Letter to the Editor
Alagille syndrome and hepatocellular carcinoma in a non-cirrhotic adult
Síndrome de Alagille y carcinoma hepatocelular en adulto no cirrótico
Juan Antonio Vázquez Rodríguez
, Carmen Molina Villalba, Matías Estévez Escobar
Corresponding author
UGC Aparato Digestivo, Hospital de Poniente, El Ejido, Almería, Spain
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This gene is essential in cell development, and is expressed in different organs, causing liver, cardiovascular, kidney, eye and bone involvement.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It is usually diagnosed in childhood as a result of intrahepatic cholestasis secondary to ductopenia and has a benign course; the development of cirrhosis and hepatocellular carcinoma (HCC) is rare.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> The development of extrahepatic metastases is relatively common in this tumour and peritoneal involvement is rare.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Treatment of intra- and extrahepatic recurrence is surgical and, in non-resectable cases, systemic treatment with sorafenib is an alternative.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3–5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We report a case of Alagille syndrome with development of hepatocellular carcinoma in non-cirrhotic liver, which was treated with initial curative resection and subsequent treatment with sorafenib due to early development of unresectable peritoneal recurrence.</p><p id="par0015" class="elsevierStylePara elsevierViewall">This is a 47-year-old male diagnosed with Alagille syndrome at the age of 12 according to clinical criteria (arteriohepatic dysplasia, pulmonary artery stenosis, “butterfly” vertebrae, chronic cholestasis) and family history (father and 2 siblings with genetic diagnosis). An increase in cholestasis was observed during progression (GGT 2738 U/L, alkaline phosphatase 186 U/L, total bilirubin 1.26 mg/dL) with moderate elevation of α-fetoprotein (AFP) (200 ng/mL). Dynamic magnetic resonance imaging identified a 16 mm non-specific lesion in segment II, classified as a hepatic haemangioma. A marked growth of the lesion was observed at 6 months (68 mm), with a heterogeneous appearance on computed tomography and an increase in AFP, so a percutaneous ultrasound-guided biopsy was performed, obtaining material with evidence of fibrosis and ductopenia, without cytological atypia. Given the growth, the radiological characteristics of the lesion and the increase in AFP, a left hepatic lobectomy was decided. Histological analysis revealed a well-differentiated HCC on a non-cirrhotic liver with marked ductopenia and no evidence of vascular or capsular infiltration or involvement of the surgical margins. After this, a pre-transplant study was started. In an abdominal CT scan 4 months after surgery, several peritoneal implants were found with no signs of hepatic tumour recurrence, confirming the diagnosis of carcinoma of probable hepatic origin after biopsy of one of them.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The patient was excluded from the liver transplant waiting list and started treatment with sorafenib (800 mg/day). A reduction in AFP was initially achieved in the first 2 months (from 6,000 to 690 ng/mL), but with evidence of tumour progression on imaging tests and a new rise in AFP levels during follow-up. The patient died 5 months after starting treatment with sorafenib due to respiratory infection.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The most common involvement in Alagille syndrome is that of the liver. Chronic, progressive cholestasis occurs in 95% of cases, although it is the cardiovascular abnormalities that often determine the severity and prognosis of these patients.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Liver disease usually has a benign course; the development of acute liver failure is exceptional and does not usually progress to cirrhosis in most cases.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Hepatocellular carcinoma is a rare complication of Alagille syndrome: to date only 20 cases have been published in patients with this syndrome, 7 of them in adults.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> It can develop at any age and in the absence of cirrhosis. Alagille syndrome is considered a risk factor <span class="elsevierStyleItalic">per se</span> for this neoplasm, although it is rare due to the wide genotypic-phenotypic variability.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Screening for HCC with AFP determination and imaging tests on an annual basis is recommended.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The treatment of choice for HCC in non-cirrhotic livers is surgical resection, although in these patients there is a higher risk of postoperative recurrence and extrahepatic involvement. Lung, bone, and lymph node metastases are the most common, while peritoneal metastases are very rare.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The latter can occur spontaneously, due to rupture of the primary tumour into the peritoneal cavity, or during tumour resection.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Treatment of intrahepatic recurrence is surgical. In case of distant involvement, surgical resection should be considered when recurrence is limited to one site and complete resection is feasible, provided that the patient has good liver function and good control of the primary tumour. Treatment with sorafenib has shown similar efficacy and safety in patients with advanced HCC with and without extrahepatic metastases,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> although it has not been validated for the treatment of extrahepatic recurrence.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,5</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">We report the exceptional case of a patient with Alagille syndrome who developed HCC in a non-cirrhotic liver, with development of peritoneal metastases after tumour resection and who was treated with sorafenib as an <span class="elsevierStyleItalic">off-label</span> indication, without clear benefit.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interests</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interests" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Vázquez Rodríguez JA, Molina Villalba C, Estévez Escobar M. Síndrome de Alagille y carcinoma hepatocelular en adulto no cirrótico. Med Clin (Barc). 2022;158:295–296.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Alagille syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "E. Mitchell" 1 => "M. Gilbert" 2 => "K.M. Loomes" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cld.2018.06.001" "Revista" => array:6 [ "tituloSerie" => "Clin Liver Dis." 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