elsevierStyleHsp" style=""></span>μg/dL, [NV<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>60–180]) and a high platelet count (570,000/mm<span class="elsevierStyleSup">3</span>). Viral hepatitis serologies, plus anti-nuclear, anti-mitochondrial and anti-smooth muscle antibodies were negative. Ceruloplasmin was normal and protein electrophoresis only showed low serum albumin (2.46<span class="elsevierStyleHsp" style=""></span>g/dL [NV<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3.5–5.2]). Other infectious disease panels – including HIV, toxoplasmosis, mononucleosis, and blastomycosis – were negative.</p><p id="par0020" class="elsevierStylePara elsevierViewall">A digestive endoscopy revealed erosive and hemorrhagic pangastritis; an abdominal ultrasonography was unremarkable; and magnetic resonance cholangiography showed hepatomegaly with a transient perfusional disorder of the liver, reactive lymph node enlargement in the hepatic hilum (larger measuring 2.3<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>1.1<span class="elsevierStyleHsp" style=""></span>cm), without intra- and extrahepatic bile ducts dilatation. On suspicion of DILI, all potentially harmful substances were discontinued, and ursodeoxycholic acid was commenced. The patient's abdominal pain and pruritus had resolved, and there was a partial biochemical improvement (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>), so the patient was discharged from the hospital.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">At the outpatient follow-up, there was a new increase in bilirubin levels and canalicular enzymes. One month after hospital discharge, a percutaneous liver biopsy showed mild portal fibrosis, significant loss of intrahepatic bile ducts, and moderate to intense ductular reaction. Over the next 4 months, the patient presented weight loss (20<span class="elsevierStyleHsp" style=""></span>kg), night sweats, and intense pruritus. An unsuspected factor had worsened the cholestasis, and the cervical lymph nodes were enlarged. The thorax and abdomen computed tomography evidenced splenomegaly and wide lymph node conglomerates, which were more evident in the aortic, caval, colic, and iliac chains, and in the hepatic hilum (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Exeresis of the left cervical lymph node was performed and the histological analysis revealed a partially nodular growth pattern neoplasm, with fibrous bands, and an inflammatory background with lymphocytes, histiocytes, and some eosinophils, plus large multinucleated neoplastic cells with two mirror-image nuclei (Reed–Sternberg cells), which were positive for CD30 and CD15 on immunohistochemistry stains. This confirmed the diagnosis of nodular sclerosis—a subtype of classic HL (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). The bone marrow biopsy was negative for lymphoma involvement. The liver biopsy was reviewed, and the finding of loss of intrahepatic bile ducts (previously described) was compatible with VBDS, which was confirmed by using cytokeratin 19 on immunohistochemistry (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>). There was no lymphoma spread in the liver fragment.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The patient was started on prednisone 40<span class="elsevierStyleHsp" style=""></span>mg/day and completed six cycles of chemotherapy with Adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine. The first cycle was infused without doxorubicin and vinblastine; the remaining doses were full because of better liver function. The patient presented a slight clinical improvement and weight gain, but a poor response to chemotherapy (<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>), and is currently awaiting biological therapy with brentuximab, an anti-CD30 antibody drug.</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="par0035" class="elsevierStylePara elsevierViewall">VBDS is a rare group of disorders related to progressive destruction and disappearance of intrahepatic bile ducts leading to cholestasis <a class="elsevierStyleCrossRef" href="#bib0130">[5]</a>. The pathogenesis is poorly understood, but it has been associated with many conditions, including drug reactions, ischemia, infection, autoimmune disease, allograft rejection, and neoplasms <a class="elsevierStyleCrossRef" href="#bib0135">[6]</a>. The diagnosis is confirmed when less than 50% of bile ducts are seen on liver biopsy. This exam is fundamental and should not be postponed <a class="elsevierStyleCrossRef" href="#bib0130">[5]</a>.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The disorder has been associated with more than 40 drugs, including chlorpromazine, amoxicillin, carbamazepine, clindamycin, meropenem, ajmaline, phenytoin, trimethoprim–sulfamethoxazole, arsenic derivatives, and tetracyclines <a class="elsevierStyleCrossRefs" href="#bib0120">[3,7,8]</a>. Even though the pathogenesis of VBDS secondary to DILI has not been fully elucidated, multiple mechanisms have been proposed, including tumor necrosis factor-α-activated apoptosis, the inhibition of mitochondrial function, and neoantigen formation <a class="elsevierStyleCrossRef" href="#bib0140">[7]</a>. It is possible that an immune response, mainly mediated by T cells, leads to antigen recognition on biliary epithelial cells, resulting in immune cell infiltration into the intraepithelial layer of the bile ducts, apoptosis, and T-cell cytotoxicity <a class="elsevierStyleCrossRefs" href="#bib0120">[3,9]</a>. Sundaram and Björnsson described a prospective report from the DILI network, where 26 of 363 (7%) patients were reported to experience VBDS secondary to drug injury. The most frequently implicated agents were amoxicillin/clavulanate, temozolomide, herbal products, and azithromycin <a class="elsevierStyleCrossRef" href="#bib0120">[3]</a>.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Unfortunately, a major limitation in DILI diagnosis is the current lack of specific biomarkers <a class="elsevierStyleCrossRefs" href="#bib0120">[3,10]</a>. Several promising DILI biomarker candidates have been discovered, such as glutamate dehydrogenase, high-mobility group box 1 protein, and keratin-18. Furthermore, microRNAs have lately received attention as potential non-invasive DILI biomarkers, in particular miR-122 <a class="elsevierStyleCrossRef" href="#bib0155">[10]</a>. A thorough history is necessary regarding a timing relation between the beginning of the use of these medications (or vitamins and herbal supplements) and the appearance of the disease <a class="elsevierStyleCrossRef" href="#bib0120">[3]</a>. In fact, among all the medications ingested by our patient, field horsetail (<span class="elsevierStyleItalic">E. arvense</span>) <a class="elsevierStyleCrossRef" href="#bib0160">[11]</a>, garcinia (<span class="elsevierStyleItalic">G. cambogia</span>) <a class="elsevierStyleCrossRef" href="#bib0165">[12]</a>, bupropion <a class="elsevierStyleCrossRef" href="#bib0170">[13]</a>, sertraline <a class="elsevierStyleCrossRefs" href="#bib0175">[14,15]</a>, orlistat <a class="elsevierStyleCrossRef" href="#bib0185">[16]</a>, and ketoprofen <a class="elsevierStyleCrossRef" href="#bib0190">[17]</a> have been associated with DILI. And only sertraline has been associated with VBDS as well <a class="elsevierStyleCrossRef" href="#bib0180">[15]</a>.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The association of VBDS with HL is rare and poorly understood <a class="elsevierStyleCrossRef" href="#bib0110">[1]</a>. Hubscher et al. first described it in 1993 in three patients with intrahepatic cholestasis and ductopenia <a class="elsevierStyleCrossRef" href="#bib0195">[18]</a>. It may be a paraneoplastic phenomenon associated with HL, which is typically presented as jaundice, pruritus, and weight loss; this can even precede the diagnosis of lymphadenopathy <a class="elsevierStyleCrossRefs" href="#bib0115">[2,5]</a>, as seen in our patient. Despite the uncertain pathophysiology, the most common hypothesis to explain HL-related VBDS is an immune-mediated lesion of the bile epithelium, due to autoantibodies produced by the lymphoma or a T cell-mediated toxicity (or both), and direct damage to the bile duct by cytokines <a class="elsevierStyleCrossRefs" href="#bib0125">[4,5]</a>.</p><p id="par0055" class="elsevierStylePara elsevierViewall">VBDS treatment is based on the intervention of the underlying cause. The first step is to discontinue the offending agent (when present) as soon as possible, as it is critical to spontaneous recovery and is generally followed by clinical improvement <a class="elsevierStyleCrossRef" href="#bib0145">[8]</a>. Alternative causes of acute liver injury should be excluded, including alcohol consumption; viral, autoimmune, and ischemic hepatitis; and other metabolic liver diseases. All patients with jaundice should undergo abdominal ultrasound as a means of identifying evidence of extrahepatic biliary obstruction, with subsequent cross-sectional imaging (computed tomography or magnetic resonance imaging) as appropriate <a class="elsevierStyleCrossRef" href="#bib0140">[7]</a>.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Treatment of cholestasis and pruritus is necessary. The use of ursodeoxycholic acid and cholestyramine may benefit the patient's symptoms <a class="elsevierStyleCrossRefs" href="#bib0115">[2,3]</a>. Ursodeoxycholic acid protects the epithelium against cytotoxicity caused by toxic bile salts. It stimulates hepatobiliary secretion, has antioxidant activity, enhances glutathione levels, and inhibits liver cell apoptosis <a class="elsevierStyleCrossRef" href="#bib0120">[3]</a>. Other drugs that manage pruritus secondary to severe cholestasis include antihistamines, rifampicin, phenobarbital, and opioid analogs <a class="elsevierStyleCrossRefs" href="#bib0120">[3,5]</a>.</p><p id="par0065" class="elsevierStylePara elsevierViewall">When HL is the factor, treatment is challenging; however, the need for aggressive chemotherapy – which is limited by the degree of hepatic dysfunction and worsening cholestasis – should be balanced. The most commonly used regimen is Adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine; however, there is no consensus whether the dose of chemotherapy should be total or reduced <a class="elsevierStyleCrossRefs" href="#bib0130">[5,19,20]</a>. Radiotherapy has shown to improve liver-failure-free survival, and chemoradiation can be performed <a class="elsevierStyleCrossRef" href="#bib0115">[2]</a>.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Up to 30% of patients with HL in stage III or IV harbor refractory disease or relapse after frontline treatment with Adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine <a class="elsevierStyleCrossRef" href="#bib0205">[20]</a>. Autologous hematopoietic cell transplantation is an option for treatment, as described by Wong et al., where a 38-year-old man with HL-related VBDS achieved complete remission with normalization of serum bilirubin after eight cycles of Adriamycin/doxorubicin, bleomycin, vinblastine, and dacarbazine, followed by autologous hematopoietic cell transplantation. However, its long-term benefit requires further observation <a class="elsevierStyleCrossRef" href="#bib0125">[4]</a>. Brentuximab vedotin is an anti-CD30 monoclonal antibody with direct action to Reed–Sternberg cells in classic HL. It has been approved for treatment after autologous stem-cell transplantation failure, or after two or more chemotherapy regimens in patients who are not candidates for transplantation. The drug has also been approved as a post-transplantation consolidation therapy in patients with increased risk for relapse or progression of the neoplasm <a class="elsevierStyleCrossRef" href="#bib0205">[20]</a>.</p><p id="par0075" class="elsevierStylePara elsevierViewall">While hepatic failure is a major cause of mortality among patients with HL-related VBDS, many reported subjects had complete remission of the disease and improvement of hepatic function after lymphoma treatment. Some patients have significant liver dysfunction requiring liver transplantation; however, this remains controversial given the limited data and rarity of this syndrome <a class="elsevierStyleCrossRef" href="#bib0130">[5]</a>.</p><p id="par0080" class="elsevierStylePara elsevierViewall">The prognosis of VBDS is variable and depends on the etiological trigger of biliary epithelium apoptosis and the capacity for biliary regeneration. Various factors can influence the prognosis, including the severity of hepatic dysfunction, disease stage, performance status, comorbidities, history of ethanol consumption, pre-existing liver disease, and histologic features on the bile ducts <a class="elsevierStyleCrossRef" href="#bib0200">[19]</a>. Ballonoff et al. reported that one-third of patients could have a reversible disease course <a class="elsevierStyleCrossRef" href="#bib0210">[21]</a>, although it is often progressive, leading to prolonged bile duct loss, biliary cirrhosis, liver failure, and death <a class="elsevierStyleCrossRefs" href="#bib0115">[2,3,19]</a>. In a study from the DILI network cohort, approximately 19% of liver-related mortality was observed among patients with bile duct loss, either as the primary or the contributing cause of death <a class="elsevierStyleCrossRef" href="#bib0120">[3]</a>. This mortality rate is numerically greater than the 6.2% overall mortality seen in a recently published report of 899 DILI patients, in which half of the deaths were ultimately liver related, thus underscoring the seriousness of VBDS compared to other presentations of DILI <a class="elsevierStyleCrossRef" href="#bib0120">[3]</a>.</p><p id="par0085" class="elsevierStylePara elsevierViewall">To our knowledge, this is the first case reporting VBDS related to HL and DILI overlap. It is not possible to define whether both conditions were involved or if one of them was the trigger and the other was just a confounding factor. There may have been a higher susceptibility to DILI in the setting of lymphoma, and the large number of toxic drugs found a proper scenario to induce VBDS. It is crucial for physicians to create a broad differential diagnosis in suspected VBDS patients, especially to rule out malignancies.<span class="elsevierStyleDefList"><span class="elsevierStyleSectionTitle" id="sect0030">Abbreviations</span><span class="elsevierStyleDefTerm">VBDS</span><span class="elsevierStyleDefDescription"><p id="par0090" class="elsevierStylePara elsevierViewall">vanishing bile duct syndrome</p></span><span class="elsevierStyleDefTerm">DILI</span><span class="elsevierStyleDefDescription"><p id="par0095" class="elsevierStylePara elsevierViewall">drug-induced liver injury</p></span><span class="elsevierStyleDefTerm">HL</span><span class="elsevierStyleDefDescription"><p id="par0100" class="elsevierStylePara elsevierViewall">Hodgkin lymphoma</p></span><span class="elsevierStyleDefTerm">AST</span><span class="elsevierStyleDefDescription"><p id="par0105" class="elsevierStylePara elsevierViewall">aspartate aminotransferase</p></span><span class="elsevierStyleDefTerm">NV</span><span class="elsevierStyleDefDescription"><p id="par0110" class="elsevierStylePara elsevierViewall">normal value</p></span><span class="elsevierStyleDefTerm">ALP</span><span class="elsevierStyleDefDescription"><p id="par0115" class="elsevierStylePara elsevierViewall">alkaline phosphatase</p></span><span class="elsevierStyleDefTerm">GGT</span><span class="elsevierStyleDefDescription"><p id="par0120" class="elsevierStylePara elsevierViewall">gamma-glutamyl transferase</p></span><span class="elsevierStyleDefTerm">INR</span><span class="elsevierStyleDefDescription"><p id="par0125" class="elsevierStylePara elsevierViewall">international normalized ratio</p></span><span class="elsevierStyleDefTerm">HIV</span><span class="elsevierStyleDefDescription"><p id="par0130" class="elsevierStylePara elsevierViewall">human immunodeficiency virus</p></span><span class="elsevierStyleDefTerm">CD</span><span class="elsevierStyleDefDescription"><p id="par0135" class="elsevierStylePara elsevierViewall">cluster of differentiation</p></span><span class="elsevierStyleDefTerm">ABVD</span><span class="elsevierStyleDefDescription"><p id="par0140" class="elsevierStylePara elsevierViewall">Adriamycin/doxorubicin, bleomycin vinblastine and dacarbazine</p></span><span class="elsevierStyleDefTerm">TNF</span><span class="elsevierStyleDefDescription"><p id="par0145" class="elsevierStylePara elsevierViewall">tumor necrosis factor</p></span><span class="elsevierStyleDefTerm">RNA</span><span class="elsevierStyleDefDescription"><p id="par0150" class="elsevierStylePara elsevierViewall">ribonucleic acid</p></span><span class="elsevierStyleDefTerm">RS</span><span class="elsevierStyleDefDescription"><p id="par0155" class="elsevierStylePara elsevierViewall">Reed–Sternberg</p></span><span class="elsevierStyleDefTerm">PET/CT</span><span class="elsevierStyleDefDescription"><p id="par0160" class="elsevierStylePara elsevierViewall">positron emission tomography/computed tomography</p></span></span></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Authors’ contributions</span><p id="par0165" class="elsevierStylePara elsevierViewall">R.D.G., M.C.S. and J.G.C. contributed substantially to the conception and design of the study, and drafting of manuscript. L.B.E.C. performed the histological examination of the liver and was a major contributor in writing the manuscript. D.F.C.M.; T.S.P. and J.R.S.A. provided critical revision of the article and final approval of the version to be published. M.M.C.N.; I.E.P.; F.C.O.; G.A.S.F. and F.L.P.N. contributed substantially to the acquisition, analysis and interpretation of data.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Ethical approval</span><p id="par0170" class="elsevierStylePara elsevierViewall">The study was approved by the hospital ethics committee at the University of Campinas and written informed consent was obtained from the patient.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Funding</span><p id="par0175" class="elsevierStylePara elsevierViewall">The authors received no specific funding for this work.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflict of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors have declared that no competing interests exist.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1289619" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1191501" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:2 [ "identificador" => "sec0010" "titulo" => "Case report" ] 4 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 5 => array:2 [ "identificador" => "sec0020" "titulo" => "Authors’ contributions" ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Ethical approval" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Funding" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-02-22" "fechaAceptado" => "2019-06-10" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1191501" "palabras" => array:5 [ 0 => "Cholestasis" 1 => "Adverse drug reaction" 2 => "Bile duct disease" 3 => "Lymphoproliferative disease" 4 => "Drug induced liver injury" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Vanishing bile duct syndrome is a rare acquired condition, characterized by progressive loss of intrahepatic bile ducts leading to ductopenia and cholestasis. It can be associated with infections, ischemia, drug adverse reactions, neoplasms, autoimmune disease, and allograft rejection. Prognosis is variable and depends on the etiology of bile duct injury. We report the case of a 25-year-old female with cholestatic hepatitis and concomitant intakes of hepatotoxic substances, such as garcinia, field horsetail, and ketoprofen. On suspicion of a drug-induced liver injury, the drugs were promptly withdrawn and ursodeoxycholic acid was started with initial clinical and laboratory improvement, and the patient was discharged from the hospital. One month later, she had a new increase in bilirubin levels and canalicular enzymes, requiring a liver biopsy that showed significant loss of intrahepatic bile ducts, which was compatible with vanishing bile duct syndrome. This was confirmed by using cytokeratin 19 on immunohistochemistry. There was subsequent lymph node enlargement in several chains, and relevant weight loss. Histological analysis of a cervical lymph node revealed nodular sclerosis-subtype classic Hodgkin lymphoma. In this setting, vanishing bile duct syndrome was related to Hodgkin lymphoma and a drug-induced liver injury overlap, leading to progressive cholestasis with a worse prognosis. The patient's response to chemotherapy was poor, requiring biological therapy with brentuximab vedotin. It is crucial for physicians to create a broad differential diagnosis in suspected vanishing bile duct syndrome patients, especially to rule out malignancies.</p></span>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1039 "Ancho" => 2082 "Tamanyo" => 118831 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Range of aminotransferases and total bilirubin during the course of the disease. ALT: alanine aminotransferase; AST: aspartate aminotransferase; Bil: total bilirubin.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1110 "Ancho" => 2167 "Tamanyo" => 98940 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Range of canalicular enzymes during the course of the disease. ALP: alkaline phosphatase; GGT: gamma-glutamyl transpeptidase.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1016 "Ancho" => 1305 "Tamanyo" => 122219 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Axial section thorax and abdomen computed tomography, with contrast in the arterial phase. (A) Splenomegaly and enlarged lymph node in aortic chain (white arrow). (B) Bilateral iliac chain. (C) Large lymph node next to the right bronchus measuring 4<span class="elsevierStyleHsp" style=""></span>cm.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1865 "Ancho" => 950 "Tamanyo" => 519262 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Lymph node biopsy. (A) Reed–Sternberg cells (arrows) are seen in a cellular background rich in lymphocytes, histiocytes, and some eosinophils. (B) The typical membrane and paranuclear dot-like staining of Reed–Sternberg cells for CD15 on immunohistochemistry. (C) These cells were also positive for CD30.</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1876 "Ancho" => 955 "Tamanyo" => 587345 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Liver biopsy. (A) Masson trichrome stain shows moderate portal fibrosis without septa. (B) The portal areas show a relatively mild lymphocytic infiltrate with prominent ductular reaction and cholestasis (pseudoxanthomatous change, arrow). (C) Cytokeratin 19 stain was used to identify the remaining ducts (arrow); they were positive in ductular reaction (arrowhead). The sample showed 10 portal tracts, of which 6 did not exhibit bile ducts, corroborating the diagnosis of loss of intrahepatic original ducts.</p>" ] ] 5 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Fig. 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 949 "Ancho" => 1255 "Tamanyo" => 99816 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Positron emission tomography/computed tomography. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 15 | 5 | 20 |
| 2024 October | 232 | 8 | 240 |
| 2024 September | 212 | 11 | 223 |
| 2024 August | 192 | 9 | 201 |
| 2024 July | 247 | 8 | 255 |
| 2024 June | 199 | 13 | 212 |
| 2024 May | 202 | 4 | 206 |
| 2024 April | 228 | 16 | 244 |
| 2024 March | 292 | 8 | 300 |
| 2024 February | 297 | 13 | 310 |
| 2024 January | 304 | 21 | 325 |
| 2023 December | 256 | 11 | 267 |
| 2023 November | 232 | 21 | 253 |
| 2023 October | 284 | 15 | 299 |
| 2023 September | 231 | 12 | 243 |
| 2023 August | 143 | 25 | 168 |
| 2023 July | 109 | 6 | 115 |
| 2023 June | 171 | 3 | 174 |
| 2023 May | 185 | 6 | 191 |
| 2023 April | 175 | 26 | 201 |
| 2023 March | 166 | 5 | 171 |
| 2023 February | 129 | 11 | 140 |
| 2023 January | 123 | 10 | 133 |
| 2022 December | 124 | 13 | 137 |
| 2022 November | 175 | 11 | 186 |
| 2022 October | 181 | 13 | 194 |
| 2022 September | 126 | 16 | 142 |
| 2022 August | 156 | 15 | 171 |
| 2022 July | 127 | 16 | 143 |
| 2022 June | 128 | 18 | 146 |
| 2022 May | 139 | 17 | 156 |
| 2022 April | 100 | 25 | 125 |
| 2022 March | 143 | 19 | 162 |
| 2022 February | 135 | 17 | 152 |
| 2022 January | 143 | 13 | 156 |
| 2021 December | 92 | 13 | 105 |
| 2021 November | 146 | 29 | 175 |
| 2021 October | 174 | 29 | 203 |
| 2021 September | 151 | 32 | 183 |
| 2021 August | 109 | 12 | 121 |
| 2021 July | 148 | 20 | 168 |
| 2021 June | 136 | 23 | 159 |
| 2021 May | 142 | 11 | 153 |
| 2021 April | 434 | 38 | 472 |
| 2021 March | 256 | 19 | 275 |
| 2021 February | 119 | 22 | 141 |
| 2021 January | 103 | 20 | 123 |
| 2020 December | 100 | 12 | 112 |
| 2020 November | 112 | 15 | 127 |
| 2020 October | 108 | 18 | 126 |
| 2020 September | 94 | 23 | 117 |
| 2020 August | 77 | 15 | 92 |
| 2020 July | 76 | 18 | 94 |
| 2020 June | 48 | 16 | 64 |
| 2020 May | 66 | 21 | 87 |
| 2020 April | 71 | 12 | 83 |
| 2020 March | 79 | 19 | 98 |
| 2020 February | 146 | 18 | 164 |
| 2020 January | 85 | 10 | 95 |
| 2019 December | 32 | 9 | 41 |
| 2019 November | 35 | 2 | 37 |
| 2019 October | 4 | 8 | 12 |
| 2019 September | 0 | 26 | 26 |
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