Benign recurrent intrahepatic cholestasis: late initial diagnosis in adulthood
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Erb, Eric M. Yoshida" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Maznar" "apellidos" => "Haque" ] 1 => array:2 [ "nombre" => "Almoutaz" "apellidos" => "Hashim" ] 2 => array:2 [ "nombre" => "Erica D." "apellidos" => "Greanya" ] 3 => array:2 [ "nombre" => "Urs P." "apellidos" => "Steinbrecher" ] 4 => array:2 [ "nombre" => "Siegfried R." "apellidos" => "Erb" ] 5 => array:2 [ "nombre" => "Eric M." "apellidos" => "Yoshida" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119316643?idApp=UINPBA00004N" "url" => "/16652681/0000000900000002/v1_201907070740/S1665268119316643/v1_201907070740/en/main.assets" ] "en" => array:16 [ "idiomaDefecto" => true "titulo" => "Benign recurrent intrahepatic cholestasis: late initial diagnosis in adulthood" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "207" "paginaFinal" => "210" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Fatih Ermis, Kemal Oncu, Melih Ozel, Yusuf Yazgan, Ahmet Kemal Gurbuz, Levent Demirturk, Hakan Demirci, Taner Akyol, Aptullah Hahoglu" "autores" => array:9 [ 0 => array:5 [ "preGrado" => "MD" "nombre" => "Fatih" "apellidos" => "Ermis" "email" => array:1 [ 0 => "fatihermis2@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor1" ] ] ] 1 => array:3 [ "nombre" => "Kemal" "apellidos" => "Oncu" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] ] ] 2 => array:3 [ "nombre" => "Melih" "apellidos" => "Ozel" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] ] ] 3 => array:3 [ "nombre" => "Yusuf" "apellidos" => "Yazgan" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] ] ] 4 => array:3 [ "nombre" => "Ahmet" "apellidos" => "Kemal Gurbuz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] ] ] 5 => array:3 [ "nombre" => "Levent" "apellidos" => "Demirturk" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] ] ] 6 => array:3 [ "nombre" => "Hakan" "apellidos" => "Demirci" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] ] ] 7 => array:3 [ "nombre" => "Taner" "apellidos" => "Akyol" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] ] ] 8 => array:3 [ "nombre" => "Aptullah" "apellidos" => "Hahoglu" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">**</span>" "identificador" => "aff2" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Gastroenterology, Gulhane Military Medical Academy, Haydarpasa Training Hospital, Istanbul, Turkey" "etiqueta" => "*" "identificador" => "aff1" ] 1 => array:3 [ "entidad" => "Department of Pathology, Gulhane Military Medical Academy, Haydarpasa Training Hospital, Istanbul, Turkey" "etiqueta" => "**" "identificador" => "aff2" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Correspondence and reprint request:" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 763 "Ancho" => 997 "Tamanyo" => 119287 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Histologic appearence of the liver biopsy. Portal tracts and hepatic cords are preserved (H&E, ×200).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive or sporadic disorder characterized by recurrent episodes of intense pruritus and jaundice that resolve spontaneously without leaving considerable liver damage. The onset of the disease may be at any age, but it usually starts in the first decade, 80% of cases shows up before the age of 20. Each attack lasts from weeks to months before resolving spontaneously. Patients are completely asymptomatic for months to years between symptomatic periods. BRIC diagnosis can be only confirmed after exclusion of other possible congenital or acquired causes of intrahepatic cholestasis according to the recurrent character of the jaundice with hepatic biopsy.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Case Report</span><p id="p0010" class="elsevierStylePara elsevierViewall">A 23-year-old man was referred to emergency department of our hospital complaining of obvious jaundice and itching. He also suffered malaise, dark urine and intermittent pale stools. He recalled that his symptoms developed after an episode of upper respiratory tract infection. When he was 11 and 17 years old, he had two more self remitting jaundice attacks which lasted approximately 2 months. He had been initially diagnosed as infectious hepatitis at these occasions without an extensive investigation. There was no family history of liver disease. There was no history of ingestion of toxins or any other drugs, either. On physical examination he was icteric and he had diffuse excoriations all around in his body caused by severe itching. He had neither hepatomegaly nor splenomegaly. There were no signs of cirrhosis in the form of spider angiomas, palmar erythema or thenar atrophy. Laboratory examination revealed a sedimentation rate of 17 mm/hour, a white blood cell count of 8.4 x 10<span class="elsevierStyleSup">3</span>/<span class="elsevierStyleItalic">μ</span>L, a hemoglobin of 13.8 g/dL, a hematocrit of 41.7% and a platelet count of 318 x 10<span class="elsevierStyleSup">3</span>/<span class="elsevierStyleItalic">μ</span>L with a normal smear. Total bilirubin was 29.6 mg/dL with a direct component of 24.6 mg/dL. Serum total bile acids (TBA) concentration was 735 <span class="elsevierStyleItalic">μ</span>mol/L (< 15 <span class="elsevierStyleItalic">μ</span>mol/L). Liver enzymes were increased as 2 folds of upper normal limits, alanine aminotransferase (ALT) was 92 IU/L (5-40), aspartate aminofransferase (AST) was 104 IU/L (5-40). Alkaline phosphatase (ALP) was elevated with a value of 331 IU/L (35-125), gamma glutamyl transpeptidase (GGT) was within normal limits, 29 IU/L (10-45). His coagulation parameters at admission include a prothrombin time of 12.8 s, an international normalized ratio of 1.03, and a partial thromboplastin time of 33.1 s. The patient’s blood urea nitrogen, creatinine. serum electrolytes, cholesterol, calcium, phosphorus, uric acid, thyroid stimulating hormone, free thyroxine and free triiodothyronine were all normal. Serologic tests for viral hepatitis (HAV, HBV, and HCV), adenovirus, cytomegalovirus and Ebstein-Barr virus were all negative. He was also negative for anti-nuclear antibody, anti-mitochondrial antibody, anti-smooth muscle antibody and anti-liver kidney microsome-1 antibody. The diagnosis of Wilson disease, α1-anti-trypsin deficiency were excluded by normal plasma levels of copper, ceruloplasmin, and α1-antitrypsin. The liver appeared normal on ultrasonography with non dilated intrahepatic and extrahepatic bile ducts. There were neither gallstones nor intrahepatic or extrahepatic bile duct obstruction. Spleen was in normal size and there was no ascites or another abdominal abnormality. Bile ducts were also normal on magnetic resonance cholangiography. Since his bilirubin levels were persistently high, a liver biopsy was performed for further investigation. Tru-cut biopsy of the liver showed normal portal tracts and intact sinusoidal patern of hepatic cords (<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>) and revealed intracellular and canalicular cholestasis with some ballooning of heptocytes. Mild inflammatory cell infiltrates in occasional portal tracts and a few foci of parenchymal inflammation were also seen. There was no evidence of portal tract fibrosis or ductopenia. There were no Mallory or Councilman bodies, no siderosis and no steatosis (<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>).</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0015" class="elsevierStylePara elsevierViewall">Laboratory and pathology findings made it possible to exclude congenital or acquired causes of intrahepatic cholestasis for us and when the relapsing and benign feature of the disease was taken into account a diagnosis of “benign recurrent intrahepatic cholestasis” was made. We also looked for DNA analysis to verify our diagnosis and to find out the BRIC type. Our patient was homozygous for the IVS 26 + 2 T > A mutation in ATP8B1. In the course of the disease ursodeoxycholic acid 500 mg q.i.d, cholestyramine 4 g t.i.d and an antihistaminic tablet was commenced as a first line therapy. A 10-days ursodeoxycholic acid and cholestyramine treatment in adequate doses seemed to have no biochemical and clinic response. Then both of the drugs were ceased and rifampicin in a dose of 300 mg per day was commenced. Rifampicin treatment was accompanied with improvement of symptoms. Four weeks after initial rifampicin dosage laboratory findings changed as follows: total bilirubin was 3.4 mg/dL with a direct component of 2.8 mg/dL, TBA was 312 <span class="elsevierStyleItalic">μ</span>mol/L, ALP was 185, AST was 26 IU/L, ALT was 25 IU/L. Eight weeks later, the patient was free of symptoms with all normal laboratory findings (<a class="elsevierStyleCrossRef" href="#t0005">Table 1</a>). He is on regular follow up for 10 months and has not suffered another attack.</p><elsevierMultimedia ident="t0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="p0020" class="elsevierStylePara elsevierViewall">BRIC is a rare autosomal recessively inherited or sporadic liver disease that is characterized by intermittent attacks of cholestasis. It was first described by Summerskill and Walshe in 1959.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Cholestatic attacks can last for several weeks to months. Symptom-free intervals can lead from several months to years. Liver biopsies are characterized by intrahepatic cholestasis with preservation of normal liver structure. There is no progression to liver cirrhosis.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Although attacks seem to be associated with a viral prodrome, an inciting viral agent or toxin has not been defined.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Mutations in a single gene, FIC1 (recently renamed ATP8B1) were found to be responsible for this disease in most families described to date,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> although genetic heterogeneity is present.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Recently BRIC type 2 (BRIC 2) caused by another mutational change in ABCB11 gene has been demonstrated.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> In comparison to patients with ATP8B1 mutations, patients with ABCB11 mutations lack extrahepatic symptoms such as pancreatitis and are more likely to exhibit cholestasis.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">The attacks can start at any age, but the first attack is usually seen before the second decade of life. In a large series of patients the age of presentation varied from 1 to 59 years and duration of icteric phase was also variable lasting from weeks to months.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In our patient, the first attack was seen at age 11 followed by another one when he was 17. Each episode lasted approximately for 2 months. He had been initially diagnosed as infectious hepatitis, but there are no documented causative agents in his history. It is most probable that the physician in charge at those occasions suspected an undetermined viral agent as the cause of the disease, without laboratory evidence.</p><p id="p0030" class="elsevierStylePara elsevierViewall">In such cases, during icteric phase serum bilirubin, bile acids and ALP levels are elevated but GGT is characteristically low or normal. Occasionally ALT and AST levels may be markedly elevated but usually there is only a mild elevation.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In our patient, ALT and AST levels increased 2 times of upper normal limits and the clinical presentation, laboratory characteristics and the course of the disease were consistent with the diagnosis of sporadic BRIC. The pathologic findings in his liver biopsy were typical of this entity, as well. We also verified our diagnosis with mutational analysis and concluded as BRIC type 1.</p><p id="p0035" class="elsevierStylePara elsevierViewall">To date no effective medical intervention to interrupt the cholestatic attacks in BRIC is available. Several treatment modalities have been described, such as cholestyramine, ursodeoxycholic acid.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> However these interventions did not have a consistent effect on terminating cholestatic attack in our patient. Finally, rifampicin completely stopped the cholestatic episode in our patient. There are some reports that show beneficial role of rifampicin in remission of cholestasis. Rifampicin competes with bile acids for hepatic uptake, thereby lowering hepatocyte bile salt concentration.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Rifampicin also promotes the elimination of bile salts by inducing the 6-hydroxylation of secondary bile salts, this intervention warrants further investigation.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> When medical therapy is not effective to interrupt the cholestatic attacks partial biliary diversion and nasobiliary drainage may be employed successfully. Partial biliary diversion is less advisable because of its permanent character in an episodic disease. Temporal endoscopic biliary diversion with nasobiliary drainage has also been shown effective in interrupting attacks in BRIC patients, recently.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="p0040" class="elsevierStylePara elsevierViewall">In the present case, rifampicin treatment provided laboratory improvement and symptomatic relief with resolution of jaundice and pruritus. Our patient made an uneventful recovery within 8 weeks. He is on regular follow up for 10 months and has not suffered another attack.</p><p id="p0045" class="elsevierStylePara elsevierViewall">We report here a case of BRIC initially diagnosed in adulthood, whose two previous attacks were undiagnosed in local hospitals. Although in adulthood, BRIC diagnosis should be kept in mind in patients with recurrent cholestatic attacks with symptom free intervals after main bile duct obstruction and other congenital or acquired causes of intrahepatic cholestasis excluded.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:6 [ 0 => array:3 [ "identificador" => "xres1217538" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abs0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1132919" "titulo" => "Key words" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:2 [ "identificador" => "sec0010" "titulo" => "Case Report" ] 4 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 5 => array:1 [ "titulo" => "Reference" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Key words" "identificador" => "xpalclavsec1132919" "palabras" => array:3 [ 0 => "Benign recurrent intrahepatic cholestasis" 1 => "Adulthood" 2 => "Rifampicin" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abs0005" class="elsevierStyleSection elsevierViewall"><p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive or sporadic disorder, characterized by recurrent episodes of intense pruritus and jaundice that resolve spontaneously without leaving considerable liver damage. The attacks can start at any age, but the first attack is usually seen before the second decade of life. We report the case of a young adult male patient with BRIC who presented with recurrent cholestatic jaundice and pruritus with negative work up for all possible etiologies and a liver biopsy consistent with intrahepatic cholestasis. He improved on treatment with rifampicin and has not suffered another attack on follow up. Although in adulthood, BRIC diagnosis should be kept in mind in patients with recurrent cholestatic attacks with symptom free intervals after main bile duct obstruction and other congenital or acquired causes of intrahepatic cholestasis excluded.</p></span>" ] ] "NotaPie" => array:4 [ 0 => array:3 [ "etiqueta" => "*" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Baseline laboratory results, ursodeoxycholic acid and cholestyramine treatment commenced.</p>" "identificador" => "fn0005" ] 1 => array:3 [ "etiqueta" => "<span class="elsevierStyleSup">†</span>" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Ursodeoxycholic acid and cholestyramine treatment ceased, rifampicin treatment commenced.</p>" "identificador" => "fn0010" ] 2 => array:3 [ "etiqueta" => "<span class="elsevierStyleSup">‡</span>" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">4<span class="elsevierStyleSup">th</span> week of rifampicin treatment.</p>" "identificador" => "fn0015" ] 3 => array:3 [ "etiqueta" => "<span class="elsevierStyleSup">§</span>" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">8<span class="elsevierStyleSup">th</span> week of rifampicin treatment.</p>" "identificador" => "fn0020" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 763 "Ancho" => 997 "Tamanyo" => 119287 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Histologic appearence of the liver biopsy. Portal tracts and hepatic cords are preserved (H&E, ×200).</p>" ] ] 1 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 705 "Ancho" => 1001 "Tamanyo" => 144745 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">In some areas, intracytoplasmic and intracanaliculer bile deposition is prominent. Focal inflammatory cells were also discernible (H&E, ×400).</p>" ] ] 2 => array:7 [ "identificador" => "t0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="npara0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleFootnote" id="fn0005"><span class="elsevierStyleLabel">*</span><p class="elsevierStyleNotepara" id="npar0005">Baseline laboratory results, ursodeoxycholic acid and cholestyramine treatment commenced.</p></span><span class="elsevierStyleFootnote" id="fn0010"><span class="elsevierStyleLabel"><span class="elsevierStyleSup">†</span></span><p class="elsevierStyleNotepara" id="npar0015">Ursodeoxycholic acid and cholestyramine treatment ceased, rifampicin treatment commenced.</p></span><span class="elsevierStyleFootnote" id="fn0015"><span class="elsevierStyleLabel"><span class="elsevierStyleSup">‡</span></span><p class="elsevierStyleNotepara" id="npar0020">4<span class="elsevierStyleSup">th</span> week of rifampicin treatment.</p></span><span class="elsevierStyleFootnote" id="fn0020"><span class="elsevierStyleLabel"><span class="elsevierStyleSup">§</span></span><p class="elsevierStyleNotepara" id="npar0025">8<span class="elsevierStyleSup">th</span> week of rifampicin treatment.</p></span></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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="middle" scope="col">Status \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="middle" scope="col">Baseline laboratory<a class="elsevierStyleCrossRef" href="#fn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="middle" scope="col">Ursodeoxycholic acid<a class="elsevierStyleCrossRef" href="#fn0010"><span class="elsevierStyleSup">†</span></a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="middle" scope="col">4<span class="elsevierStyleSup">th</span> week<a class="elsevierStyleCrossRef" href="#fn0015"><span class="elsevierStyleSup">‡</span></a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="middle" scope="col">8<span class="elsevierStyleSup">th</span> week<a class="elsevierStyleCrossRef" href="#fn0020"><span class="elsevierStyleSup">§</span></a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">Date \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">30 May 2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">10 April 2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">11 May 2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">12 June 2009 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">Total bilirubin (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">29.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">28.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">3.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">0.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">Direct bilirubin (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">24.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">23.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">2.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">0.3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">Serum total bile acids (μmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">735 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">705 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">312 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">ALP (IU/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">331 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">325 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">185 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">110 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">GGT (IU/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">27 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">AST (IU/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">104 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">110 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">23 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">ALT (IU/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">92 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="middle">27 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2078595.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Laboratory findings of the patient during the course of treatment.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "Reference" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:19 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 10 | 1 | 11 |
| 2024 October | 308 | 10 | 318 |
| 2024 September | 326 | 13 | 339 |
| 2024 August | 320 | 31 | 351 |
| 2024 July | 418 | 35 | 453 |
| 2024 June | 222 | 4 | 226 |
| 2024 May | 279 | 6 | 285 |
| 2024 April | 228 | 9 | 237 |
| 2024 March | 293 | 21 | 314 |
| 2024 February | 341 | 26 | 367 |
| 2024 January | 325 | 29 | 354 |
| 2023 December | 250 | 25 | 275 |
| 2023 November | 218 | 25 | 243 |
| 2023 October | 195 | 19 | 214 |
| 2023 September | 204 | 18 | 222 |
| 2023 August | 186 | 11 | 197 |
| 2023 July | 119 | 23 | 142 |
| 2023 June | 188 | 14 | 202 |
| 2023 May | 189 | 21 | 210 |
| 2023 April | 210 | 7 | 217 |
| 2023 March | 160 | 12 | 172 |
| 2023 February | 154 | 16 | 170 |
| 2023 January | 105 | 11 | 116 |
| 2022 December | 130 | 11 | 141 |
| 2022 November | 116 | 12 | 128 |
| 2022 October | 104 | 9 | 113 |
| 2022 September | 109 | 10 | 119 |
| 2022 August | 122 | 21 | 143 |
| 2022 July | 126 | 21 | 147 |
| 2022 June | 71 | 9 | 80 |
| 2022 May | 116 | 14 | 130 |
| 2022 April | 126 | 24 | 150 |
| 2022 March | 117 | 25 | 142 |
| 2022 February | 146 | 15 | 161 |
| 2022 January | 139 | 17 | 156 |
| 2021 December | 126 | 37 | 163 |
| 2021 November | 131 | 14 | 145 |
| 2021 October | 132 | 23 | 155 |
| 2021 September | 136 | 28 | 164 |
| 2021 August | 156 | 33 | 189 |
| 2021 July | 141 | 15 | 156 |
| 2021 June | 117 | 15 | 132 |
| 2021 May | 151 | 11 | 162 |
| 2021 April | 462 | 66 | 528 |
| 2021 March | 264 | 20 | 284 |
| 2021 February | 154 | 12 | 166 |
| 2021 January | 108 | 9 | 117 |
| 2020 December | 130 | 17 | 147 |
| 2020 November | 83 | 12 | 95 |
| 2020 October | 42 | 3 | 45 |
| 2020 September | 75 | 10 | 85 |
| 2020 August | 45 | 4 | 49 |
| 2020 July | 27 | 6 | 33 |
| 2020 June | 38 | 9 | 47 |
| 2020 May | 27 | 5 | 32 |
| 2020 April | 16 | 5 | 21 |
| 2020 March | 16 | 1 | 17 |
| 2020 February | 16 | 2 | 18 |
| 2020 January | 5 | 5 | 10 |
| 2019 December | 8 | 3 | 11 |
| 2019 November | 10 | 2 | 12 |
| 2019 October | 5 | 0 | 5 |
| 2019 September | 3 | 3 | 6 |
| 2019 August | 2 | 4 | 6 |
| 2019 July | 1 | 9 | 10 |
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