Search

Background and Aim: The study goal was to compare the outcomes of patients with unresectable hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) as either first- or later-line systemic therapy., Methods: A total of 430 patients with HCC treated with Atezo/Bev at 22 institutions in Japan were included. Patients treated with Atezo/Bev as first-line therapy for HCC were defined as the first-line group (n = 268) while those treated with Atezo/Bev as second- or later-line therapy were defined as the later-line group (n = 162)., Results: The median progression-free survival times in the first- and later-line groups were 7.7 months (95% confidence interval [CI], 6.7-9.2) and 6.2 months (95% CI, 5.0-7.7) (P = 0.021). Regarding treatment-related adverse events, hypertension of any grade was more common in the first-line group than in the later-line group (P = 0.025). Analysis adjusted by inverse probability weighting, including patient and HCC characteristics, showed that the later-line group (hazard ratio, 1.304; 95% CI, 1.006-1.690; P = 0.045) was significantly associated with progression-free survival. In patients with Barcelona Clinic Liver Cancer stage B, the median progression-free survival times in the first- and later-line groups were 10.5 months (95% CI, 6.8-13.8) and 6.8 months (95% CI, 5.0-9.4) (P = 0.021). Among patients with a history of lenvatinib therapy, the median progression-free survival times in the first- and later-line groups were 7.7 months (95% CI, 6.3-9.2) and 6.2 months (95% CI, 5.0-7.7) (P = 0.022)., Conclusion: The use of Atezo/Bev as first-line systemic therapy in patients with HCC is expected to prolong survival., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: This study aimed to elucidate the clinical importance of muscle volume loss (pre-sarcopenia) in patients receiving lenvatinib as treatment for unresectable hepatocellular carcinoma (u-HCC)., Methods: Of 437 u-HCC patients treated with lenvatinib at specific institutions in Japan between March 2018 and May 2020, 151 with available computed tomography imaging data from the time of lenvatinib introduction were enrolled. Pre-sarcopenia was diagnosed based on a previously reported cut-off value calculation formula [psoas muscle area at level of middle of third lumbar vertebra (cm 2 )/height (m) 2 ]. Clinical features and prognostic factors for overall survival (OS) with inverse probability weighting were investigated retrospectively for their relationship with pre-sarcopenia., Results: Cox hazard multivariate analysis showed alpha-fetoprotein (≥400 ng/mL) (hazard ratio [HR] 2.271, P < 0.001), Barcelona Clinic Liver Cancer stage (C and D) (HR 1.625, P = 0.018), and positive for pre-sarcopenia (HR 1.652, P = 0.042) to be significant prognostic factors. OS rates for the pre-sarcopenia group (n = 41) were worse than those for the non-pre-sarcopenia group (n = 110) (0.5-, 1-, and 1.5-year OS: 72.5%, 27.9%, and 7.0% vs 80.7%, 56.7%, and 46.1%, respectively; P < 0.001), as was progression-free survival (P = 0.025). Time to stopping lenvatinib or disease progression was better in the non-pre-sarcopenia group (0.5-, 1-, and 1.5-year OS: 48.0%, 24.5%, and 8.4% vs 20.0%, 10.3%, and 4.2%, respectively; P < 0.001). Also, the frequency of the adverse event appetite loss (any grade) was greater in the pre-sarcopenia group (43.9% vs 18.2%, P = 0.003)., Conclusion: Pre-sarcopenia was shown to be a significant prognostic factor in patients treated with lenvatinib for u-HCC., (© 2020 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: The most important prognostic factor for non-alcoholic steatohepatitis (NASH) is liver fibrosis. The aim of this study is to examine clinical parameters involved in pathological progression in NASH patients who underwent repeated liver biopsy and to analyze the response to treatment with respect to NASH-related single nucleotide polymorphisms (SNPs). We performed longitudinal analysis of genetic and clinical factors associated with progression of NASH., Methods: Eighty NASH patients who had undergone serial liver biopsies were enrolled in this retrospective cohort study. Histological exacerbation was determined based on non-alcoholic fatty liver disease activity score (NAS) and liver fibrosis., Results: About 22.5% had progression of fibrosis, 22.5% had improvement of fibrosis, and 55.0% had no change. NAS increased in 12.5%, decreased in 61.3%, and remained stable in the remaining 26.3%. We examined factors associated with histological progression versus non-progression. Poor response of alanine aminotransferase (ALT) levels, increase in HbA1c levels, and presence of the tumor necrosis factor risk allele in the rs1799964 SNP were identified as independent risk factors contributing to histological progression in NASH patients. In addition, we found that the histological progression rate varies with ALT response, HbA1c levels, and rs1799964 genotype., Conclusions: In this study, we clarified the serum ALT level and the clinical significance of HbA1c to evaluate the progression of fibrosis in Japanese NASH patients. Furthermore, the tumor necrosis factor SNP was more likely to be involved in the response than PNPLA3 SNP. By simultaneously evaluating three factors, it is possible to estimate the risk of histological progression more accurately., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Certain thrombocytopenic patients with chronic liver disease have inadequate platelet count recovery after platelet transfusion or lusutrombopag administration. We aimed to identify the reasons for this phenomenon., Methods: We investigated 58 and 86 thrombocytopenic patients with chronic liver disease who received lusutrombopag (3 mg orally for up to 7 days) or underwent blood transfusions, respectively. Thirty patients underwent simultaneous hepatic surgery and splenectomy. Factors preventing platelet count recovery above 50 × 10 3 /μL were identified., Results: The median patient age was 64 years. Eleven, 78, and 55 patients had hepatitis B, hepatitis C, or another etiology, respectively; 59, 69, and 16 had Child-Pugh classes A, B, and C, respectively. The median spleen volume was 432 mL, and a median of 10 blood units were transfused per patient. The median platelet count rose significantly (from 41.5 × 10 3 /μL to 81.0 × 10 3 /μL) after lusutrombopag administration but not after blood transfusion before invasive procedures. However, maximum platelet counts in patients who underwent splenectomy before platelet transfusion were markedly improved over those who did not. Increasing platelet counts above 50 × 10 3 /μL required baseline platelets > 30 × 10 3 /μL and lusutrombopag administration for all patients. Platelet count recovery was dependent on a spleen volume of < 300 mL and baseline platelets of > 40 × 10 3 /μL in patients who underwent platelet transfusions, while a baseline platelet count of > 30 × 10 3 /μL was required for patients administered with lusutrombopag., Conclusion: Neither blood transfusion nor lusutrombopag improves thrombocytopenia in patients with severe conditions; however, the degree of platelet count elevation following lusutrombopag administration is higher than that following blood transfusion., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Albumin-bilirubin (ALBI) grade was developed as a new method to assess hepatic function. Sorafenib has been confirmed to be effective in improving survival in patients with advanced hepatocellular carcinoma (HCC). In this study, we investigated the impact of ALBI grade versus Child-Pugh classification on survival in HCC patients who received sorafenib., Methods: A total of 567 patients with advanced HCC who received sorafenib were included. We analyzed survival based on Child-Pugh classification or score and ALBI grade or score. We also compared the ability of ALBI and Child-Pugh scores to predict survival using time-dependent receiver operating characteristic analysis., Results: Cumulative survival rates at 90, 180, 360, and 720 days were 84.1%, 66.6%, 47.0%, and 23.3%, respectively. Median survival was 316 days (95% confidence interval, 279-377). Both Child-Pugh classification and ALBI grade were independently associated with overall survival in multivariate analyses. In addition, overall survival differed significantly between patients with ALBI grades 1 and 2 (hazard ratio, 1.44; 95% confidence interval, 1.09-1.92, P = 0.011) among patients with a Child-Pugh score of 5. Time-dependent receiver operating characteristic analysis showed that ALBI score predicted overall survival better than Child-Pugh score., Conclusions: Albumin-bilirubin grade is a better predictor of survival in patients with advanced HCC who received sorafenib therapy than Child-Pugh classification., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: The aim of the present prospective study was to evaluate tumor recurrence (intrasubsegmental recurrence-free survival and local tumor recurrence-free survival) and hepatic functional reserve following no-touch ablation., Methods: The prospective cohort study protocols were approved by the institutional ethics committee. All patients provided written, informed consent. Between January 2014 and September 2016, 231 patients with 277 hepatocellular carcinoma nodules were prospectively enrolled. An internally cooled bipolar electrode was used for no-touch ablation, while a monopolar electrode was used for direct puncture ablation. The intrasubsegmental recurrence-free survival rate was the primary end-point. The secondary outcomes were the local recurrence-free survival rate, the disease-free survival rate, and the changes in the Child-Pugh score., Results: No-touch ablation resulted in significantly higher cumulative intrasubsegmental tumor recurrence-free survival rates than direct puncture ablation (98.0% vs 87.1% at 1 year, 96.9% vs 76.8% at 2 years, and 91.0% vs 68.3% at 3 years, P < 0.001). The no-touch group also showed significantly better local recurrence-free survival and disease-free survival. Even when only primary cases were analyzed, the same results were obtained. To adjust for differences in the background characteristics, inverse probability of treatment weighting adjustment was performed. Only intrasubsegmental tumor recurrence-free survival was significantly better in the no-touch group (hazard ratio [HR], 0.08; 95% confidence interval [CI], 0.02-0.20, P < 0.001); there was no difference in local tumor recurrence-free survival (HR, 0.36; 95% CI, 0.10-1.02, P = 0.071)., Conclusions: No-touch ablation appears to be an ideal method for the prevention of intrahepatic dissemination., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV) infected-patients. However, the real-world efficacy and safety of the therapy for patients with cirrhosis are unknown., Methods: A total of 252 patients with genotype 1 HCV infection (158 with chronic hepatitis and 94 with compensated liver cirrhosis) were treated with 24 weeks of daclatasvir and asunaprevir combination therapy. Plasma concentrations of daclatasvir and asunaprevir at day 5 of treatment, end-of-treatment response, sustained virological response (SVR), and the frequencies of adverse events were analyzed., Result: Plasma asunaprevir concentration was significantly higher, and daclatasvir concentration tended to be higher, in cirrhosis patients compared with chronic hepatitis patients. End-of-treatment response was achieved in 95.6% and 94.7% of chronic hepatitis and cirrhosis patients, respectively, and SVR was achieved in 94.3% and 92.6%. Although pre-treatment NS5A drug resistant-associated variants were detected, a high SVR rate was achieved when the population frequency of the variant was low. The frequencies of treatment-related adverse events in cirrhosis patients were similar to those in chronic hepatitis patients. Treatment discontinuation due to adverse events occurred in three and two patients in chronic hepatitis and cirrhosis groups, respectively; however, four out of five patients with treatment discontinuation nonetheless achieved SVR., Conclusion: Patients with compensated liver cirrhosis have similar virological response and tolerance for daclatasvir plus asunaprevir therapy to patients with chronic hepatitis. This combination therapy might offer a safe and effective treatment for chronic HCV infected-patients with compensated cirrhosis., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: We assessed the risk factors for the development of hepatocellular carcinoma (HCC) following successful eradication of hepatitis C virus (HCV) with interferon (IFN) therapy in a long-term, large-scale cohort study., Methods: We reviewed 1094 consecutive patients with HCV who achieved sustained virological response (SVR) following IFN therapy between January 1995 and September 2013., Results: During the observation period (median 50 months: range 13-224), 36 (3%) of 1094 patients developed HCC after SVR. The median period from SVR to diagnosis of HCC was 37 months (range 17-141), and the cumulative rates of HCC at 5, 10, and 15 years were 4%, 6%, and 12%, respectively. Multivariate analysis identified old age (≥60 years, HR, 3.1: 95%CI, 1.3-6.6: P = 0.009), male sex (HR, 12.0: 95%CI, 2.8-50.0: P < 0.0001), advanced fibrosis stage (F3/4, HR, 3.2: 95%CI, 1.6-7.2: P < 0.0001), and alpha-fetoprotein ≥10 ng/mL at 1 year after SVR (HR, 7.8: 95%CI, 2.9-16.8: P < 0.0001) as significant and independent risk factors for post-SVR HCC., Conclusions: Older age and male sex (host factors), advanced fibrosis stage (pre-IFN treatment factor), and higher alpha-fetoprotein values (post-treatment factor) were significantly associated with HCC development after HCV eradication., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and is used to reduce cancer-induced osteolysis. We reported previously that ZOL delayed both the growth and pain progression of bone metastases from hepatocellular carcinoma. The present study was designed to evaluate the effects of ZOL on hepatoma cell lines and the molecular mechanisms of such effects., Methods: Cell viability assay, scratch assay, immunohistochemistry, Western blotting, and flow cytometry analysis were performed using Huh7 and HepG2 cells treated with and without ZOL., Results: ZOL reduced cell growth in a dose-dependent manner and prevented cell migration when used at a concentration exceeding 10 μM. Immunohistochemistry showed that the inhibitory effects of ZOL on hepatoma cell progression was not due to the suppression of Ras and RhoA expression but due to inhibition of their translocation from the cytosol to the cell membrane, which terminates mevalonate pathway. Immunoblotting and flow cytometry showed that ZOL inhibited the mitogen-activated protein kinase pathway (MAPK) and induced apoptosis of hepatoma cells., Conclusions: Our results indicated that ZOL prevented cell growth and metastasis based on direct antitumor effects in hepatoma cells. The use of ZOL could not only suppress the progression to bone metastatic lesions but also prevented growth of primary hepatocellular carcinoma., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background and Aim: Changes in microRNA (miRNA) expression have been detected in a broad range of biological processes including cancer. Here we determined the role of miRNA dysregulation in hepatocellular carcinoma (HCC)., Methods: We investigated the expression of nine cancer-related miRNAs in HCC. Among these, miR-224 was the most significantly uprgulated in HCC tissues (n = 18), compared with normal (n = 9) and HCC adjacent non-tumorous liver tissues (n = 18). After leading-in currently reported gene targets from Sanger miRBase, we characterized the expression profiles of target genes of miR-224 using cDNA microarray. The altered expression was subsequently validated by real-time polymerase chain reaction and Western blot. The phenotypic changes by miR-224 expression were identified by cell viability, apoptosis, and in vitro scratch assays., Results: The microarray analysis and miRNA target prediction analysis allowed the identification of significant changes in 68 putative gene targets after overexpression of miR-224. The high-ranking genes CDC42, CDH1, PAK2, BCL-2, and MAPK1 were confirmed as important targets of miR-224 and involvement in hepatocarcinogenesis. Overexpression of miR-224 significantly in Hek293 and Huh7 cells altered the expression levels of CDC42, CDH1, PAK2, and BCL-2 at both mRNA and protein levels. Similar changes in the expression of the same genes were also observed in HCC tissues. Via functional analyses, cell proliferation, migration and anti-apoptosis were proved to be affected by miR-224 expression., Conclusion: The results suggest that miR-224 plays a role in cell proliferation, migration, invasion, and anti-apoptosis in HCC by directly binding to its gene targets, implicating this RNA in HCC development and progression., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background and Aim: Interleukin-28B (IL28B) single nucleotide polymorphism (SNP) influences viral response (VR) to interferon (IFN) therapy in patients with hepatitis C. We studied the relationship between VR and the IL28B polymorphism (rs8099917) in patients on long-term pegylated IFN plus ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after living-donor liver transplantation (LDLT)., Methods: Thirty-five patients with recurrent hepatitis C after LDLT were treated with PEGIFN/RBV. We evaluated the effect of IL28B SNP on the outcome in 20 patients infected with hepatitis C virus genotype 1 who completed IFN therapy., Results: The sustained VR (SVR) rate was 54% (19/35) for all patients; 46% (13/28) for genotype 1. The SVR rate of donors' TT group (major genotype) was higher than that of donors' TG+GG group (minor genotype) (73% vs 20%), while that of recipients' TT group was similar to that of recipients' TG+GG group (64% vs 50%). With regard to the combined effect of donors' and recipients' IL28B SNP, the SVR rates of TT:TT (donors':recipients'), TT:TG+GG, TG+GG:any group were 81%, 50%, and 20%, respectively. The VR rate of TT:TT, TT:TG+GG and TG+GG:any group at 12 weeks were 28%, 0%, and 0%; those at 48weeks were 70%, 50%, 20%, and those at the end of treatment were 100%, 50%, 20%, respectively. The multivariate analysis identified IL28B of donors:recipients (TT:TT) as the only independent determinant of SVR (odds ratio 15.0, P=0.035)., Conclusion: Measurement of donors' and recipients' IL28B SNP can predict the response to PEGIFN/RBV therapy, and the donors' IL28B SNP might be a more significant predictor than that of the recipients., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background and Aim: Advanced glycation end products (AGE), senescent macroprotein derivatives formed at an accelerated rate in diabetes, play important roles in the pathogenesis of diabetic vascular complications. Recently, AGE have also been found to be involved in insulin resistance. Although non-alcoholic steatohepatitis (NASH) is generally considered a hepatic manifestation of insulin resistance, there are no reports showing the link of AGE to NASH. The aim of this study was to evaluate the clinical significance of AGE in patients with NASH., Methods: Glyceraldehyde-derived AGE levels were assayed from serum obtained from 106 patients: 66 with NASH, 10 with simple steatosis, and 30 controls., Results: Serum glyceraldehyde-derived AGE levels (U/mL) were significantly elevated in NASH patients (9.78 +/- 3.73) compared with simple steatosis (7.17 +/- 2.28, P = 0.018) or healthy controls (6.96 +/- 2.36, P = 0.003). Moreover, these were inversely correlated with adiponectin, an adipocytokine with insulin-sensitizing and anti-inflammatory properties. In addition, immunohistochemistry of glyceraldehyde-derived AGE showed intense staining in the livers of NASH patients., Conclusion: The present data suggest that the sustained increase of glyceraldehyde-derived AGE could at least in part contribute to the pathogenesis of NASH. The serum glyceraldehyde-derived AGE level may be a useful biomarker for discriminating NASH from simple steatosis.

Background: Absorption of water, as well as emptying of bile, are important functions of the gallbladder. We studied the changes of gallbladder function with age in gallstone patients and their influence on the outcome of extracorporeal shockwave lithotripsy (ESWL)., Methods: (i) A total of 123 consecutive patients with complete stone clearance by ESWL were examined. Gallbladder emptying was assessed before treatment using intravenous cholecystography. After stone clearance, the recurrence of gallstones was monitored by using ultrasonography. Cox regression analysis was used to determine the risk factors associated with stone recurrence. (ii) Gallbladder bile was sampled from 59 gallstone patients during surgery. Biliary cholesterol, phospholipids, and total bile acids were simultaneously quantified by using gas-liquid chromatography., Results: Impaired gallbladder function, but not gallstone recurrence, was more frequently observed in older patients (>/=65 years old) than in younger patients (<65 years old). Cox regression analysis revealed that poor gallbladder emptying was an independent predictor of stone recurrence after ESWL in the total study population, but not in the older patients (>/=65 years old). Analysis of bile from surgically treated patients with cholesterol stones showed a significantly higher total lipid concentration and a shorter nucleation time in the younger group (<65 years old), but the cholesterol saturation index did not differ between the younger and older groups., Conclusions: Our data suggest that the reduced concentrating function of the gallbladder in elderly gallstone patients helps to counteract stone recurrence despite their abnormal gallbladder motility. Therefore, aged gallstone patients may be preferentially treated by a non-surgical strategy.

Background: Osteoporosis is associated with cirrhosis of the liver, but the effects of therapy for osteoporosis associated with cirrhosis are still controversial., Methods: We evaluated the effects of calcitriol (1alpha,25-dihydroxyvitamin D3) on bone mineral density (BMD) in 76 patients (26 men and 50 women) with cirrhosis who were assigned randomly to receive calcitriol (0.5 mg twice per day) or not. The BMD of the lumbar vertebrae was measured by dual-energy X-ray absorptiometry at least twice, 12-57 months apart., Results: For men, the mean annual change in BMD was 1.1% in the treated group and -0.4% in the control group. The median (25th and 75th percentiles) annual change in BMD was 0.6 (-0.1, 2.1%) in the treated group and -1.4 (-1.9, 1.6%) in the control group. The difference in the median annual change between the two groups was significant (P = 0.013). For women, the mean annual change in BMD was -0.5% in the treated group and -2.3% in the control group. The median (25th and 75th percentiles) annual change in BMD was -0.5 (-1.8, 1.3%) in the treated group and -1.5 (-3.8, -0.7%) in the control group. This difference was significant (P = 0.011)., Conclusions: Our results suggest that calcitriol can prevent bone loss and, therefore, may be useful for the treatment of bone disease in patients with cirrhosis of the liver.

Background: Conventional models for prediction of survival in patients with primary biliary cirrhosis (PBC) are based on the results of blood tests and on the clinical condition, which may be affected by treatment. We evaluated the usefulness of hepatic receptor imaging with [99mtechnetium]-diethylenetriaminepentaacetic acid galactosyl human serum albumin (GSA) for the staging and prognosis of PBC without the need for reference to laboratory test results., Methods: The subjects were 45 patients with PBC, 10 healthy subjects, 62 patients with chronic hepatitis and 144 patients with cirrhosis. Computer acquisition of gamma-camera data was started just before the injection of 185 MBq [99mTc]-GSA and was stopped 20 min later. Time-activity curves were generated from regions of interest (ROI) for the heart and liver. A receptor index was calculated by dividing the radioactivity of the liver ROI by that of the liver-plus-heart ROI 15 min after the injection. An index of blood clearance was calculated by dividing the radioactivity of the heart ROI 15 min after the injection by that of the heart ROI 3 min after the injection., Results: The median receptor index was higher in patients with PBC than in those with cirrhosis. Among patients with PBC, the receptor index was lower in those with stage IV disease than in those in stages I, II or III. The index of blood clearance was lower in patients with PBC than in those with cirrhosis. Among patients with PBC, the index of blood clearance was higher in those with stage IV disease than in those in stages I, II or III. The receptor index was correlated significantly both to the risk score of the Mayo model and to the prognostic index of the Japanese model. The index of blood clearance was also correlated significantly to this score and prognostic index., Conclusions: Hepatic receptor imaging with [99mTc]-GSA is useful for the evaluation of hepatic functional reserve, staging of PBC and assessment of prognosis.

The formation of cholesterol monohydrate crystal initiates cholesterol gallstone formation. The nucleation time (NT), a light microscopy method, is used currently to estimate human bile metastability. Recently, a cholesterol crystal growth (CCG) assay utilizing photometric turbidity to quantitate cholesterol crystallization was developed using model bile systems. The object of this study was to determine whether this novel CCG assay was applicable to the quantitative assessment of native human bile metastability. Human gall-bladder bile samples were collected from patients undergoing cholecystectomy. There were five patients with cholesterol gallstone and five stone-free patients. A significant correlation between the onset time measured by the CCG assay and the NT observed by light microscopy was found in our modified assay condition where interference by bilirubin was negligible (P < 0.01). Also, the growth rate measured by the CCG assay significantly correlated with the NT (P < 0.05). These results indicate that the CCG assay is applicable to quantitative assessment of human bile metastability reflected by cholesterol crystal nucleation and that the cholesterol crystal growth is also conveniently estimated by this method.

The reasons for the high frequency of endotoxaemia in cirrhosis, whether poor liver function or abnormal portal circulation, are not known. Accurate measurement of endotoxin itself is difficult. Instead, in this study an enzyme-linked immunosorbent assay was used to measure levels of IgA, IgG and IgM antibodies to endotoxin in patients with chronic liver disease and underlying hepatic viral infection. The relationships between the results and clinical symptoms or the presence of a portal systemic shunt were investigated. The median level of IgA antibodies was not different in patients with chronic hepatitis and those with cirrhosis, and the same was found for IgM, but the median level of IgG antibodies was significantly higher in the patients with cirrhosis. When patients with cirrhosis were grouped by the presence or absence of ascites or hepatocellular carcinoma, no significant difference was observed in any of these antibody levels. However, in cirrhotic patients with varices, the level of IgG antibodies to endotoxin was significantly higher than in patients without varices. For evaluation of the portal systemic shunt, the per-rectal portal shunt index was calculated. There was a significant correlation (R = 0.431, P < 0.001) between the per-rectal portal shunt index and the level of IgG antibodies to endotoxin. That is, the degree of abnormality in the portal haemodynamics was correlated with the level of IgG antibodies to endotoxin in patients with liver disease.

The effect of a concomitant infusion of organic anions, structurally related phthaleins, on bile flow was studied in anaesthetized dogs. A combination of rose bengal and sulfobromophthalein was found to uniquely and synergistically produce an acute, reversible form of intrahepatic cholestasis (< 10% of control level). This phenomenon was not observed with the administration of those individual organic anions at concentrations previously associated with the induction of intrahepatic cholestasis. The infusion of either a micelle forming bile salt, sodium taurocholate, or a non-micelle forming bile salt, sodium dehydrocholate, rapidly reversed the intrahepatic cholestasis (within 20 min after bile salt infusion). During the choleretic phase immediately following the bile salt infusion, a transient but marked hypersecretion, a disproportionately increased output in relation to that of bile acids, of biliary phospholipid (176% of control level by taurocholate and 138% of control level by dehydrocholate), and an even more striking amount of biliary protein hypersecretion were observed (392% of control level by taurocholate and 357% of control level by dehydrocholate). Although the significance of these new post-cholestatic observations requires clarification, it is suggested that the intrahepatic cholestasis induced by organic anions reflects a reversible defect in the mechanism(s) involved in transcellular transport.

The degree of involvement of blood flow in the superior mesenteric vein and inferior mesenteric vein in the formation of oesophageal varices is not known. We have developed a method by which the contributions of these veins to portal blood flow can be evaluated simultaneously in a relatively non-invasive way. An enteric-coated capsule containing [123I]iodoamphetamine (IMP) is given by mouth and 3 h later [123I]IMP is instilled into the rectum. The data obtained are treated by computer to calculate the portal shunt index via the inferior and superior mesenteric veins. In chronic hepatitis and cirrhosis, when varices were absent, the difference in these indices was not significant. In the presence of varices, the portal shunt index via the inferior mesenteric vein was significantly higher than that via the superior mesenteric vein. It was suggested that the contribution of blood flow in the inferior mesenteric vein the portal/splenic axis is important in the formation of varices.

Capsules (8 x 30 mm) of technetium-99m pertechnetate were designed for measurement of portal blood flow. Most of the radionuclide entered the superior mesenteric vein. The capsule was taken orally and monitored with a collimator for scintigraphy until it reached the small intestine, when a magnetic field completed an electrical circuit in a sensor, burning a thread, releasing a spring, and discharging the preparation. A study in crab-eating monkeys (Macaca fascicularis) showed that the radionuclide in the small intestine circulated through the superior mesenteric vein to the portal vein and liver. Portal scintigraphy through the small intestine could be analysed in the same way as per-rectal portal scintigraphy, in which blood flow mostly from the inferior mesenteric vein is evaluated. A study of four volunteers showed that, after the radionuclide was released, it circulated through the superior mesenteric vein to the portal vein and liver. Use of a capsule enclosing a radioisotope was possible, and the procedure seemed to be safe. The use of the per-small intestine method plus the per-rectal method should give more accurate results than either method used alone, because the haemodynamics of both the superior and inferior mesenteric vein would be reflected.