Ultrasound Visualization of Hepatic Peribiliary Cysts: A Comparison with Morphology

We report herein a hitherto unrecognized, interesting ultrasound finding ("hilar multicystic echo complex"), the result of peribiliary cysts in the liver. This ultrasound finding was discovered around intrahepatic large bile ducts and large portal vein branches near the hepatic hilum in an autopsy case with hepatocellular carcinoma, submassive hepatic necrosis superimposed on chronic active hepatitis, and portal hypertension. Antemortem ultrasound examination revealed the hilar multicystic echo complex around the portal venous branches near the hepatic hilum. Autopsy confirmed that the hilar multicystic echo complex was due to peribiliary cysts that were present around the bile ducts at the hilum. The peribiliary cysts were thought to have arisen from cystic dilatation of preexisting intrahepatic peribiliary glands. These peribiliary cysts reportedly occur in livers with portal hypertension (e.g., cirrhosis, hepatocellular carcinoma, idiopathic portal hypertension, extrahepatic portal obstruction, and portal thromboembolism), adult-type polycystic disease of the liver and kidneys, and systemic infection. Therefore, recognition of peribiliary cysts at sonography would have diagnostic value, and may indicate that presence of one of the above described liver diseases.     

Multiple hepatic peribiliary cysts with cirrhosis

Multiple hepatic peribiliary cysts were found in three autopsy cases of patients who had had underlying liver diseases and obstructive jaundice. Macroscopically, the cysts were visible and present exclusively in the hepatic hilum and larger portal tracts. Histologically, the cysts were of varying size and were lined by a single layer of cuboidal or flattened epithelial cells without atypia. Intimate association between the cysts and peribiliary glands was found in the walls of large bile ducts. All three cases were associated with liver cirrhosis in patients with portal hypertension, and two of the patients had also had hepatocellular carcinoma. These findings support the previous assumption that multiple hepatic peribiliary cysts may be closely related to a portal hypertensive condition. Although peribiliary cysts have been considered to be clinically asymptomatic in general, in one of our patients, the cystic dilatation appeared to have been responsible for the progression of obstructive jaundice.     

Expression of bile duct-type cytokeratin in noncancerous hepatocytes in patients with hepatitis B virus-related hepatocellular carcinoma

BACKGROUND/AIMS: Hepatocytes express bile duct-type cytokeratin in various conditions, which indicates the presence of hepatic progenitor cells. We investigated the clinical significance of cytokeratin 7 expression in the noncancerous hepatitis tissue in patients with hepatitis B virus-related hepatocellular carcinoma. METHODOLOGY: Specimens were obtained from 24 patients who underwent liver resection for hepatitis B virus-related hepatocellular carcinoma. The hepatocytes in the noncancerous hepatic tissue were examined immunohistochemically using monoclonal antibodies against cytokeratin 7. RESULTS: Expression of cytokeratin 7 was observed in 9 patients (group 1). Group 2 consisted of the other 15 patients. Serum transaminases were significantly higher in group 1 than in group 2. The percentage of patients with moderate or severe active hepatitis, the percentage of patients with cirrhosis, and the percentage of patients with portal invasion were significantly higher in group 1 than in group 2. The tumor-free survival rate was significantly lower in group 1 than in group 2. CONCLUSIONS: The expression of cytokeratin 7 in noncancerous hepatic tissue is closely related to the severity of and duration of chronic hepatitis B. The expression of cytokeratin 7 in the noncancerous hepatic tissue is a possible risk factor for recurrence after resection of hepatitis B virus-related hepatocellular carcinoma.     

Hepatic nodular hamartoma containing liver cysts,ductal plate malformations and peribiliary glands

An 83‐year‐old man with hepatocellular carcinoma was found to have a low‐echoic and low‐density tumor measuring 7.2 cm × 5.6 cm. Caroli's disease was absent. Clinical diagnosis was intrahepatic cholangiocarcinoma. Three cores of liver biopsy were obtained from the tumor. Histologically, it consisted of liver cysts, ductal plate malformations, peribiliary glands, hepatocytes, portal tracts and mesenchymal tissue. Apparent features of cirrhosis were not found. The liver cysts were lined by a layer of cuboidal cells with multiple papillary protrusions. The ductal plate malformations resembled fetal ductal plates. The peribiliary glands were seromucous glands. Immunohistochemically, these abnormal ductal structures showed positive reaction to biliary type cytokeratins, namely, cytokeratin (CK)7, CK8, CK18 and CK19. Mucin gene expression showed that these biliary structures are positive for fetal antigen MUC1. MUC6 is also positive in them. Aberrant expression of CD10 was observed in these biliary structures. MUC2, MUC5AC and CDX2 were negative. The author thinks that this lesion is hepatic hamartoma with ductal plate malformations, liver cysts and peribiliary glands. To the best of the author's knowledge, this type of liver nodule has not been reported in the published work.     

Multiple hilar cysts of the liver in patients with alcoholic cirrhosis: Report of three cases

The present report concerns the clinicopathological study of three patients with alcoholic cirrhosis (a 40-year-old man, a 52-year-old woman and a 48-year-old man) who had multiple cysts along their intrahepatic bile ducts. The cysts were visible on gross examination of the liver and, in two cases, an enlargement of the cysts had been detected in abdominal computed tomography scans performed 1 year apart. Histologically, the cysts consisted of proliferating and dilated peribiliary glands. The cysts occasionally compressed the original bile ducts. The latter showed mucosal hyperplasia with antral-type gland metaplasia. Neoplastic changes and necroinflammation were not seen. Immuno-histochemical assays revealed that the peribiliary glands and antral-type glands expressed not only cytokeratin and carbohydrate antigen 19-9, but also c-MET protein, the hepatocyte growth factor receptor which may be related, at least in part, to the cystic dilatation of the peribiliary glands.     

Editorial: Treatment of patients with HCV-related cirrhosis with peginterferon and ribavirin: Swinging the pendulum toward treatment

Patients with hepatitis C virus-related cirrhosis are at increased risk for hepatic decompensation and hepatocellular carcinoma (HCC). They also responded less well to standard therapy compared with those without cirrhosis. Several recent studies have demonstrated that patients with cirrhosis can be safely treated and those who achieve a sustained virological response have better clinical outcomes compared with nonresponders. These results support treatment for patients with compensated cirrhosis. In addition, cirrhotic patients should be monitored after a sustained virological response is obtained, because some patients remain at risk for complications of liver disease, particularly HCC. Newer, more effective therapy is needed for patients with cirrhosis.     

Intrahepatic peribiliary glands of humans. II. Pathological spectrum

Abstract The pathological spectrum of intrahepatic peribiliary glands is reviewed here. Several categories of histopathological changes such as necro-inflammation, cystic dilatation, hyperplasia and neoplasia have been identified in this glandular system. Necro-inflammation is associated with biliary tract diseases and chronic advanced liver diseases and may also appear in the livers of subjects with extrahepatic diseases such as sepsis. Cystic changes of microscopic sizes are not uncommon in autopsy livers of chronic advanced liver diseases, portal hypertensive diseases and also polycystic liver of adult type. Grossly recognizable cysts are, however, infrequent and occasionally cause compression of the adjoining bile ducts. Hyperplasia of these glands, which occurs consistently in hepatolithiasis and more variably in other conditions (e.g. biliary tract infection and submassive hepatic necrosis), may be associated with hypersecretion of seromucinous substances. Hyperplasia of peribiliary glands may then lead to mucin-related biliary diseases. In addition, these glands, particularly the hyperplastic ones, could be a precursor of cholangiocarcinoma. The pathological spectrum of the intrahepatic peribiliary glands is being expanded, although a clinical pathological correlation remains uncharted. Furthermore, age-related variations and non-specific reactive changes of these glands remain unexplored.     

Cystic micropapillary neoplasm of peribiliary glands with concomitant perihilar cholangiocarcinoma

We report a case of a 75-year-old man with cystic micropapillary neoplasm of peribiliary glands detected preoperatively by radiologic examination. Enhanced computed tomography showed a low-density mass 2.2 cm in diameter in the right hepatic hilum and a cystic lesion around the common hepatic duct. cholangiocarcinoma, right hepatectomy with caudate lobectomy and bile duct resection were performed. Pathological examination revealed perihilar cholangiocarcinoma mainly involving the right hepatic duct. The cystic lesion was multilocular and covered by columnar lining epithelia exhibiting increased proliferative activity and p53 nuclear expression; it also contained foci of micropapillary and glandular proliferation. Therefore, the lesion was diagnosed as a cystic micropapillary neoplasm of peribiliary glands and resembled flat branch-type intraductal papillary mucinous neoplasm of the pancreas. Histological examination showed the lesion was discontinuous with the perihilar cholangiocarcinoma. Immunohistochemistry showed the cystic neoplasm was strongly positive for MUC6 and that the cholangiocarcinoma was strongly positive for MUC5 AC and S100 P. These results suggest these two lesions have different origins. This case warrants further study on whether this type of neoplasm is associated with concomitant cholangiocarcinoma as observed in pancreatic intraductal papillary mucinous neoplasm with concomitant pancreatic duct adenocarcinoma.     

Decompensated hepatitis B virus-related cirrhosis successfully treated with lamivudine allowing surgery for hepatocellular carcinoma

A 39-year-old man was diagnosed with hepatitis B virus-related cirrhosis, and because of hepatic exacerbations with icterus and ascites, he had been repeatedly hospitalized. He was treated with lamivudine. Several months later, his ascites disappeared and his liver function was improved from class C to A according to the Child-Pugh classification. Two years later, one small hepatocellular carcinoma was detected, and he underwent a successful hepatectomy. From this case, we consider lamivudine to be useful for improving hepatic function in decompensated liver cirrhosis type B and lamivudine might enable surgical resection of hepatocellular carcinoma.     

A case of multiple hepatic peribiliary cysts which contributed to the obstructive jaundice and led to liver failure at the young man with von Recklinghausen's disease.

We treated a young man with obstructive jaundice, in whom multiple hepatic peribiliary cysts were detected at autopsy. He had been diagnosed with von Recklinghausen's disease in early childhood and had undergone surgery for a ventricular septal defect with massive blood transfusion at the age of 4 years. Examination at the age of 21 revealed prominent splenomegaly and a low platelet count. He underwent splenectomy and liver cirrhosis was confirmed by open biopsy of the liver. He was followed up at a local hospital and was admitted several times. When he was 41 years old, he was transferred to our hospital with severe jaundice and hepatic encephalopathy. Computed tomography showed marked dilation of the intrahepatic bile ducts and liver function tests showed that jaundice was mainly due to an increase of direct bilirubin. Despite endoscopic nasobiliary drainage, plasma exchange, and continuous hemodiafiltration, he died of hepatic failure after 5 days. At autopsy, multiple hepatic peribiliary cysts were found. Although peribiliary cysts have generally been considered to cause no symptoms, this report describes a patient with multiple hepatic peribiliary cysts which appear to have been responsible for the progression of obstructive jaundice.     

Contrast-enhanced ultrasound to evaluate the severity of chronic hepatitis C

BACKGROUND: Non-invasive techniques are being developed to assess the severity of liver disease. Haemodynamic changes in the hepatic circulation during the development of liver disease can be evaluated with contrast-enhanced ultrasound. AIM: To evaluate the possible correlation between ultrasound contrast-agent transit times and different stages of chronic hepatitis C. PATIENTS: Sixteen patients with clinically evident hepatitis C virus-related cirrhosis, 22 non-cirrhotic patients with chronic hepatitis C and 14 controls with no clinical evidence of liver disease were studied. METHODS: Contrast-enhanced hepatic ultrasonography was performed with a sulphur hexafluoride-filled microbubble contrast agent, and time curves of hepatic vein signal intensity were analysed to determine the time of enhancement onset (hepatic vein arrival time) and peak enhancement (hepatic vein peak enhancement). RESULTS: Hepatic vein arrival time in cirrhotic patients was significantly shorter (p<0.001) than in non-cirrhotic patients and controls. Within the group with chronic hepatitis C, METAVIR scores of fibrosis and necro-inflammatory changes had no significant effect on hepatic vein arrival times. CONCLUSION: Analysis of the time of onset of ultrasound contrast enhancement of the hepatic vein appears to be a simple, non-invasive method for reliably excluding cirrhosis with signs of portal hypertension, but not for assessing the severity of either chronic hepatitis C or cirrhosis.     

Double primary liver cancer (intrahepatic cholangiocarcinoma and hepatocellular carcinoma) in a patient with hepatitis C virus-related cirrhosis

We herein report a rare case of double primary liver cancer, consisting of intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC). A 67-year-old Japanese man with hepatitis C virus-related liver cirrhosis was diagnosed with multiple HCC in S7 and S8 of the liver. We performed a hepatic resection of S7 and S8. The liver tumors in S7 and S8 were pathologically diagnosed as HCC and ICC, respectively. Multiple recurrence of the HCC found 7 years after the surgery was successfully treated with transcatheter arterial chemoembolization. Subsequently, this patient has been doing well, without HCC recurrence. Double primary liver cancer is very rare, and only 21 resected cases have been reported, including that in our patient. We reviewed at all cases in the Japanese- and English-language literature to investigate the clinicopathological features. Our literature review revealed that the present patient is the longest survivor among patients who have undergone hepatectomy for double primary liver cancer.     

Hepatitis C virus RNA quantitation in hepatic veins and peripheral blood in patients with liver cirrhosis: evidence for low level intrahepatic hepatitis C virus replication in advanced liver disease

BACKGROUND: Very few data exist concerning the level of hepatitis C virus replication within the cirrhotic liver and its relationship to disease severity and progression. AIMS: To quantitate hepatitis C virus RNA in hepatic vein blood and peripheral blood in patients with cirrhosis, to evaluate the correlation of hepatitis C virus levels in paired blood samples, and to compare the results with clinical features. PATIENTS: A series of 25 patients with hepatitis C virus-related liver cirrhosis undergoing hepatic vein catheterization were studied: 11 belonged to Child Pugh class A, 8 to class B and 6 to class C. RESULTS: Hepatitis C virus RNA levels did not differ between hepatic vein blood and peripheral blood (p = 0.26), despite a trend towards higher peripheral hepatitis C virus RNA levels. Hepatitis C virus RNA levels did not differ between patients with genotype 1b and non-1b either in hepatic veins or peripheral blood. Hepatitis C virus loads varied according to the severity of cirrhosis. The patients with more severe liver disease had significantly lower RNA titres than those with less advanced cirrhosis, both in hepatic veins (p = 0.002) and peripheral blood (p = 0.004). No differences in hepatitis C virus load were observed between patients in Child Pugh classes B and C. CONCLUSIONS: The present data show that in patients with cirrhosis hepatitis C virus RNA concentrations do not differ between hepatic blood and peripheral blood and, furthermore, confirm that hepatitis C virus replication is reduced in patients with advanced cirrhosis, compared with patients with less severe liver disease. These findings might indicate that patients with liver cirrhosis maintain an efficient intrahepatic hepatitis C virus replication even in end-stage disease, although hepatitis C virus viraemia decreases according to the severity of liver disease.     

Intrahepatic peribiliary glands of humans. I. Anatomy, development and presumed functions

Abstract The intrahepatic biliary tree is regarded as an excretory duct of two secretory units: hepatocytes and intrahepatic peribiliary glands. This review describes the anatomy, development and presumed functions of the latter. These glands are preferentially located around the intrahepatic large bile ducts, and are histologically divided into intramural and extramural structures. The former consist of simple tubular glands with much mucin, and are sparsely and irregularly distributed within the ductal wall. The latter are characterized by the presence of excretory units that consist of seromucinous acini and a conducting system in the periductal tissue. Pancreatic exocrine acini are occasionally admixed with extramural glands. These peribiliary glands appear in the late fetal period and complete their development about 15 years after birth. Extramural and intramural glands secrete neutral and acid mucin into the ductal lumen. Extramural glands contain several enzymes for digestion of protein and lipids. Neural and vascular supply of these glands may be related to the regulation of their secretion. Specific and non-specific immune responses within this glandular system may also be essential in the sterility of bile.     

Cholangiocarcinoma arising in Von Meyenburg complex associated with hepatocellular carcinoma in genetic haemochromatosis

A 61-year-old man had a liver resection for a bilobar mass thought to be, by imaging techniques, an hepatocellular carcinoma. He had been treated for the last 12 years by venesections for genetic haemochromatosis complicated by well-compensated cirrhosis. At surgery, prothrombin time and platelet count were normal, as was alpha-fetoprotein. On the resected specimen, the non-tumoral liver was not cirrhotic; septal fibrosis was present as well as mild iron overload and numerous Von Meyenburg complexes. The bilobar tumour was composed of two different parts: one was a cholangiocarcinoma arising from Von Meyenburg complexes, the other was a moderately differentiated hepatocellular carcinoma with a partially invaded capsule. The two tumours, in close proximity, did not communicate. This observation raises three questions: the relative risk of primary liver cancer including both hepatocellular carcinoma and cholangiocarcinoma in haemochromatosis without cirrhosis; the development of cholangiocarcinoma from Von Meyenburg complexes; the reversibility of cirrhosis in treated patients.     

Liver transplantation for hepatocellular carcinoma in the world: the Taiwan experience

Liver transplantation (LT) has been regarded as “potentially curative” in a cirrhotic patient with hepatocellular carcinoma (HCC) because it removes the cancer and eradicates the cirrhosis. In Taiwan, HCC ranks first among the leading causes of cancer mortality in males and 4th in females. The most common causes are chronic hepatitis B virus-related cirrhosis, hepatitis C virus-related cirrhosis, and combined hepatitis B and C virus-related cirrhosis. The aggregate lifetime cost of hepatitis and HCC constitutes a significant burden on the Taiwanese health-care system. The reported overall (living-donor LT and deceased donor LT) 1- and 3-year survival rates for HCC after LT in Taiwan ranged from 86 to 98% and 61 to 96%, respectively. Microscopic vascular invasion did not influence the outcome of patients, but high alpha-fetoprotein levels >200 ng/ml may be a risk factor for HCC recurrence after transplant.     

Multiple hepatic peribiliary cysts discovered incidentally at a medical examination

We report a living patient with multiple hepatic peribiliary cysts. It was discovered incidentally during an ultrasonographic screening at a medical examination. Peribiliary cysts are multiple retention cysts of peribiliary glands. Although many autopsy cases of peribiliary cysts have been reported, there are few clinical cases of it in living patients. A CT performed immediately after drip-infusion cholangiography (DIC) was most useful for diagnosis in various imaging tests we performed.     

Hepatocellular carcinoma with sarcomatous change arising in primary biliary cirrhosis

We report an autopsy case of hepatocellular carcinoma (HCC) with sarcomatous change arising in the context of primary biliary cirrhosis (PBC) in a 79-year-old man. Primary biliary cirrhosis was diagnosed (stage I according to Scheuer's classification) by findings on blood biochemical analysis, laparoscopy, and liver biopsy at age 69 years. Five years later, (at age 74 years), a mass lesion was detected in the S₆ region of the liver by abdominal ultrasonography, and target biopsy revealed well differentiated HCC. Blood biochemistry, ultrasonography, and computed tomography findings showed that the PBC had progressed to stage IV (cirrhotic stage). Percutaneous ethanol injection therapy (PEIT) was administered to the HCC several times over a 5-year period; however, the patient died of liver failure in February, 1994 (at age 79 years). Viral markers for hepatitis B and C were negative during the course, and hepatitis C virus RNA was not detected by polymerase chain reaction. Autopsy findings showed liver cirrhosis and diffuse involvement of spindle-shaped sarcomatoid cells in the liver, particularly in the S₆ region, associated with several nodules of trabecular HCC cells. A zone of transition between the sarcomatoid cells and the trabecular hepatocellular carcinoma cells was observed. The sarcomatoid cells were diffusely disseminated in the peritoneal cavity and had metastasized to multiple organs. Immunohistochemically, the cells were positive for fibrinogen, as were the coexisting trabecular hepatocellular carcinoma cells. The HCC had been treated several times with PEIT. Of interest, PEIT may be an important factor in this type of tumor progression.     

Effect of alcohol, cigarette smoking, and diabetes on occurrence of hepatocellular carcinoma in patients with transfusion-acquired hepatitis C virus infection who develop cirrhosis

AIM: Alcohol drinking, cigarette smoking, and diabetes have been claimed as risk factors for hepatocellular carcinoma in case-control studies. The aim of this study was to define the impact of these risk factors on the development of hepatocellular carcinoma in hepatitis C virus-related liver cirrhosis. METHODS: A historical cohort of 138 patients with posttransfusion hepatitis C virus-related cirrhosis was selected by reviewing all files of patients referred to our liver unit. Sixty-three of them (46%) developed hepatocellular carcinoma. RESULTS: At univariate analysis, risk factors for hepatocellular carcinoma were observed in patients aged above 59 years [P=0.004; relative risk (RR): 2.08, 95% confidence interval (CI): 1.19-3.68], male sex (P<0.001; RR: 2.48, 95% CI: 1.59-3.87), habit of alcohol drinking (P=0.001; RR: 1.89, 95% CI: 1.24-2.88), and duration of alcohol consumption of more than 30 years (P=0.02; RR: 2.08, 95% CI: 0.98-4.40). At Cox regression analysis, only male sex was an independent predictive factor (beta=0.86; P=0.002; hazard ratio=2.4, 95% CI: 1.3-4.1). CONCLUSION: Diabetes, smoking, and alcohol drinking were not independently related to the risk of developing hepatocellular carcinoma in hepatitis C virus-related cirrhosis.     

Intraductal oncocytic papillary neoplasm of the bile duct: the first case of peribiliary gland origin

We report herein the first case of intraductal oncocytic papillary neoplasm of the bile duct arising from a peribiliary gland of the left hepatic duct. The patient was a 63-year-old Japanese man. Radiological and cholangioscopic examinations revealed intraductal tumor of the left hepatic duct. After pathological diagnosis of adenocarcinoma by cholangioscopic biopsy, a surgical hepatobiliary resection was performed. Pathological examination revealed papillary tumor in the left hepatic duct. Histologically, the tumor was identified as papillary neoplasm comprising oncocytic cells and delicate fibrovascular cores. Interestingly, this tumor originated from the cystic space in the bile duct wall. This cystic space was histologically identified as a cystically dilated peribiliary gland. Carcinoma in situ was observed in this cystic peribiliary gland at the bottom of the tumor, but not on any areas of biliary epithelium. This case suggests that intraductal papillary neoplasm can arise from both biliary epithelium and peribiliary glands.