Branch duct intraductal papillary mucinous neoplasms in a retrospective series of 190 patients.

BACKGROUND: A consensus conference has recommended close observation of branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) smaller than 30 mm, without symptoms or mural nodules. This study investigated whether these recommendations could be validated in a single-centre experience of BD-IPMNs. METHODS: Some 190 patients with radiological imaging or histological findings consistent with BD-IPMN were enrolled between 1998 and 2005. Those with less than 6 months' follow-up and no histological confirmation were excluded. RESULTS: BD-IPMN was diagnosed by computed tomography and pancreatography in 105 patients and pathologically in 85. Eighteen patients had adenoma, 53 borderline malignancy, five carcinoma in situ and nine invasive carcinoma. Findings associated with malignancy were the presence of radiologically suspicious features (P < 0.001) and a cyst size of at least 30 mm (P = 0.001). Had consensus guidelines been applied, 54 patients would have undergone pancreatic resection, whereas only 28 of these patients actually had a resection; 12 of the latter patients had a malignancy compared with none of the 26 patients who were treated conservatively. CONCLUSION: A simple increase in cyst size is not a reliable predictor of malignancy. Observation is recommended for patients with a BD-IPMN smaller than 30 mm showing no suspicious features on imaging.

Comparison of a novel teeth-protecting mouthpiece with a traditional device in preventing endoscopy-related complications involving teeth or temporomandibular joint: a multicenter randomized trial.

BACKGROUND AND STUDY AIMS: After upper endoscopy, patients have complained of symptoms involving teeth or the temporomandibular joint; however, these endoscopy-related complications are usually ignored with few attempts to prevent them. The aim of this study was to identify the incidence of endoscopy-related complications involving teeth or temporomandibular joint, and to compare the effectiveness of a newly developed teeth-protecting mouthpiece (TPM) with a traditional mouthpiece (the MB-142) in preventing these complications. PATIENTS AND METHODS: 872 patients from 28 centers, who were undergoing their first upper endoscopy, were randomly assigned to TPM and MB-142 groups. At 3 - 4 days after the procedure, the occurrence of endoscopy-related complications involving the teeth or the temporomandibular joint was investigated using a structured questionnaire. Finally 865 patients (TPM group, n = 423; MB-142, n = 442) responded to this questionnaire and were included in the analysis. RESULTS: Overall, the incidence of complications was significantly lower in the TPM than in the MB-142 group (0.9% vs. 3.2%). With stratification according to sedation status, in nonsedated patients no significant difference was found between the two groups (0.7% vs. 0.9%). In sedated patients, however, the TPM group showed a significantly lower incidence of complication than the MB-142 group (1.7% vs. 11.6%). Clinically serious problems such as a tooth fracture or a loose tooth occurred only in sedated patients in the MB-142 group. CONCLUSIONS: The TPM showed an advantage over the MB-142 mouthpiece for preventing endoscopy-related complications involving teeth or the temporomandibular joint.

A phase II trial of S-1 and cisplatin in patients with metastatic or relapsed biliary tract cancer.

BACKGROUND: Optimal chemotherapy for advanced biliary tract cancer (BTC) is yet to be defined. We carried out this study to evaluate the efficacy and toxicity of combination chemotherapy with S-1 and cisplatin in metastatic or relapsed BTC. PATIENTS AND METHODS: Patients with pathologically proven BTC were eligible. The chemotherapy regimen consisted of S-1 (40 mg/m(2) p.o. b.i.d. from D1-14) and cisplatin (60 mg/m(2) on D1), repeated every 3 weeks. RESULTS: Fifty-one BTC patients (metastatic:relapsed = 37:14, Gall-bladder:intrahepatic bile ducts:extrahepatic bile ducts = 16:25:10) were enrolled from January 2005 to December 2006. Median age was 57 years (range, 31-71) and most patients had a good performance status. The overall response rate was 30% [95% confidence interval (CI), 17.3-42.7] and complete response was observed in two patients (4%), partial response in 13 (26%), stable disease in 21 (42%), and progressive disease in 9 (18%). With a median follow-up of 12.4 months, the median time to progression was 4.8 months (95% CI, 3.3-6.3) and median overall survival was 8.7 months (95% CI, 6.0-11.4). Major toxic effects were grade 3/4 neutropenia (8.9% of all cycles) and febrile neutropenia was observed in six cycles (2.7% of all cycles). CONCLUSION: Combination chemotherapy with S-1 and cisplatin was a moderately effective outpatient-based regimen in BTC patients. Toxic effects were moderate but manageable.

Risk factors for pancreatitis in patients with anomalous union of pancreatobiliary duct.

BACKGROUND/AIMS: The clinical features of pancreatitis in patients with an anomalous union of the pancreatobiliary duct (AUPBD) are unclear. This study analyzed the clinical features, pathogenic mechanisms, risk factors, and clinical courses after treatment in AUPBD patients. METHODOLOGY: The medical records and cholangiopancreatograms of 58 patients with AUPBD and a choledochal cyst diagnosed between 1982 and 2001 were retrospectively reviewed. RESULTS: Sixteen (27.6%) out of the 58 AUPBD patients experienced pancreatitis. The incidence of pancreatitis was significantly higher in those patients with a long (>21mm) and wide (>5mm) common channel, a wide diameter of the proximal pancreatic duct (>2.5mm), the presence of a filling defect in the common channel, and the presence of a pancreatic duct anomaly (p<0.05). A bile duct diversion from the pancreatic duct by a choledochal cyst excision prevented the recurrence of pancreatitis in most cases. A duodenopancreatectomy was required in some cases. CONCLUSIONS: The morphological characteristics of the common channel and pancreatic duct contribute to the development pancreatitis in AUPBD patients and bile reflux into the pancreatic duct might be the main mechanism of pancreatitis in these patients.

Factors predicting concurrent cholangiocarcinomas associated with hepatolithiasis.

BACKGROUND/AIMS: Hepatolithiasis is a risk factor for cholangiocarcinoma. However, it is difficult to detect early cholangiocarcinoma that occurs as a complication of hepatolithiasis. To identify the factors, which can be used for predicting cholangiocarcinomas in patients with hepatolithiasis, we compared the clinical characteristics of patients who had cholangiocarcinoma associated with hepatolithiasis with those of patients with hepatolithiasis only. METHODOLOGY: Forty patients with cholangiocarcinoma associated with hepatolithiasis (group HC) and 73 patients with hepatolithiasis only (group H) were randomly selected for this study. Mean tumor size was 6.1 +/- 2.4 cm in diameter. RESULTS: Patients of group HC were older (56.7 +/- 8.9 yr) than those of group H (49.2 +/- 12.9 yr) (p < 0.001). Weight loss was more frequent in group HC (51.5%) than in group H (5.5%) (p < 0.001) and serum alkaline phosphatase levels were higher in group HC (181 +/- 184 IU/L) than in group H (426 +/- 385 IU/L) (p < 0.001). The proportion of the patients who had hepatolithiasis in the right or both lobes of the liver was higher in group HC (72.5%) than in group H (50.6%) (p = 0.024). The optimal cutoff value of serum CEA level for cholangiocarcinoma detection was set at 4.2 ng/mL using ROC cure to give a sensitivity of 67.6% and a specificity of 90.5%. Group HC differed from group H because of its lower rates of both abdominal pain and cholangitis, longer duration of stone history, and lower serum albumin level. Factors that did not predict cholangiocarcinoma included sex ratio, white blood cell count, serum bilirubin level, and hepatic atrophy. CONCLUSIONS: Cholangiocarcinoma should be suspected in patients with hepatolithiasis, especially when, the patient is over 40 years old, has a long history of hepatolithiasis with weight loss, a higher level of serum alkaline phosphatase, a lower level of serum albumin, a serum carcinoembryonic antigen level exceeding 4.2 ng/mL, and hepatolithiasis that is located either in the right or both lobes of the liver.

Establishment and characterisation of six human biliary tract cancer cell lines.

Human cell lines established from biliary tract cancers are rare, and only five have been reported previously. We report the characterisation of six new six biliary tract cancer cell lines (designated SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079 and SNU-1196) established from primary tumour samples of Korean patients. The cell lines were isolated from two extrahepatic bile duct cancers (one adenocarcinoma of common bile duct, one hilar bile duct cancer), two adenocarcinomas of ampulla of Vater, one intrahepatic bile duct cancer (cholangiocarcinoma), and one adenocarcinoma of the gall bladder. The cell phenotypes, including the histopathology of the primary tumours and in vitro growth characteristics, were determined. We also performed molecular characterisation, including DNA fingerprinting analysis and abnormalities of K-ras, p15, p16, p53, hMLH1, hMSH2, DPC4, beta-catenin, E-cadherin, hOGG1, STK11, and TGF-betaRII genes by PCR-SSCP and sequencing analysis. In addition, we compared the genetic alterations in tumour cell lines and their corresponding tumour tissues. All lines grew as adherent cells. Population doubling times varied from 48-72 h. The culture success rate was 20% (six out of 30 attempts). All cell lines showed (i) relatively high viability; (ii) absence of mycoplasma or bacteria contamination; and (iii) genetic heterogeneity by DNA fingerprinting analysis. Among the lines, three lines had p53 mutations; and homozygous deletions in both p16 and p15 genes were found three and three lines, respectively; one line had a heterozygous missense mutation in hMLH1; E-cadherin gene was hypermethylated in two lines. Since the establishment of biliary tract cancer cell lines has been rarely reported in the literature, these newly established and well characterised biliary tract cancer cell lines would be very useful for studying the biology of biliary tract cancers, particularly those related to hypermethylation of E-cadherin gene in biliary tract cancer.

Hepatopulmonary syndrome in poorly compensated postnecrotic liver cirrhosis by hepatitis B virus in Korea.

BACKGROUND: Hepatopulmonary syndrome (HPS) refers to the association of hypoxemia, intrapulmonary shunting and chronic liver disease. But there is no clear data about the prevalence of HPS in postnecrotic liver cirrhosis by hepatitis B virus (HBV), the most common cause of liver disease in Korea. The aim of this study was to investigate the prevalence of HPS in poorly compensated postnecrotic liver cirrhosis by HBV, and the correlation of the hepatopulmonary syndrome with clinical aspects of postnecrotic liver cirrhosis by HBV. METHODS: Thirty-five patients underwent pulmonary function test, arterial blood gas analysis and contrast-enhanced echocardiography. All patients were diagnosed as HBV-induced Child class C liver cirrhosis and had no evidence of intrinsic cardiopulmonary disease. RESULTS: Intrapulmonary shunt was detected in 6/35 (17.1%) by contrast-enhanced echocardiography. Two of six patients with intrahepatic shunts had significant hypoxemia (PaO2 < 70 mmHg) and four showed increased alveolar-arterial oxygen gradient over 20 mmHg. Only cyanosis could reliably distinguish between shunt positive and negative patients. CONCLUSIONS: The prevalence of intrapulmonary shunt in poorly compensated postnecrotic liver cirrhosis by HBV was 17.1% and the frequency of hepatopulmonary syndrome was relatively low (5.7%). 'Subclinical' hepatopulmonary syndrome (echocardiographically positive intrapulmonary shunt but without profound hypoxemia) exists in 11.4% of cases with poorly compensated postnecrotic liver cirrhosis by HBV. Cyanosis is the only reliable clinical indicator of HPS of HBV-induced poorly compensated liver cirrhosis. Further studies are required to determine if the prevalence and clinical manifestations of HPS varies with etiology or with geographical and racial differences.

Genetic alterations in gallbladder adenoma, dysplasia and carcinoma.

Adenoma and dysplasia in the gallbladder (GB) have been reported as precancerous lesions, but the genetic evidence of this is not clearly defined. The purpose of this study was to analyze the frequencies of K-ras, p53, and p16 gene mutations, of microsatellite instability (MI) and of loss of heterozygosity (LOH) in GB cancer, dysplasia, and adenoma. Tissues from 15 GB cancers, five dysplasias around cancerous tumors, and three adenomas were collected prospectively. The mutation rates of K-ras, p53, and p16 were 20.0, 35.7, and 30.7%, respectively, in GB cancers. However, no mutations were found in dysplasia or adenoma. Reduced staining for p16 was seen in 23% of carcinomas. All of the GB carcinomas and four out of five (80%) of the dysplasias showed LOH in a minimum of one locus, but one out of three (33%) cases of adenoma displayed LOH in only one locus. All of the loci of LOH in the dysplasias, except one, showed the same patterns of allelic loss as the adjacent carcinomas. Only one dysplasia showed multiple MI. In conclusion, multiple LOH may be associated with the development of dysplasia and the malignant transformation of GB carcinoma. Gene alterations of K-ras, p53, and p16 are important steps in the malignant changes of dysplasia. However, MI seems to have only a limited role in GB cancer development.

A precipitation reaction found in patients with hepatitis C as a marker for the purification of virus-like particles.

Even after the molecular cloning of the hepatitis C virus (HCV), an HCV-specific precipitation reaction has not yet been identified. We attempted to develop a precipitation system exclusively for anti-HCV-positive sera as a first step in finding an HCV-specific antigen and HCV-associated particles. In some patients being in a final stage of different liver diseases, we found sera (179/132,761; designated 'a-CK') which specifically precipitated with anti-HCV- and HCV-RNA-positive sera (designated 'CK'). When CK-positive sera were searched for in patients with various liver diseases using standard a-CK-positive plasma, CK was detected in 420 (57.9%) of 726 anti-HCV-positive sera and in none of the 1,630 anti-HCV-negative ones. The nature of CK and a-CK has not been fully clarified yet; CK demonstrated inter-betagamma mobility, whereas a-CK showed beta-globulin mobility; CK was not detected in cryoprecipitate, but HCV RNA was present in precipitates of CK-positive plasma incubated with one that was a-CK positive. Transmission electron microscopy revealed two size ranges of particles in the precipitate of CK- and a-CK-positive plasmas, 23-38 nm and 48-65 nm. We have found a novel precipitation system which is exclusive to anti-HCV-positive sera and which specifically precipitates an HCV-RNA-containing serum fraction and particles. This system can be useful for the purification and characterization of the circulating particles. Furthermore, it may be a new approach to the nature of HCV-RNA-carrying material.

Association between genetic polymorphisms of the cytochromes P-450 (1A1, 2D6, and 2E1) and the susceptibility to pancreatic cancer.

OBJECTIVES: Metabolic activation is a prerequisite for the carcinogenic effect of many carcinogens, and considerable interindividual variation exists in the metabolic capacity to activate the carcinogens. The cytochromes P-450 (CYPs) are responsible for the activation mechanism, and polymorphisms of the CYPs (CYP1A1, CYP2D6, and possibly CYP2E1) are known to be related to increased susceptibility to smoking related Kreyberg type I lung cancer. The aim of this study is to clarify the relationship of genetic polymorphisms of the CYPs to susceptibility to pancreatic cancer, another smoking-related cancer. METHODS: We analyzed 45 samples from patients with pancreatic cancer and 53 samples from controls. DNA was isolated from blood samples and the CYP1A1, 2D6 and 2E1 genes were amplified by PCR. Analyzing the genotypes of the CYPs by allele-specific PCR or RFLP analysis, we assessed the allele frequencies for each mutation of the CYPs among the patients with pancreatic cancer and the controls. RESULTS: The allele frequencies for the mutation in the 3'-flanking region of the CYP1A1 among the cases and the controls were 0.31 and 0.36, respectively. The allele frequencies for the exon 7 mutation of the CYP1A1 were 0.16 and 0.23, respectively, but with no statistical significance. The frequencies for the mutant c2 allele of the CYP2E1 were 0.19 and 0.30, respectively, but with no statistical significance. Two persons homozygous for a gene deletion of the CYP2D6 were observed among control subjects; other mutations were not observed among either the patients or controls. CONCLUSION: We could not find any evidence that polymorphisms of the CYPs are associated with increased susceptibility to pancreatic cancer.

Detection of pancreatic adenocarcinoma: relative value of arterial and late phases of spiral CT.

BACKGROUND: Spiral computed tomography (CT) allows the pancreas to be imaged during peak contrast levels owing to the capability of fast data acquisition. The objective of this study was to evaluate the relative value of the arterial and late phases of spiral CT for detecting pancreatic adenocarcinomas. METHODS: Twenty-two patients with pathologically proved pancreatic adenocarcinomas underwent two-phase spiral CT. The CT scans were performed with 5 mm collimation and 5 mm/s table speed. Images during the arterial and late phases were obtained at 30- and 180-second delays, respectively. The images of the arterial phase were compared with those of the late phase in terms of tumor conspicuity from surrounding pancreatic parenchyma and tumor detectability by means of a 3-point grading system: 1 (poor), 2 (fair), and 3 (good). RESULTS: In terms of tumor conspicuity from surrounding pancreatic parenchyma, 16 lesions (73%) were good, 5 lesions (23%) were fair, and 1 lesion (4%) was poor during the arterial phase, whereas 6 lesions (27%) were good, 9 lesions (41%) were fair, and 7 lesions (32%) were poor during the late phase (p = 0.0007). The arterial phase was superior to the late phase in 16 patients (73%) and equal in 6 patients (27%). For tumor detectability, 18 lesions (82%) were good, 3 lesions (14%) were fair, and 1 lesion (4%) was poor during the arterial phase, whereas 10 lesions (45%) were good, 7 lesions (32%) were fair, and 5 lesions (23%) were poor during the late phase (p = 0.0033). For detectability, the arterial phase was superior to the late phase in 14 patients (64%) and equal in 8 patients (36%). CONCLUSION: The arterial phase of spiral CT is superior to the late phase, which is equivalent to conventional CT for detecting pancreatic adenocarcinoma.

Cobalt-induced occupational asthma associated with systemic illness.

We report a case of occupational asthma caused by cobalt associated with systemic symptoms. He was a non-atopic, ex-smoker and had worked in a glassware factory for 14 months. A skin prick test with CoSO4 up to 100 mg/ml showed a negative result. A bronchoprovocation test with CoSO4 demonstrated an isolated asthmatic response with systemic symptoms such as fever, arthralgia and myalgia. Although an initial methacholine bronchial challenge test showed a negative result, the following methacholine bronchial challenge test which was done 24 hours after the challenge testing demonstrated an increased airway hyperresponsiveness at 2.5 mg/ml which recovered 7 days later. An intradermal skin test with 10 mg/ml and 100 mg/ml CoSO4 solution demonstrated positive responses respectively(13 x 12/40 x 32, 20 x 15/40 x 37 , histamine 16 x 14/64 x 50). A patch test including cobalt showed a negative result. Bronchoalveolar lavage fluid after the cobalt inhalation testing and other laboratory findings showed no evidence of hypersensitivity pneumonitis. These results suggested that cobalt could induce occupational asthma with systemic illness in an exposed worker.

Macrocystic serous cystadenoma of pancreas--a case report.

The macrocystic variant of serous cystadenomas of the pancreas has only recently been described. We present a case of a 40 year-old female, who presented with vague indigestion. The cyst was unilocular, and was lined by simple cuboidal, ciliated serous type epithelium. Fine needle aspiration, immunohistochemical, light microscopic, and electron microscopic studies are discussed.

Piezoelectric lithotripsy of radiopaque gallstones: results and six-month follow-up.

Sixty-eight patients with radiopaque gallbladder stones (38 with a single stone, 30 with multiple stones) were treated with piezoelectric extracorporeal shock wave lithotripsy (ESWL) and results were compared with those of 69 patients with radiolucent stones (28 with a single stone, 41 with multiple stones). Stones were fragmented to 4 mm or less in 76.8% after 41,466 +/- 36,504 shock waves in the radiolucent stone group and 77.9% after 54,686 +/- 51,024 shock waves in the radiopaque stone group (p = 0.876 and 0.130, respectively). In 137 patients, ten patients were lost to follow-up. Average period of follow-up was 220 +/- 198 days. Six-month clearance rate of the radiolucent stone group was 43.5% and that of the radiopaque stone group was 16.4% (p less than 0.05) Figure 1. Six-month clearance rate of patients with single stones smaller than 2 cm was also significantly higher in the radiolucent stone group than in the radiopaque stone group (69.5% vs 18.6%; p less than 0.01). However, in patients with multiple stones, the presence of calcification did not affect rates of successful fragmentation or 6-month clearance. There was no statistically significant difference in incidence of complications between the radiolucent and radiopaque stone groups. Although the number of cases are small and the follow-up period is short, our results of ESWL on radiopaque gallstones are so far not satisfactory in terms of stone clearance. Strict patient selection is needed unless there is an improvement in the lithotripsy procedure or post-lithotripsy management.

Retained intrahepatic stones: treatment with piezoelectric lithotripsy combined with stone extraction.

Extracorporeal shock wave lithotripsy (ESWL) was performed in 11 patients with oriental cholangiohepatitis and intrahepatic stones associated with segmented strictures of intrahepatic ducts. All patients had previously undergone biliary surgery and basket extraction via a T-tube tract at the time of lithotripsy. The indication for ESWL was failure of, or anticipated difficulty with, basket extraction of the stones via a T-tube tract. A piezoelectric lithotriptor was used in all procedures. The average total number of shock waves administered was 29,756 (range, 10,000-61,395). The average number of treatment sessions was 3.1 (range, 1-6); the number of shock waves used in a single session ranged from 10,000 to 15,000 with a frequency of five shots per second and 30%-50% power. In six patients, the stones were successfully fragmented and completely removed; in three of the others of the stones were fragmented and removed. The overall success rate, including complete (54%) and incomplete (27%) success, was 82%. Difficulty in targeting stones, and severe strictures and deformities of intrahepatic ducts, were the factors responsible for failure. No significant complications were observed.

Differing effects of nor-ursodeoxycholic or ursodeoxycholic acid on hepatic histology and bile acid metabolism in the rabbit.

Nor-ursodeoxycholate, the C23 analogue of ursodeoxycholate, is a potent choleretic agent in rodents when given acutely but, to be used in humans, chronic toxicity studies are required. In the rabbit, ingestion of ursodeoxycholate or chenodeoxycholate leads to accumulation of lithocholate, its major bacterial metabolite, in biliary bile acids, which causes inflammation in portal tracts of the liver and bile duct proliferation. To test whether chronic administration of nor-ursodeoxycholate would cause an analogous accumulation of nor-lithocholate and hepatotoxicity, rabbits were fed a Chow diet containing nor-ursodeoxycholate (5 or 50 mg/day): control groups received Chow alone, and "disease control" groups received Chow plus ursodeoxycholate or Chow plus chenodeoxycholate. After 3 wk, animals were killed, liver sections were interpreted by a pathologist, and the steroid moiety of the glycine (and taurine) conjugates of gallbladder bile acids were analyzed by high-pressure liquid chromatography. Ingestion of nor-ursodeoxycholate did not cause hepatotoxicity, and neither it nor its presumed metabolite, nor-lithocholate, accumulated in biliary bile acids. To explain this unexpected finding, the hepatic metabolism of nor-ursodeoxycholate was investigated in biliary fistula rabbits. Nor-ursodeoxycholate was well absorbed from the intestine and secreted in the bile as a glucuronide as well as the unchanged compound, but conjugation with glycine and taurine was not observed. As glucuronides are poorly absorbed from the gut, it is proposed that the hepatic biotransformation of nor-ursodeoxycholate to a glucuronide rather than to a glycine amidate in the liver prevented its accumulation in the bile acid pool. Thus, shortening the side chain of ursodeoxycholate by a single carbon atom resulted in a bile acid with novel metabolism, which when administered chronically, does not accumulate in the enterohepatic circulation and does not cause hepatotoxicity.

Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents.

To define whether side-chain length influences the physiologic properties of bile acids, nor-ursodeoxycholate (nor-UDC), the C23-nor derivative of ursodeoxycholate (UDC), was synthesized in both nonradioactive and radioactive forms (23-14C). Its hepatic translocation, hepatic biotransformation, and effect on bile flow, biliary bicarbonate, and biliary lipid secretion were compared with that of UDC and those of their respective glycine and taurine conjugates in anesthetized biliary fistula hamsters, rats, and guinea pigs, as well as the isolated perfused hamster liver. Hepatic uptake and biliary output of nor-UDC was slower than that of UDC or cholyltaurine in the isolated perfused hamster liver. In biliary fistula animals, nor-UDC was secreted only in bile. Biliary recovery of nor-UDC as compared to that of UDC was prolonged in the rat and hamster, although not in the guinea pig. Hepatic biotransformation, assessed by chromatography of bile, showed that conjugation of nor-UDC was inefficient, as unconjugated nor-UDC was present in bile; there was little amidation with glycine or taurine in any species, but sulfates and glucuronides, as well as other metabolites, were formed, with the pattern of biotransformation varying among species. When infused over a dosage range of 0.2-30 mumol/kg X min, nor-UDC induced a striking choleresis of canalicular origin. The bile acid-dependent flow was increased threefold in hamsters, ninefold in rats, and nearly twofold in guinea pigs when compared to that induced by UDC. The choleresis was associated with a linear increase in bicarbonate output and concentration in bile, and little phospholipid or cholesterol secretion was induced. A competition experiment in the bile fistula hamster indicated that nor-UDC or its metabolites, or both, appeared to compete for canalicular transport of ursocholyltaurine (a cholyltaurine epimer) when the latter was secreted under its Vmax conditions. Conjugates of nor-UDC and UDC were promptly and almost completely recovered in bile without appreciable hepatic biotransformation; the conjugates did not induce a hypercholeresis or increase biliary bicarbonate concentration. It is proposed that a fraction of nor-UDC is secreted into canalicular bile in the unconjugated form and is protonated by a hydrogen ion derived from carbonic acid that was generated by the hydration of luminal CO2 by carbonic anhydrase present in biliary ductular cells. The protonated bile acid is absorbed, thus generating a bicarbonate anion. The bile acid passes through the cholangiocyte, returns to the sinusoids via the periductular capillary plexus, and is resecreted into bile.(ABSTRACT TRUNCATED AT 400 WORDS)