The rate of cholangiocarcinoma in Caroli Disease A German multicenter study.

BACKGROUND: Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts. CD/CS are associated with cholangiocarcinoma (CCA). However, the true incidence of CCA is still unclear, although it may serve as an indication for surgery. In this paper, we analyzed (I) the incidence of CCA in German centers, (II) reviewed our single center population together with its clinical presentation and (III) performed a thorough literature review. METHODS: 17 large HPB-centers across Germany were contacted and their patients after surgical treatment due to CD/CS with histopathology were included. Medline search for all studies published in English or German literature was performed. Patients who underwent surgery at our department between 2012 and 2020 due to CD or CS were analyzed. RESULTS: In the multicenter study, 79 patients suffered from CD and 119 patients from CS, with a total number of 198 patients. In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%). Between 2012 and 2020, 1661 liver resections were performed at our department. 14 patients underwent surgery due to CD or CS. Histological examination showed synchronous cholangiocarcinoma in one patient. The literature review revealed a CCA-rate of 7,3% in large series, whereas in case reports a rate of 6,8% was found. CONCLUSION: There is risk of malignant transformation and patients with CD might also benefit from resection due to improvement of symptoms. Therefore, resection is strongly advised. As certain patients with CS require transplantation, treatment should not be guided by the relatively low rate of CCA but by the concomitant diseases that come along with hepatic failure.

Risk of malignancy in Caroli disease and syndrome: A systematic review.

BACKGROUND: Congenital intrahepatic bile duct dilatation without fibrosis is called Caroli disease (CD), and is called Caroli syndrome (CS) when it has fibrotic and cirrhotic liver morphology. The development of intrahepatic carcinoma is described in both conditions, but the reported incidence varies extensively. Potential risk factors for the malignant transformation were not described. Furthermore, conservative or surgical treatment is performed depending on the extent of cystic malformation, hepatic dysfunction and structural hepatic changes, but little is known about which treatment should be offered to patients with CD or CS and cancer. AIM: To further investigate the malignant transformation in these conditions. METHODS: A systematic review of the current literature until January 2019 was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A search using Medline (PubMed) was performed using a combination of Medical Subject Headings terms "caroli disease", "caroli syndrome", "tumor", "malignant", and "cholangiocarcinoma". Only human studies published in English were used for this systematic review. The following parameters were extracted from each article: year of publication, type of study, number of patients, incidence of malignant tumor, duration of symptoms, age, sex, diagnostics, identification of tumor, surgical therapy, survival and tumor recurrence. RESULTS: Twelve retrospective studies reporting the courses of 561 patients (53% females) were included in this systematic review. With a mean age of 41.6 years old (range 23 to 56 years old), patients were younger than other populations undergoing liver surgery. Depending on the size of the study population the incidence of cholangiocarcinoma varied from 2.7% to 37.5% with an overall incidence of 6.6%. There were only few detailed reports about preoperative diagnostic work-up, but a multimodal work-up including ultrasound of the liver, computed tomography, magnetic resonance imaging and endoscopic retrograde cholangiopancreatography was used in most studies. Disease duration was variable with up to several years. Most patients had episodes of cholangitis, sepsis, fever or abdominal pain. Tumor detection was an incidental finding of the surgical specimen in most cases because it is currently often impossible to detect tumor manifestation during preoperative diagnostics. Liver resection or liver transplantation was performed depending on the extent of the biliary pathology and additional alterations of the liver structure or function. No postoperative adjuvant chemotherapy was reported, but chemotherapy was administered in selected cases of tumor recurrence. Overall survival rates after one year were low at 36% and a high recurrence rate of up to 75% during the observation period. CONCLUSION: Only few retrospective studies reported a low tumor incidence. Despite the high rate of mortality and tumor recurrence, definite surgical treatment should be offered as soon as possible.

Cholangiocarcinoma: Current Knowledge and New Developments.

Cholangiocarcinoma (CCA) is the second most common primary malignancy. Although it is more common in Asia, its incidence in Europe and North America has significantly increased in recent decades. The prognosis of CCA is dismal. Surgery is the only potentially curative treatment, but the majority of patients present with advanced stage disease, and recurrence after resection is common. Over the last two decades, our understanding of the molecular biology of this malignancy has increased tremendously, diagnostic techniques have evolved, and novel therapeutic approaches have been established. This review discusses the changing epidemiologic trends and provides an overview of newly identified etiologic risk factors for CCA. Furthermore, the molecular pathogenesis is discussed as well as the influence of etiology and biliary location on the mutational landscape of CCA. This review provides an overview of the diagnostic evaluation of CCA and its staging systems. Finally, new therapeutic options are critically reviewed, and future therapeutic strategies discussed.

Hepatorenal fibrocystic diseases in children.

BACKGROUND: Hepatorenal fibrocystic diseases (HRFCDs) are a group of monogenic disorders characterized by developmental abnormalities involving the liver and kidney. In this study, we performed genotype and phenotype analyses of children with HRFCDs to determine the distribution of underlying diseases. METHODS: A total of 36 children with HRFCDs were recruited, with genetic tests being performed in 22 patients and 14 patients diagnosed clinically as having autosomal recessive polycystic kidney disease (ARPKD). RESULTS: In children with HRFCDs, ARPKD was the most common disease, found in 16/36 (44.4 %), followed by nephronophthisis 13 (NPHP13) in 11/36 (30.6 %) and Meckel-Gruber syndrome type 3 (MKS3) in 4/36 (11.1 %). Renal function deteriorated faster in children with NPHP13. The main hepatic pathology was Caroli disease in the NPHP13 patients, while most other patients had Caroli syndrome or congenital hepatic fibrosis. Of note, three of four MKS3 patients had an accompanying choledochal cyst. No ARPKD patient had other organ involvement, while several NPHP13 patients had ocular and/or neurodevelopmental involvement. In contrast, all MKS3 patients had severe ocular and neurodevelopmental involvement. CONCLUSIONS: NPHP13 is a major disease in the HRFCD category, and thorough evaluation of its clinical features, including kidney, liver and other organ involvement, may aid in the differential diagnosis of HRFCD.

Phenotypic variation and long-term outcome in children with congenital hepatic fibrosis.

BACKGROUND AND OBJECTIVE: Congenital hepatic fibrosis (CHF) and Caroli syndrome are frequently associated with renal cystic diseases. They have a variable clinical course, and the natural history is not well defined despite molecular advances. Our study describes the clinical manifestations and long-term outcome in children with this disorder. METHODS: A retrospective case review of children with CHF at a single centre diagnosed on the basis of clinical features, radiological and endoscopic evidence of portal hypertension (PHT), and compatible histopathological findings. Children were categorised based on hepatic phenotype-group 1 (Caroli syndrome) and group 2 (CHF). Hepatobiliary as well as renal manifestations were recorded at presentation, and their evolution followed up until transplant or last follow-up. RESULTS: There were 40 children (22 boys) with a median age of 1.3 years at clinical presentation. Fourteen of 40 (35%) children presented in the neonatal period with primarily renal disease, of whom 11 (78%) had Caroli syndrome (P = 0.02). Significant PHT with oesophageal varices was seen in 86%, with no difference in the incidence of gastrointestinal bleeding and varices between Caroli syndrome and CHF. Cholangitis developed in 10 of 40 (25%) and was more common in the Caroli syndrome group (P = 0.009). A higher proportion of children with Caroli syndrome developed chronic kidney disease (CKD) stage 3 and above as compared with CHF (85% vs 42%; P = 0.007). Twelve of 21 (57%) and 8 of 19 (42%) children in the Caroli syndrome and CHF groups required either combined liver-kidney or isolated liver transplant, with the most common indication for renal transplantation being end-stage renal disease (CKD5d) with or without advanced PHT or cholangitis. All 14 (100%) children with neonatal presentation developed CKD5d and required combined liver-kidney transplant before 14 years of age, whereas 77% of children presenting beyond the neonatal period survived without liver-kidney transplant (P < 0.001). Neonatal presentation was the best predictor of the need for transplant. CONCLUSIONS: Caroli syndrome is more likely to present in the neonatal period and these patients are more likely to develop CKD5d. CKD stage 3 or above with recurrent cholangitis is more common in Caroli syndrome presenting beyond the neonatal period and adds to the significant morbidity in these patients. Children presenting in the neonatal period have a more severe phenotype and should be considered early for combined liver-kidney transplant.

Fibropolycystic disease of the liver and kidney in Oman.

BACKGROUND AND STUDY AIMS: Fibropolycystic disease of liver and kidney (FPCDLK) is an uncommon group of conditions inherited in an autosomal fashion. The group encompasses autosomal dominant polycystic disease of the kidney (ADPDK), autosomal recessive polycystic disease of the kidney (ARPDK), congenital hepatic fibrosis (CHF) and Caroli's disease (CD). There are limited data of this disease in the world. We report our experience in the Royal Hospital (RH) in Oman and data regarding long-term follow-up. The aim of the study was to document the frequency of encounter, clinical presentation and outcome of FPCDLK in Division of Child Health in RH, Muscat. PATIENTS AND METHODS: Charts of patients diagnosed with ARPDK, ADPDK, CHF and CD were reviewed from the period of 16 February 2006 till 31 December 2011. Parameters including anthropometry, liver function tests, renal function tests, presence of oesophageal varices, hypersplenism, renal or liver transplantation and performance of porto-systemic shunt surgeries were all investigated. RESULTS: A total of 33 patients were identified, including 19 males and 14 females. The frequency of encounter of FPCDLK in RH was 1.5/1,000,000 population. The mean age of patients was 7.4years. The mean age at diagnosis was 27months. The mean duration of follow-up was 5.5years. A total of 31% of patients had an incidental finding of hepatomegaly, and 25% were detected by antenatal screening. Three children presented with renal failure, and 13 children in total had renal function abnormalities by the end of the study period. One child presented with haematemesis at the age of 1year. Two children underwent renal transplant and one child required splenectomy with a splenorenal shunt. A total of 54% had endoscopic variceal screen and two required banding on first endoscopy. The demise of one patient was observed during the study. CONCLUSION: FPCDLK is uncommon in Oman but carries major mortality and morbidity for the patient and family. The gene is present in the Gulf countries. Management is mainly through portal hypertension and renal supportive care until definitive dual organ transplant. This disease needs to be further investigated in the Arab world.

Trasplante hepático en pacientes con lesiones hepáticas benignas / Liver transplantation in patients with benign hepatic lesions

Las lesiones benignas hepáticas son enfermedades poco frecuentes y el trasplante hepático en ellas es excepcional. Presentamos una revisión del tema, con comentarios sobre las entidades subsidiarias de trasplante hepático, de las que destacan: la adenomatosis, la poliquistosis y el hemangioendotelioma epitelioide hepático (aunque este proceso sea de grados bajo a intermedio de malignidad). Valoramos aspectos específicos de estas lesiones, desde el punto de vista epidemiológico, etiopatogénico, clínico, diagnóstico, terapéutico, indicación del trasplante y experiencia de los diferentes autores en estas afecciones (AU)

Benign hepatic lesions are rare and liver transplantation in these cases is exceptional. We present a review of the subject, commenting on the aspects that have been subsidiary to liver transplantation, of which are highlighted: adenomatosis, polycystosis and hepatic epithelioid haemangioendothelioma (although this process may be a low to intermediate malignant grade). We assessed specific epidemiological, aetiopathogenic, clinical, diagnostic, therapeutic and aspects of the lesions as well as indication for transplantation, and the experiences of different authors on these pathologies (AU)

Caroli's disease and outcomes after liver transplantation.

Caroli's disease is a rare autosomal recessive disorder characterized by intrahepatic cystic dilatation of the bile ducts that, when progressive, leads to intrahepatic stones, recurrent cholangitis, portal hypertension, cholangiocarcinoma, and liver failure. Liver transplantation is a promising curative option for advanced Caroli's disease. The aim of this study was to determine the outcomes of liver transplantation in unselected patients with Caroli's disease and recommend an evidence-based therapeutic algorithm for the management of Caroli's disease. Of the 78,124 patients transplanted in the United States between 1987 and 2006, 104 had Caroli's disease; 96 of these underwent liver alone, and 8 underwent combined liver/kidney transplantation. The patient survival and graft survival were analyzed by Kaplan-Meier survival analysis, and risk of death and risk of graft loss were analyzed by Cox proportional hazards regression. The overall 1-, 3-, and 5-year graft (79.9%, 72.4%, and 72.4%) and patient (86.3%, 78.4%, and 77%) survival rates were excellent for patients after liver transplantation. For combined liver/kidney transplantation (n = 8), the 1-year patient survival and graft survival were 100%. Proportional hazards analysis identified Asian ethnicity, elevated bilirubin, requirement of life support or hospitalization prior to transplantation, and a cold ischemia time greater than 12 hours as associated with increased risk of both graft loss and death. A history of prior transplant or prior abdominal surgery was also associated with increased risk of graft loss. In conclusion, liver transplantation is an excellent treatment option for patients with advanced Caroli's disease and should be considered in a timely fashion to prevent worsening complications including refractory cholangitis and cholangiocarcinoma.

Neurofibromatosis and Caroli's disease: an extremely rare association.

Neurofibromatosis type-1 (NF-1) is a rare genetic disorder with an extremely variable phenotype. A broad spectrum of associations have also been reported with it. We present a florid case of NF, presenting with unusual symptoms, which was found to have an associated Caroli's disease, a rare congenital disorder of the intrahepatic bile ducts. The case is reported along with a brief review of both the disorders.

An atypical course of Caroli's disease in a renal transplant patient--case report and review of the literature.

This is a rare case of Caroli's disease, diagnosed following renal transplantation in a patient with autosomal recessive polycystic kidneys. Despite advanced cystic transformation of the biliary tree with striking architectural changes, there was no evidence of portal hypertension or hepatic fibrosis. Moreover, the patient did not suffer a single episode of cholangitis, a most interesting feature of this case. Her clinical course was punctuated by repeated episodes of gastrointestinal and urinary tract infections with resistant organisms; but fortunately, she had no evidence of septicemia. Recurrent Salmonella gastroenteritis indicated a chronic carrier state with the dilated bile ducts possibly acting as a potential reservoir. This has significant implications considering the immune suppression associated with renal transplantation. In general, Caroli's disease is rare. Therefore, a high index of suspicion for the diagnosis of Caroli's disease is warranted especially in patients with ARPKD or ADPKD. Once confirmed, affected patients with end-stage renal disease such as our patient, should ideally undergo combined liver-kidney transplantation.

[Hepatolithiasis and Caroli's disease in Argentina: results of a multicenter study]. / Hepatolitiasis y enfermedad de Caroli en Argentina: resultados de un estudio multicéntrico.

The goal of this study was to determine the prevalence, epidemiology and clinical-therapeutical evolution of hepatolithiasis (HL) in Argentina. With this purpose a survey was conducted sending a questionnaire to ten referencial and interventional radiology centers in the country. Seven centers answered on time. In the last five years a total of 8,736 consecutive patients were examined for cholangiography (endoscopic retrograde cholangiography, PTC). A total of 5,920 (68%) were biliary lithiasis and 53 (0.9%, range 0.5-2.6%) of these were HL. In case of HL the diagnostic procedure was the ERCP in 68% of the cases, and the PTC in the remainder 32%. The patients with HL (53% females, mean age 52, range 23-85) clinically presented cholangitis (79%); pancreatitis (6%) and five (9.4%) showed evolution to a biliary cirrhosis. Associated diseases or abnormalities of the biliary tree were: biliary postsurgical strictures (BPS), 28%; Caroli's Syndrome, 20%; and choledocholithiasis, 28%. While a 9.4% presented a "biliary history" (that was defined as two or more episodes of biliary surgery) and a 5.7% lacked associated or predisposing diseases. Follow-up was lost in 23% of the cases and in 77% a follow up of 38 months (range 8-60) was observed with 4.8% mortality rate. The treatment was hepatobiliary surgery in 58% of the cases; endoscopic papillotomy in 17% and combined treatments that included extracorporeal shock wave lithotripsy and ursodeoxycholic acid (UDCA) in 15%. Four out of 53 cases (7.5%) received UDCA as the only successful therapy. HL is an entity with high biliary morbidity in 85% of the cases and development in to cirrhosis in 9.4%. When the diagnosis is made in the western world both BPS and Caroli must be discarded first. Combined treatments or only UDCA are new therapeutical alternative in the western world.

Hepatolitiasis y enfermedad de Caroli en Argentina: resultados de un estudio multicéntrico / Hepatolithiasis and Caroli's disease in Argentina: results of a multicenter study

A fin de determinar la prevalencia epidemiología y comportamiento clínico-terapêutico de la hepatolitiasis (HL) en el país se envió un cuestionario a 10 centros de referencia, en Radiología invasiva de vía biliar. De 10 centros encuestados, 7 (70 por ciento) contestaron en tiempo y forma. Reuniéndose un total de 8.736 colangiografías (C) en los últimos 5 años: 5.920 (68 por ciento) fueron litiasis biliares y 53 de estas resultaron HL (0.9 por ciento, rango 0,5-2.6 por ciento). El método diagnóstico fue la C. retrógrada en el 36 (68 por ciento) y en el 17 (32 por ciento) la C. transhepática. De 53 pacientes con HL (53 por ciento, x de edad 52, rango 23-85); el 79 por ciento (42/53) se presentó clínicamente con una colangitis; un 6 por ciento 3/53) padeció una pancreatitis aguda y un 9.4 por ciento (5/53), evolucionó a una cirrosis biliar. Las enfermedades predisponentes a HL fueron: en el 28 por ciento (15/53) estenosis postquirúrgica de la via biliar (EPQ); en el 20 por ciento (11/53) Enfermedad de Carolí en otro 28 por ciento (15/53) panlitiasiscoledociana. Mientras que un 9,4 por ciento (5/53) presentó una "historia biliar" (dos o más intervenciones sobre la via biliar) y en un 5,7 por ciento (3/53) no se hallaron factores predisponentes. En un 77 por ciento se observó un follow-up de 38 meses (rango 8-60), con una mortalidad de 4,8 por ciento (2/41): siendo tratados con cirurgía en el 58 por ciento de los casos (31/53); papilotomía en el 17 por ciento (9/53) y tratamiento combinados en el 15 por ciento (8/53) que incluían a litotripsia extracorpórea y Ac. Ursodesoxicólico(AUDC). Cuatro de 53 (7.5 por ciento) recibieron AUDC como única terapéutica. Se concluye que la HL es una entidad con alta morbilidad biliar (85 por ciento) y heoática (cirrosis en el 9.4 por ciento). Cuando se diagnostica en Occidente, debe buscarse EPQ o un Carolí. Siendo los tratamientos combinados o el AUDC como única alternativa, una nueva modalidad terapéutica del mundo occidental.

Hepatolitiasis y enfermedad de Caroli en Argentina: resultados de un estudio multicéntrico / Hepatolithiasis and Carolis disease in Argentina: results of a multicenter study

A fin de determinar la prevalencia epidemiología y comportamiento clínico-terapÛutico de la hepatolitiasis (HL) en el país se envió un cuestionario a 10 centros de referencia, en Radiología invasiva de vía biliar. De 10 centros encuestados, 7 (70 por ciento) contestaron en tiempo y forma. Reuniéndose un total de 8.736 colangiografías (C) en los últimos 5 años: 5.920 (68 por ciento) fueron litiasis biliares y 53 de estas resultaron HL (0.9 por ciento, rango 0,5-2.6 por ciento). El método diagnóstico fue la C. retrógrada en el 36 (68 por ciento) y en el 17 (32 por ciento) la C. transhepática. De 53 pacientes con HL (53 por ciento, x de edad 52, rango 23-85); el 79 por ciento (42/53) se presentó clínicamente con una colangitis; un 6 por ciento 3/53) padeció una pancreatitis aguda y un 9.4 por ciento (5/53), evolucionó a una cirrosis biliar. Las enfermedades predisponentes a HL fueron: en el 28 por ciento (15/53) estenosis postquirúrgica de la via biliar (EPQ); en el 20 por ciento (11/53) Enfermedad de Carolí en otro 28 por ciento (15/53) panlitiasiscoledociana. Mientras que un 9,4 por ciento (5/53) presentó una "historia biliar" (dos o más intervenciones sobre la via biliar) y en un 5,7 por ciento (3/53) no se hallaron factores predisponentes. En un 77 por ciento se observó un follow-up de 38 meses (rango 8-60), con una mortalidad de 4,8 por ciento (2/41): siendo tratados con cirurgía en el 58 por ciento de los casos (31/53); papilotomía en el 17 por ciento (9/53) y tratamiento combinados en el 15 por ciento (8/53) que incluían a litotripsia extracorpórea y Ac. Ursodesoxicólico(AUDC). Cuatro de 53 (7.5 por ciento) recibieron AUDC como única terapéutica. Se concluye que la HL es una entidad con alta morbilidad biliar (85 por ciento) y heoática (cirrosis en el 9.4 por ciento). Cuando se diagnostica en Occidente, debe buscarse EPQ o un Carolí. Siendo los tratamientos combinados o el AUDC como única alternativa, una nueva modalidad terapéutica del mundo occidental. (AU)

Caroli's disease: study of six cases, including one with epithelial dysplasia.

Six cases of Caroli's Disease are reviewed. Three of the patients had an associated form of the disease, one of which had a congenital hepatic fibrosis, another a cystic dilatation of extrahepatic bile duct and the last one suffered both the above mentioned associated anomalies. Three patients presented with the simple form which was initially described by Caroli. The distribution of the biliary lesions was a bilobar one in four cases and monolobar in two. One patient presented areas of biliary ectasia partially lined by dysplastic epithelium. Surgical treatment was used in four cases, a left hepatectomy being carried out in two of them and an internal biliary drainage by Roux-Y hepaticojejunostomy in the other two. This is a rare disease, frequently associated with congenital hepatic fibrosis, possibly pre-malignant and whose treatment of choice is hepatic resection.