Right hepatectomy with a cholangiojejunostomy and hepaticojejunostomy for unilobar Caroli's syndrome.

Caroli...s syndrome is a rare entity. It is characterized by multi-cystic dilatation of intrahepatic bile ducts with congenital hepatic fibrosis. Here we describe a 43-year-old female with unilobar Carolis syndrome presented recurrent episodes of cholangitis. She subsequently had a right hepatectomy and complex bilio-enteric anastomoses which included a cholangiojejunostomy. This case illustrates a safe and novel surgical strategy employed to manage a patient with unilobar Caroli...s syndrome.

[Robotic Left Hepatectomy Using the Glissonean Pedicle Approach for the Treatment of Caroli's Syndrome]. / Roboter-assistierte Hemihepatektomie links mittels Glissonean pedicle approach bei Caroli Syndrom.

BACKGROUND: Caroli's syndrome is a rare disease characterised by non-obstructive dilation of intrahepatic bile ducts, hepatic fibrosis, and an increased risk of developing cholangiocarcinoma. Minimally invasive liver resection has recently been increasingly adopted for the treatment of patients with localised Caroli's syndrome. However, robot-assisted liver resection for the treatment of Caroli's syndrome has not been published. MATERIALS AND METHODS: We report a case of a 72-year-old Asian female who was referred to our hospital with multifocal cystic dilation of liver segments II, III, and IV. She had no family history of congenital cysts. Her past medical history was uneventful except for an open appendectomy. The liver function tests were normal, with a negative echinococcus serology test. On MRI, the biliary anatomy at the hilum and right liver appeared to be regular. Therefore, a robotic left hepatectomy was carried out for the unilobar involvement of Caroli's syndrome using the Da Vinci Xi-system. RESULTS: We performed a Glissonean pedicle approach while preserving the caudate lobe. After removing surgical adhesions from the anterior abdominal wall using robotic scissors, a routine cholecystectomy was performed. An aberrant left hepatic artery arising from the left gastric artery was clipped and divided. The left portal pedicle was controlled after lowering the hilar plate. The ischemic demarcation line on the liver surface was followed after clamping the left pedicle, and parenchymal dissection was performed using Maryland bipolar forceps. A Pringle manoeuvre was not applied. The left pedicle and the left hepatic vein were transected using a GIA stapling device while the middle hepatic vein was preserved. Indocyanin green fluorescence imaging confirmed adequate perfusion of the remnant liver tissue including the caudate lobe. The specimen was placed in an extraction bag and removed via a Pfannenstiel incision. The total operation time was 239 min, including a total blood loss of 100 ml. The postoperative course was uneventful. The patient was discharged on postoperative day 5. On 6 months follow-up, the patient had normal liver function and no signs of recurrent disease. CONCLUSION: Robotic left hepatectomy using an extrahepatic Glissonean pedicle approach is technically feasible.

Notch-Hes1 signaling activation in Caroli disease and polycystic liver disease.

The Notch signaling pathway plays a key role in the morphogenesis of the biliary tree, but its involvement in cystic biliary diseases, such as Caroli disease (CD) and polycystic liver disease (PLD), has yet to be determined. Immunostaining was performed using liver sections of CD and PLD, and the results were compared with those of congenital hepatic fibrosis (CHF) and von Meyenburg complex (VMC). The expression of Notch receptor 1 (Notch1) was increased in the nuclei of biliary epithelial cells in all cases of CD and PLD, whereas it remained at a low level in CHF and VMC. In addition, Notch2 and Notch3 were preferably expressed in the nuclei of biliary epithelial cells of PLD. Accordingly, the Notch effector Hes1 was highly expressed in biliary epithelial cells of CD and PLD, and the cell proliferative activity was significantly higher in CD and PLD. The expression of the Notch ligand Delta-like 1 was significantly increased in biliary epithelial cells of CD and PLD, which may be causally associated with the nuclear overexpression of Notch1 and Hes1. These results indicate that aberrant activation of the Notch-Hes1 signaling pathway may be responsible for the progression of biliary cystogenesis in CD and PLD.

[Upper abdominal pain and febrile episodes in a 44-year-old Filipino woman]. / Oberbauchschmerzen und Fieberschübe bei einer 44­jährigen Philippinerin.

A 44-year-old Filipino woman presented with abdominal pain and fever. Clinical examination and blood tests revealed no pathological results; however, (cross-sectional) imaging showed saccular cystic bile duct dilatation in the right liver with solid intraductal masses. Due to the clinical presentation the patient was admitted for surgical intervention with the diagnosis of Caroli disease. During the surgical procedure histopathology showed an intraductal papillary neoplasm of the bile duct (IPNB). The planned segmentetomy was extended to hemihepatectomy. IPNB is a rare entity of premalignant lesions of the bile duct system first recognized by the World Health Organization in 2010.

Ductal Plate Malformation in the Liver of Boxer Dogs: Clinical and Histological Features.

Ductal plate malformations (DPMs) represent developmental biliary disorders with a wide phenotypic spectrum. This study characterizes DPM in 30 Boxer dogs. Median age was 1.5 (range, 0.3-10.0) years, with 12 dogs <1 year. Clinical features included increased serum levels of liver enzymes (28), gastrointestinal signs (16), poor body condition (14), abdominal effusion (9), and hepatic encephalopathy (2). Additional malformations included gallbladder atresia (8), atrophied left liver (2), absent quadrate lobe with left-displaced gallbladder (1), portal vasculature atresia (left liver, 1), intrahepatic portosystemic shunt (1), and complex intrahepatic arteriovenous malformation (1). All dogs had portal tracts dimensionally expanded by a moderate-to-severe multiple small bile duct phenotype embedded in abundant extracellular matrix; 80% displayed variable portal-to-portal bridging. Quantitative analysis confirmed significantly increased fibrillar collagen and a 3-fold increased portal tract area relative to 6 Boxer and 10 non-Boxer controls. Biliary phenotype was dominated by tightly formed CK19-positive ductules, typically 10 to 15 µm in diameter, with 3 to >30 profiles per portal tract, reduced luminal apertures, and negative Ki-67 immunoreactivity. CK19-positive biliary epithelium intersected directly with zone 1 hepatocytes as a signature feature when considered with other DPM characteristics. Phenotypic variation included a multiple small bile duct phenotype (all dogs), predominantly thin-walled sacculated ducts (4), well-formed saccular ducts (4), and sacculated segmental, interlobular, and intralobular ducts (Caroli malformation, 2 dogs, one with bridging portal fibrosis). Histologic evidence of portal venous hypoperfusion accompanied increased biliary profiles in every case. We propose that this spectrum of disorders be referred to as DPM with appropriate modifiers to characterize the unique phenotypes.

A Unique Case of Caroli Disease in Kenya's Medical Landscape.

BACKGROUND If a young patient presents with fever, abdominal pain, jaundice and significant imaging abnormalities, especially dilation of the biliary system, it is usually due to obstruction from stones or strictures. However, on very rare occasions, it can be due to complications of congenital cystic dilatation of the biliary system, known as Caroli disease. We present such a patient and discuss the differential diagnosis and implications for long-term management. CASE REPORT A 14-year-old boy presented to the Emergency Department with a sudden onset of high-grade fever and abdominal pain for 2 weeks, accompanied by vomiting of blood. The patient had no relevant medical history. He was malnourished and had moderate pallor, jaundice, and right upper quadrant pain. Imaging revealed cystic dilatation of intrahepatic ducts and a central dot sign. There were no features suggesting advanced liver disease otherwise, and no tumors or cysts in the kidneys. A diagnosis of Caroli disease was made. The symptoms were ascribed to acute cholangitis and improved with antibiotics. He was discharged home 1 week later. No further blood loss was observed. CONCLUSIONS This case study describes a patient with ascending cholangitis, a complication of Caroli disease. This diagnosis should be considered in the differential diagnosis when a child or young adult presents with features of cholangitis, abnormal biliary imaging, and/or upper gastrointestinal bleeding, or portal hypertension. No prior cases of this disease have been encountered, documented, or published in Kenya. This case can increase awareness among primary care clinicians, including pediatricians.

Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.

Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal-recessive cystic kidney diseases. More than 13 genes are implicated in its pathogenesis to date, accounting for only 40 % of all cases. High-throughput mutation screenings of large patient cohorts represent a powerful tool for diagnostics and identification of novel NPHP genes. We here performed a new high-throughput mutation analysis method to study 13 established NPHP genes (NPHP1-NPHP13) in a worldwide cohort of 1,056 patients diagnosed with NPHP-RC. We first applied multiplexed PCR-based amplification using Fluidigm Access-Array™ technology followed by barcoding and next-generation resequencing on an Illumina platform. As a result, we established the molecular diagnosis in 127/1,056 independent individuals (12.0 %) and identified a single heterozygous truncating mutation in an additional 31 individuals (2.9 %). Altogether, we detected 159 different mutations in 11 out of 13 different NPHP genes, 99 of which were novel. Phenotypically most remarkable were two patients with truncating mutations in INVS/NPHP2 who did not present as infants and did not exhibit extrarenal manifestations. In addition, we present the first case of Caroli disease due to mutations in WDR19/NPHP13 and the second case ever with a recessive mutation in GLIS2/NPHP7. This study represents the most comprehensive mutation analysis in NPHP-RC patients, identifying the largest number of novel mutations in a single study worldwide.

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.

Caroli disease, bilateral diffuse cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas: a ciliopathy caused by a homozygous NPHP3 mutation.

UNLABELLED: We report the rare association of Caroli disease (intrahepatic bile duct ectasia associated with congenital hepatic fibrosis), bilateral cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas in a female child. She presented with end-stage renal disease at the age of 1 month, followed by a rapidly progressing hepatic fibrosis and dilatation of the intrahepatic bile ducts, leading to secondary biliary cirrhosis and portal hypertension. Combined liver-kidney transplantation was performed at the age of 4 years, with excellent outcome. DNA analysis showed a NPHP3 (coding nephrocystin-3) homozygote mutation, confirming that this malformation complex is a ciliopathy. CONCLUSION: This rare association required an exceptional therapeutic approach: combined simultaneous orthotopic liver and kidney transplantation in a situs inversus recipient. The long-term follow-up was excellent with a very good evolution of the renal and hepatic grafts and normalization of growth and weight. This malformation complex has an autosomal recessive inheritance with a 25% recurrence risk in each pregnancy.

Caroli syndrome associated with atrial septal defect and polydactyly: a case report.

INTRODUCTION: Caroli disease is multifocal segmental dilatation of the large intrahepatic bile ducts that connect to the main duct. It is considered a rare disease with an incidence rate of 1 in 1,000,000 births. There are two types of Caroli: the first type is the simple type, Caroli disease, which includes only cystic dilatation of the intrahepatic bile ducts. The second is called Caroli syndrome, which consists of Caroli disease and congenital hepatic fibrosis and might lead to portal hypertension leading to esophageal varices and splenomegaly. Atrial septal defect is one of the most common congenital heart diseases, occurring when the connection between the left and the right atriums fails to close. Polydactyly is one of the most common congenital malformations of the hands and feet. It manifests in excess fingers on the hands or toes. CASE PRESENTATION: A 6-year-old Arab girl presented to the hospital with abdominal pain for the last month with abdominal enlargement. The patient was already diagnosed with Caroli disease and polydactyly (six fingers on each limb) when she was born. Investigations including complete blood count, blood smear, bone marrow biopsy, esophagoscopy, abdominal ultrasound, and computed tomography scan showed splenomegaly associated with hypersplenism, fourth-grade non-bleeding varices, intrahepatic cystic formations in the left and right lobes, and an atrial septal defect with a left-to-right shunt. The patient was scheduled for a splenectomy after she was vaccinated with the appropriate vaccines. After follow-up for a week in the hospital, complete blood count showed an improvement. A month after that, the patient had liver abscesses and biliary fistula that were treated appropriately and her symptoms resolved. CONCLUSION: The association of liver diseases, polydactyly, and congenital heart diseases is extremely rare and was only documented few times in the literature. However, to our knowledge, atrial septal defect has never been part of this combination before. The family history also makes this case unique and strongly suggests genetic etiology.

Biliary infection may exacerbate biliary cystogenesis through the induction of VEGF in cholangiocytes of the polycystic kidney (PCK) rat.

Cholangitis arising from biliary infection dominates the prognosis in Caroli's disease. To clarify the influences of bacterial infection on the biliary cystogenesis, in vivo and in vitro studies were performed using the polycystic kidney (PCK) rat as an animal model of Caroli's disease. Cholangitis became a frequent histological finding in aged PCK rats, and neovascularization around the bile ducts also increased in aged PCK rats. Immunohistochemistry revealed that expression of vascular endothelial growth factor (VEGF) was increased in PCK rat biliary epithelium. In vitro, PCK cholangiocytes overexpressed VEGF, and the supernatant of cultured PCK cholangiocytes significantly increased the proliferative activity, migration, and tube formation of cultured rat vascular endothelial cells. Stimulation with lipopolysaccharide (LPS) further induced VEGF expression in PCK cholangiocytes, which might be mediated by signaling pathways involving phosphatidylinositol 3-kinase (PI3K)-Akt and c-Jun N-terminal kinase (JNK). Both LPS and VEGF increased cell proliferative activity in PCK cholangiocytes, and siRNA against VEGF significantly reduced LPS-induced cell proliferation. Thus, LPS-induced overexpression of VEGF in the biliary epithelium may lead to hypervascularity around the bile ducts; concurrently, LPS and VEGF act as cell proliferation factors for cholangiocytes. Biliary infection may thus exacerbate biliary cystogenesis in PCK rats.

Meckel syndrome with Caroli disease and choledochal cysts.

Meckel syndrome is a lethal autosomal recessive disorder characterized by the triad of cystic renal dysplasia, occipital encephalocele, or other anomaly of the central nervous system and post-axial polydactyly. Malformation of the ductal plate is an integral component of Meckel syndrome. Ductal plate malformations include congenital hepatic fibrosis, biliary hamartoma, autosomal dominant polycystic liver disease, Caroli disease, and choledochal cyst. The occurrence of cystic hepatic disease, Caroli disease, and choledochal cyst have not been highlighted. This is a report of a 26-week fetus with features of Meckel syndrome, Caroli disease, and choledochal cyst.

[Caroli disease--dilatation of intrahepatic bile ducts]. / Caroliho nemoc--dilatace intrahepatálních zlucových cest.

Caroli disease is a rare congenital condition characterized by a non-obstructive saccular or fusiform multi-focal segmental dilatation of the intrahepatic bile ducts and the frequent formation of the intrahepatic calculi. It can affect the entire liver with manifestations in the childhood, or only some segments, which may be an asymptomatic condition found accidentally in the adulthood. In other cases, the condition is manifested primarily with tract infections. The authors of the three case reports describe pitafalls of the diagnosis and treatment of the segmental Caroli disease, which is manifested in the adulthood. The treatment was a resection of the affected liver segments.

Monolobar ductal plate malformation disease of the liver.

We herein report a unique monolobar hepatic disease composed of Caroli's disease, peribiliary cysts, ductal plate malformations, peribiliary gland proliferation, hepatolithiasis, and portal phlebosclerosis with thrombi. A 73-year-old man underwent abdominal imaging, which revealed multiple segmental dilations of the left intrahepatic bile ducts. Polycystic kidney diseases were absent. Intrahepatic cholangiocarcinoma was suspected, and extended left lobectomy of the liver was preformed. Grossly, the hepatic left lobe was atrophic, and partly replaced by fibrous tissue. The intrahepatic bile ducts were dilated (Caroli's disease), and showed small calcium bilirubinate hepatoliths. Microscopically, the intrahepatic bile duct showed non-obstructive segmental dilations (Caroli's disease), numerous peribiliary cysts, numerous ductal plate malformations, proliferation of intrahepatic peribiliary glands, and calcium bilirubinate hepatolithiasis. Portal veins showed phlebosclerosis with thrombi. Immunohistochemically, the various biliary epithelial cells were positive for cytokeratin (CK) 7, 8, 18, and 19, and for MUC6 and CD10. They were negative for MUC2 and MUC5AC. The ductal plate malformations were positive for fetal biliary antigen MUC1, but other biliary cell types were negative for MUC1. The present case resembles 'monolobar Caroli's disease'. We believe that the present monolobular liver disease was congenital in origin.

[Intrahepatic biliary cystic lesions]. / Lésions kystiques biliaires du foie.

Intrahepatic biliary cysts encompass a large lesional spectrum including hereditary diseases as polycystic liver disease or Caroli's syndrome, malformative lesions as non hereditary Caroli's disease or simple biliary cyst and true neoplastic lesions as cystadenoma or cystadenocarcinoma. The diagnostic approach of these lesions relies firstly on imaging. Nevertheless, the pathologist not exceptionally receives surgical specimens from cystic fenestration or liver specimen resection with one or several cystic lesions. The clues for pathological diagnosis of these lesions have to be known by pathologists. As regards neoplastic cystic lesions, true non-communicating cystic tumors and cystic variants of intraductal biliary tumors have to be distinguished; in both cases, the classification is now identical to the one of pancreatic cystic tumors.

Caroli syndrome: a clinical case with detailed histopathological analysis.

Herein we present a clinical case of the Caroli syndrome caused by the compound heterozygous mutation in the PKHD1 gene. Histopathological assessment of liver detected biliary cirrhosis, numerous dilated bile ducts of various sizes, hyperplastic cholangiocytes containing a large amount of acid mucopolysaccharides, decreased ß-tubulin expression and increased proliferation of cholangiocytes. A significant proportion of hepatic tissue was composed of giant cysts lined with a single layer of cholangiocytes, containing pus and bile in its lumen and surrounded by granulation tissue. An accumulation of neutrophils in the lumen of the bile ducts was observed, as well as an infiltration of the ducts and cysts surrounding connective tissue by CD4+ and to a lesser extent CD8+ lymphocytes. This may be caused by the expression of HLA-DR by cholangiocytes. Atrophy and desquamation of the epithelium of collecting tubules with the formation of microcysts were detected in the kidneys without a clinically significant loss of renal function. Morphopathogenetic mechanisms of the Caroli syndrome can be targets for a potential pathogenetic therapy and prevention of its manifestations and complications.

A teenage patient with autosomal recessive polycystic kidney disease, a splenorenal shunt, and congenital hepatic fibrosis: a case report.

A 16-year-old female patient previously diagnosed with autosomal recessive polycystic kidney disease (ARPKD) presented with acute bilateral pneumonia, upper gastrointestinal bleeding caused by ruptured esophageal varices, ascites, and lower limb edema. She required intensive care and an endoscopic procedure to treat the gastrointestinal bleeding. The analysis of the differential diagnosis for chronic liver disease indicated she had a spontaneous splenorenal shunt. Ultrasound-guided biopsy revealed the patient had cirrhosis, as characteristically seen in individuals with ARPKD. She had no symptoms at discharge and was referred for review for a combined transplant.