Background Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive liver diseases that present as neonatal cholestasis. Little is known of this disease in Korea.
Methods The records of five patients histologically diagnosed with PFIC, one with PFIC1 and four with PFIC2, by liver biopsy or transplant were reviewed, and ATP8B1 and ABCB11 mutation status was analyzed by direct DNA sequencing. Clinicopathological characteristics were correlated with genetic mutations.
Results The first symptom in all patients was jaundice. Histologically, lobular cholestasis with bile plugs was the main finding in all patients, whereas diffuse or periportal cholestasis was identified only in patients with PFIC2. Giant cells and ballooning of hepatocytes were observed in three and three patients with PFIC2, respectively, but not in the patient with PFIC1. Immunostaining showed total loss of bile salt export pump in two patients with PFIC2 and focal loss in two. Lobular and portal based fibrosis were more advanced in PFIC2 than in PFIC1. ATP8B1 and ABCB11 mutations were identified in one PFIC1 and two PFIC2 patients, respectively. One PFIC1 and three PFIC2 patients underwent liver transplantation (LT). At age 7 months, one PFIC2 patient was diagnosed with concurrent hepatocellular carcinoma and infantile hemangioma in an explanted liver. The patient with PFIC1 developed steatohepatitis after LT. One patient showed recurrence of PFIC2 after 10 years and underwent LT.
Conclusions PFIC is not rare in patients with neonatal cholestasis of unknown origin. Proper clinicopathologic correlation and genetic testing can enable early detection and management.
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Immunohistochemical staining was performed using the streptavidin-biotin method. RESULTS Proliferations of bile ductules at the periphery of the hepatic lobules, and diffuse HSC activation in the perisinusoidal spaces were observed in all cases.
Immunoreactivity of the hepatocytes for CK7 and CK19 suggested a possible phenotypic transformation into bile duct epithelium during fibrogenesis.
Immunohistochemical-analyses of alpha-SMA expression profiles showed that intralobular HSCs and some hepatocytes underwent early phenotypic changes, and that the accumulation of collagen coincides with that of alpha-SMA-labeled myofibroblasts around portal/septal ductular structures. CONCLUSIONS Our results showed the possibility of a phenotypic transformation of hepatocytes into bile ductular epithelium. It is suggested that hepatocytes might play a role in bile ductule proliferation in obstructive liver disease.
BACKGROUND Intrahepatic cholestasis can occur early after living donor liver transplantation (LDLT). We investigated the changes in the expressions of the bile acid transporters and the liver histology in the patients who suffered with early cholestasis (EC) following LDLT. METHODS The histological differences between 15 graft livers with EC after LDLT and 5 graft livers with biliary stricture following LDLT were evaluated. The hepatic mRNA levels of the bile canaliculi transporters (BSEP, MRP2, MRP3, MDR1, MDR3, NTCP) in 40 (20 graft livers, 20 matched donor livers) liver biopsy tissues were analyzed by performing real-time reverse-transcription polymerase chain reaction (RT-PCR). RESULTS Microscopic examination revealed hepatocellular and/or bile canalicular cholestasis around acinar zone 3 in the livers of the patients with EC. In the livers with biliary stricture, the cholestasis was dominantly observed in the hepatocytic cytoplasm and in the bile ductules around the portal area rather than around acinar zone 3. The BSEP and MRP2 mRNA levels in the EC livers were significantly reduced by 44% and 23%, respectively (p=0.000), compared to the matched donor livers. The levels of MDR3 and NTCP mRNA in the EC livers increased by 738% (p=0.000) and 281% (p<0.01), respectively. The change of the expressions of the bile acid transporters in the patients with biliary stricture was less significant than that in the EC group. CONCLUSIONS These results suggest that the altered expressions of the bile acid transporters may play a role in the pathogenesis of EC following LDLT.
BACKGROUND The diseases that cause neonatal cholestasis display several overlapping clinical feature. Making the differential diagnosis using liver biopsy specimens from infants with neonatal cholestasis is important for delivering the proper treatment. METHODS We assessed the clinical manifestations, laboratory data, and histopathologic features of the pretreatment liver biopsy specimens from patients suffering with biliary atresia (n=66), intrahepatic bile duct paucity (n=15), and neonatal hepatitis (n=21). RESULTS The gender distribution was nearly equal for the patients with biliary atresia and intrahepatic bile duct paucity, whereas males predominated for the cases of neonatal hepatitis. Only the gamma-glutamyl transferase level differed significantly amongst the groups. The diagnostic features for making the differential diagnosis of bile duct lesions included marked bile ductular proliferation, severe fibrosis, and bile duct loss. The difference of the average percentage of portal tracts with bile duct loss was statistically significant between the patients with intrahepatic bile duct paucity (73.9%) and those patients with neonatal hepatitis (39.1%) (p<0.001). CONCLUSIONS Bile ductular proliferation, bile duct loss, and advanced fibrosis are useful for the differential diagnosis of neonatal cholestasis. Moreover, stricter diagnostic criteria for bile duct loss (more than 2/3 of bile ducts) should be applied for the definitive diagnosis of intrahepatic bile duct paucity, because bile duct loss also frequently occurs in infants suffering with neonatal hepatitis.
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BACKGROUND The relationship between hepatoliths and cholangiocarcinoma is etiologically unclear. However, histogenetic sequencing with hyperplasia, dysplasia and carcinoma can occur in the bile ducts of hepatolithiasis. METHODS We studied 55 cases of hepatolithiasis and examined the specimens of resected liver tissue with a microscope.
The growth patterns of bile duct epithelium were divided into four types: flat, tufting, micropapillary and papillary. The dysplasia was also divided into low-grade dysplasia (LGD) and high-grade dysplasia (HGD). RESULTS Of 55 cases of hepatolithiasis, 30 cases (54.6%) were of the flat pattern, 13 cases (23.6%) the micropapillary pattern, and 11 cases (20%) the tufting pattern. Epithelial hyperplasia was noted in only 36 cases (65.5%) in the large bile ducts, but dysplastic changes were found in 19 cases. Of 19 cases of dysplasia, LGD was present in 14 cases (25.5% of total 55 cases) an HGD in 5 cases (9% of total 55 cases). The epithelial hyperplasia showed histologic growth of the flat pattern in 29 cases out of 36 cases. But LGD (14 cases) had 6 cases of the tufting pattern and 7 cases of the micropapillary pattern. HGD (5 cases) revealed 4 cases of the micropapillary pattern with one case of the tufting pattern. CONCLUSION This study suggests that sequences of hyperplasia, low-grade dysplasia and high-grade dysplasia can play a role in the carcinogenesis of bile duct epithelium in hepatolithiasis with the histologic pattern changing from flat to micropapillary growth.
BACKGROUND Hepatocellular cholestasis denotes the alteration of bile secretion by hepatocytes. The causes, degree of hepatocyte injury and concomitant bile duct loss are considered to influence the clinical course. METHODS The causes and pathological features of hepatocellular cholestasis were analyzed in 62 cases of liver biopsies; and the causes of primary biliary cirrhosis, primary sclerosing cholangitis, and biliary obstruction were not included. RESULTS The mean age of the patients was 42.2 years, and the ratio of male to female was 1.8:1. Fifty-eight cases (94%) showed cholestatic hepatitis, and 4 cases (6%) showed pure cholestasis without hepatitis activity. The majority of the cases (52 cases, 84%), including 19 cases of herbal medicine, was related to drugs. Loss of bile duct was found in 12 cases (19%), which were all cases of chronic cholestasis. All of them had drug histories, including 9 cases of herbal medicine. Clinical follow-up was performed in 9 out of the 12 cases with bile duct loss, and all of them showed elevated total bilirubin and/or alkaline phosphatase levels for more than 6 months. CONCLUSION Drugs are the major cause of hepatocellular cholestatic hepatitis/cholestasis; and information about drugs, including herbal medicines, should be considered for proper evaluation of liver biopsy with hepatocellular cholestasis. Bile duct loss should be evaluated in the cases of chronic hepatocellular cholestasis, especially in drug induced cases.
BACKGROUND Histologic progressive changes of bile duct epithelium with hyperplasia, dysplasia and cholangiocarcinoma could be caused by hepatolithiasis. To be clarified as a neoplastic process, this histologic process should be evaluated with various aspects of cell biology. METHODS Immunohistochemical study of proliferating cell nuclear antigen (PCNA) was performed on 45 cases (10; normal, 15; hyperplasia, 14; low-grade dysplasia:LGD, 6; high-grade dysplasia: HGD) of hepatolithiasis and 10 cases (all HGD) of hepatolithiasis with cholangiocarcinoma. RESULTS In the hepatolithiasis, mean PCNA labelling indices (LI) of normal, hyperplasia, LGD and HGD of major intrahepatic bile duct epithelium were 24.5+/-4.3, 51.5+/-0.1, 62.0+/-.4 and 84.7+/-.3, respectively and gradually increased. Mean LI of PCNA in HGD of major intrahepatic bile duct epithelium of hepatolithiasis with cholangiocarcinoma was 68.7+/-.7, which was similar to that of LGD in hepatolithiasis without cholangiocarcinoma. CONCLUSIONS Histologic transformation through hyperplasia, dysplasia and carcinoma in major intrahepatic bile duct epithelium of hepatolithiasis may be a neoplastic process if these histologic changes are evaluated in the cellular proliferation aspect.
Bile duct brush cytology has been employed as a diagnostic tool for the evaluation of pancreatic and biliary tract strictures. The specificity of this method is high however, its sensitivity is quite low. A recent study employing liquid based cytology (LBC) reported results comparable to those achieved via conventional cytology. Therefore, we have attempted to prospectively evaluate the diagnostic utility of bile duct brush cytology in pancreaticobiliary diseases.
A total of 46 cases with bile duct stricture were enrolled including 11 cases of benign stricture, 29 cases of bile duct carcinoma, 3 cases of gallbladder cancer, and 3 cases of pancreatic cancer. Both conventional smear and LBC using MonoPrep2(TM) system were conducted in each case. The cytological diagnosis of each case was classed into the following categories; benign, suspicious for malignancy, and malignancy. The diagnostic accuracy of both cytologic methods was investigated. LBC evidenced a high rate of material insufficiency (13/46), which was attributed to low cellularity. The kappa index of both cytological methods was 0.508. Cytological and tissue diagnoses were correlated in 25 cases conducted from biopsy or operation. The sensitivity, specificity, positive predictive value, and negative predictive value were 41.2% (7/17), 100% (8/8), 100% (7/7), and 44.4% (10/18) in conventional smear; 58.8% (10/17), 87.5% (7/8), 90.9% (10/11), and 50.0% (7/14) in LBC; and 94.1% (16/17), 87.5% (7/8), 94.1% (16/17), and 87.5% (7/8) in any one of both cytological methods, respectively. Based on these results, the sensitivity of LBC was found to be superior to that of conventional smear and we were able to obtain higher positive predictive value upto 94.1% by simultaneously conducting both cytologic methods.
An association between choledochal cyst and carcinoma is well established. Here, we report an extremely rare case of undifferentiated carcinoma exhibiting extensive sarcomatous features arising in a choledochal cyst. The patient in our case had a radiologically confirmed choledochal cyst and anomalous pancreaticobiliary ductal union, and mild wall thickening in the cyst was observed on endoscopic retrograde cholangiopancreatography. The patient underwent common bile duct excision and cholecystectomy. In the choledochal cyst, a nodule measuring 1.5x1 cm was detected. The lesion was composed of atypical, spindle-shaped and large, round pleomorphic tumor cells simulating sarcoma. Neither glandular nor squamous differentiation was observed. These cells were immunoreactive for both vimentin and cytokeratin by immunohistochemistry. These histologic and immunohistochemical findings were consistent with undifferentiated carcinoma, spindle and giant cell type, according to the WHO classification.
BACKGROUND The 14-3-3 sigma (sigma) protein has a negative regulatory role in the cell cycle progression of the.
Down-regulation or overexpression of the 14-3-3 sigma protein has been reported in various human cancers. METHODS Immunohistochemistry for the 14-3-3 sigma protein was performed in non-neoplastic bile duct cells, intraductal papillary neoplasms of the liver (IPNL), mass-forming intrahepatic cholangiocarcinomas (ICC) and non-papillary extrahepatic cholangiocarcinomas (ECC). We investigated the methylation status of the 14-3-3 sigma gene in 45 cases of these 3 tumor groups. RESULTS The non-neoplastic bile duct cells demonstrated negative or weakly positive cytoplasmic immunoreactivity for the 14-3-3 sigma protein and no methylation of the 14-3-3 sigma gene. Overexpression as well as negative immunoreactivity associated with hypermethylation of the 14-3-3 sigma protein was observed in 16 (69.6%) of 23 cases of IPNL, in 21 (63.6%) of 33 cases of mass-forming ICC and in 27 (71.1%) of 38 cases of non-papillary ECC. Negative immunoreactivity was increased in the invasive IPNL (4/6, 66.7%), as well as in the poorly differentiated cases of mass-forming ICC (8/12, 66.7%) and the non-papillary ECC (5/8, 62.5%). CONCLUSIONS The similar rates for the abnormal expression of the 14-3-3 sigma protein among the three groups of biliary neoplasms indicate its general association with biliary carcinogenesis. Furthermore, the loss of the 14-3-3 sigma protein may be involved in the tumor progression and differentiation in the biliary carcinogenesis.