Patients with large-duct primary sclerosing cholangitis and Crohn's disease have a better outcome than those with ulcerative colitis, or without IBD.

BACKGROUND: Approximately 20% of primary sclerosing cholangitis (PSC) patients with concomitant inflammatory bowel disease (IBD) have Crohn's disease (CD). AIM: To compare PSC/CD with other PSC patients. METHODS: Retrospective study of 240 PSC patients diagnosed between 1975 and 2012 (median follow-up 12 years). Activity of PSC at diagnosis was assessed by liver biopsy, Mayo risk and ERC scores. Survival without liver transplantation, number of transplantations and liver-related death were endpoints. RESULTS: Sixty-three per cent of patients had IBD: 105 UC, 32 CD and 14 IBD unclassified (IBDu). IBD was diagnosed before PSC in 50%. The yearly development of PSC after diagnosing IBD was similar in UC, CD or IBDu. Small-duct PSC was present in 28% of PSC/CD compared to 3% of PSC/UC. Small-duct PSC had a markedly better survival than large-duct PSC: no patient developed cholangiocarcinoma or liver-related death, but colorectal cancer occurred in three patients. In large-duct PSC, a more favourable outcome was evident in patients with CD. The liver disease was less progressive: one patient underwent liver transplantation compared to 28% and liver-related deaths were absent compared to 7% in the other PSC groups. CONCLUSIONS: The prevalence of PSC with concomitant Crohn's disease is relatively rare, but the outcome is more benign than PSC with UC or without IBD. Approximately one-fourth has small-duct PSC. In large-duct PSC/CD, liver disease is less aggressive and the outcome is much better. The outcome of PSC patients with UC resembled that of PSC without IBD.

Primary sclerosing cholangitis, Crohn's disease and HLA-B27 in black South African women.

Crohn's disease is rare in South African black people and primary sclerosing cholangitis (PSC) is also rare in black patients with IBD, from South Africa. The presence of HLA-B27 is generally associated with seronegative spondylo-arthropathies and correlates with the occurrence of ankylosing spondylitis, recurrent mouth ulcers and uveitis, in patients with IBD. We describe two women with the combination of Crohn's disease, PSC and HLA-B27 from our cohort of the last 5 years of three black patients with Crohn's disease. Crohn's disease, PSC and HLA-B27 respectively, occur rarely in black South Africans and their concurrent presence in two black women suggests a pathogenetic link of HLA-B27 between Crohn's disease and PSC in this population. Female gender might be an additional determinant in this setting.

Hepatitis C and insulin resistance: mutual interactions. A review.

Worldwide approximately 200 million people are chronically infected with hepatitis C virus (HCV). Chronic HCV infection represents the leading cause of liver cirrhosis and the main indication for liver transplantation in the western world. In addition, chronic HCV infection is associated with numerous clinical manifestations, including type 2 diabetes. An obvious and frequently suggested explanation for the connection between HCV infection and type 2 diabetes is that cirrhosis by itself causes insulin resistance. However, the prevalence of type 2 diabetes in HCV cirrhosis is higher than in HBV cirrhosis (23.6% vs 9.4%). This suggests that HCV infection by itself can lead to insulin resistance and predispose to the onset of type 2 diabetes. First, HCV core protein induces hepatic steatosis by inhibition of microsomal triglyceride transfer protein and hepatic steatosis causes insulin resistance. Secondly, HCV core protein inhibits, through elevation of TNF-alfa and other factors, the insulin-signalling pathways causing insulin resistance. Moreover, recent data strongly suggest that insulin resistance is an important predictor of poor response to antiviral therapy in chronic hepatitis patients treated with peginterferon plus ribavirin.

Selection criteria and outcome of patients referred to intestinal transplantation: an European center experience.

Until 1998, intestinal transplantation (SBT) had not been performed in our region of Flanders, Belgium. Potential SBT activity was not known and selection criteria had not been validated. A multidisciplinary SBT program was launched in 1998. We analyzed requests for SBT and outcomes in these patients whether with or without SBT. Listing for SBT was only considered for patients with irreversible short bowel syndrome who had developed life-threatening complications of total parenteral nutrition, but whose general condition was still thought compatible with surgery and immunosuppression. During the study period 1998 to 2004, one third of the requests for SBT (10/31) were deemed suitable. SBT in this group was lifesaving (100% survival) when performed in time. Mortality in this group without SBT was high (67%). Two thirds of the patients (21/31) did not fulfill the SBT inclusion criteria, either because they were "too moribund" to tolerate transplantation or because they were "too well". This preliminary study emphasized the importance of (1) early referral of potential SBT candidates, (2) adherence to strict criteria for listing patients for SBT, and (3) referral of intestinal donors to procurement organizations.

The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin.

AIMS: Cytokeratin (CK) 7 and CK19 expression, present in hepatic progenitor cells (HPCs) and in cholangiocytes but not in normal hepatocytes, has been reported in some hepatocellular carcinomas (HCCs); however, the incidence and relevance of this expression in HCC in Caucasians is not known. Therefore, our aim was to study the occurrence and clinicopathological characteristics of HCC expressing CK7 and/or CK19 in 109 Caucasian patients. METHODS AND RESULTS: The expression of hepatocellular differentiation markers (Hepar, canalicular polyclonal carcinoembryonic antigen), biliary/progenitor cell markers (CK7, CK19), alpha-fetoprotein (AFP), p53 and beta-catenin in HCC was semiquantitatively assessed by immunohistochemistry. Of 109 HCCs, 78 were CK7-/CK19- (72%), 13 CK7+/CK19- (12%), seven CK7-/CK19+ (6%), 11 CK7+/CK19+ (10%). CK19 expression was significantly associated with elevated serum AFP (400 ng/ml) (P = 0.023), tumour AFP expression (P < 0.0001), presence in serum of anti-hepatitis B core (P = 0.016), less fibrosis in non-neoplastic parenchyma (P = 0.009) and less nuclear beta-catenin expression (P = 0.021). CK7 expression was significantly associated with elevated serum bilirubin (> 2 mg/dl) (P = 0.0005) and less nuclear beta-catenin expression (P = 0.003). HCC expressing CK19 had a higher rate of recurrence (P = 0.009, hazard ratio 12.5, n = 31) after liver transplantation compared with CK19- tumours. CONCLUSIONS: In our series, 28% of HCCs contained cells expressing CK7 and/or CK19. They potentially derive from HPCs. The higher recurrence rate of CK19+ HCC after transplantation suggests a worse prognosis for these HCCs compared with CK19- HCC.

A stable model of cirrhotic portal hypertension in the rat: thioacetamide revisited.

BACKGROUND: Cirrhotic animal models are vital to investigate complications of chronic liver disease. We chronologically characterized the effect of thioacetamide, administrated orally and adapted weekly to weight changes, focusing on the optimal moment to obtain all typical features of portal hypertension and cirrhosis. MATERIALS AND METHODS: Male Wistar rats, 200-250 g, were intoxicated for 6, 12 or 18 weeks (n = 8 per group), respectively, and compared with age-matched controls (n = 4 per group). An in-situ perfusion model was used to evaluate intrahepatic resistance and endothelial function. Splanchnic blood flow and portosystemic shunting were assessed by a perivascular flow probe. RESULTS: Rats intoxicated for 6 or 12 weeks had no mortality and histologically showed hepatitis and advanced fibrosis, respectively. At 18 weeks, mortality was 16% (on a total of 56 animals) and only at that moment all animals showed homogenous macronodular cirrhosis with signs of high-grade hepatocellular dysplasia. Portal hypertension was present at 12 weeks (11 +/- 0.4 vs. 5.9 +/- 0.4 mmHg, P < 0.001), but was not associated with the hyperdynamic state until 18 weeks (12.1 +/- 0.8 vs. 5.6 +/- 0.5 mmHg, P < 0.001). At this latter time-point, we also observed increased intrahepatic resistance associated with endothelial dysfunction, hyperresponsiveness to vasoconstrictors, splanchnic hyperaemia and portosystemic shunting. These alterations were associated with increased systemic levels of nitrate/nitrite and thromboxane A(2). CONCLUSION: Thioacetamide, adapted to weekly weight changes, leads to a homogenous, reproducible model of cirrhosis in the rat in 18 weeks, which is associated with all the typical characteristics of portal hypertension, including endothelial dysfunction.

Review article: non-biological liver support in liver failure.

Liver failure, whether acute or acute-on-chronic, remains an important cause of morbidity and mortality. The lack of liver detoxification, metabolic and regulatory functions of the liver leads to life-threatening complications, such as renal failure, altered immune response, hepatic coma and systemic haemodynamic dysfunction, eventually culminating in multiorgan failure. Current medical therapy involves the management of the precipitating event and treatment of complications until the liver eventually recovers, leaving us with no other treatment options than transplantation if these attempts fail. However, the shortage in cadaveric organs and other transplant-related problems, have prompted the need for alternative methods to provide liver support. As liver failure is often potentially reversible, considerable effort has been invested in the development of liver support systems. Currently, most of the experience is available for non-biological support systems. They represent the focus of this review, which aims to define the goals of liver support, to describe the design of the different existing devices and to analyse the available data to determine their current status in the management of patients with liver failure.

Is HBV genotyping of clinical relevance?

The hepatitis B virus, as is the case of the hepatitis C virus, can be categorized in several genotypes. The genotyping of HBV is based on the nucleotide sequence divergence encoding the amino acids constituting the HBV surface proteins. Since the genotype of the hepatitis C virus is shown to be related to epidemiology and response to interferon therapy, one wonders whether this also holds for the hepatitis B virus. HBV genotypes clearly are found to be different in various geographical areas of infection. In Europe, genotypes A and D are predominant, whereas in Asian patients genotypes B and C are more frequent, and in the Middle-East the genotype D. Data concerning the clinical relevance are less clear but it seems that in Europe, the genotype A has a higher HBeAg clearance rate and a better outcome. In Asia, genotype B (and especially the genotype Bj) is associated with a higher HBeAg clearance and with less development of cirrhosis and HCC. The impact on spontaneous or therapy induced viral resolution is not yet clearly identified. Further evaluation in different countries is needed to delineate the impact of the genotype relative to other factors such as age at infection, level of serum transaminases and viral load, on the course of infection, complication, outcome of treatment and prognosis.

Nodular regenerative hyperplasia, portal vein thrombosis, and avascular hip necrosis due to hyperhomocysteinaemia.

A male patient with portal hypertension, portal vein thrombosis, spontaneous splenorenal shunt formation, and encephalopathy, thought to have post-hepatitis B cirrhosis, is described. His condition deteriorated and necessitated liver transplantation. In the explant liver, nodular regenerative hyperplasia with pronounced vascular lesions both in portal venules and in arterioles was found instead of classical cirrhosis. Two years post-transplant he developed bilateral ischaemic femur head necrosis. The three disorders (portal vein thrombosis, nodular regenerative hyperplasia, and ischaemic hip necrosis) seemed to be due to a common vasculopathy induced by hyperhomocyteinaemia. Genetic studies showed that he carried a mutation in the gene encoding for formation of methylenetetrahydrofolate reductase. Treatment with folic acid combined with pyridoxine (vitamin B6) and cyanocobalamin (vitamin B12) normalised his serum homocysteine levels.

Does ex vivo vascular resistance reflect viability of non-heart-beating donor livers?

AIMS: The use of non-heart-beating (NHB) donor livers is limited by a higher risk for primary nonfunction and the absence of methods to measure this risk. This study was designed to determine whether ex vivo vascular resistance of livers correlates with the length of warm ischemia (WI), and, thus, with viability of NHB livers. METHODS: Porcine livers were recovered after 0, 45, or 90 minutes WI. Livers were flushed by gravity and cold stored for 3 hours. Thereafter, livers were perfused at 4 degrees C. Portal vein (PV) and hepatic artery (HA) vascular resistance were calculated during liver flush-out and during 24 hours of machine perfusion. RESULTS: During flush-out, PV and HA vascular resistance were higher among livers with longer WI times; however, only in the PV did the results reach statistical significance. During machine perfusion, PV vascular resistance was low from the start and remained fairly constant. In contrast, HA vascular resistance was higher at the start but gradually diminished to reach a more constant value after 4-6 hours. No correlation was observed between HA or PV vascular resistance and WI during machine perfusion. CONCLUSIONS: The vascular resistance during ex vivo machine perfusion of NHB livers does not correlate with the extent of WI damage and, therefore, cannot predict organ viability.

Liver fatty acid-binding protein: an early and sensitive plasma marker of hepatocellular damage and a reliable predictor of graft viability after liver transplantation from non-heart-beating donors.

OBJECTIVE: Liver fatty acid-binding protein (L-FABP) is a small protein (15 kD) involved in the intracellular transport of long-chain fatty acids in the liver. The L-FABP is regarded as a sensitive marker for liver cell damage. In a pig model for liver transplantation (LTx) from non-heart-beating donors (NHBD), we evaluated plasma changes of L-FABP early after reperfusion of grafts exposed to increasing periods of warm ischemia (WI). METHODS: Porcine livers were procured after 0, 15, 30, 45, and 60 minutes' WI. After 4 hours' cold ischemia (CI), LTx was performed. Primary graft nonfunction (PNF) and day 4 survival were recorded. Plasma samples were collected prior to and 15, 60, and 180 minutes after graft reperfusion for determination of L-FABP and aspartate transaminase (AST). RESULTS: Early after reperfusion, levels of L-FABP correlated well with the duration of WI. The PNF developed in 100% of animals after 60 minutes of WI, 50% after 30, and 45 minutes' WI, and was absent after no WI and 15 minutes of WI. Day 4 survival was 100% in 0 minutes' WI, 83% in 15 minutes' WI, 50% in 30 and 45 minutes' WI, and 0% in 60 minutes of WI. CONCLUSIONS: Plasma levels of L-FABP correlated well with WI and concomitant hepatocellular damage in LTx from NHBD. Monitoring of posttransplant L-FABP plasma levels is a valuable new tool to quantify early the extent of parenchymal cell damage of NHBD livers and to predict their viability and function.

Liver transplantation using cavoportal transposition: an effective treatment in patients with complete splanchnic venous thrombosis.

Complete venous thrombosis of the splanchnic system remains a major challenge in liver transplantation surgery. Some of these patients have been treated successfully by multivisceral transplantation. Cavoportal transposition is another alternative to treat these patients. We reviewed our single-center experience with this technique. Five patients with operatively confirmed complete splanchnic thrombosis were transplanted with the cava portal transposition technique. All survived the procedure; 60% survived long term. This technique is a useful salvage procedure in moribund patients with diffuse portal thrombosis who would otherwise rapidly succumb.

Liver transplantation using livers from septuagenarian and octogenarian donors: an underused strategy to reduce mortality on the waiting list.

Shortage of liver grafts is the only limiting factor for application of liver transplantation and causes an increasing mortality on the waiting list. Very old donors (>70 to 80 years old) are rarely referred to transplant centers because of the assumption that these livers will not work properly. Alternatively, transplant teams may be reluctant to use these very old livers due to the risk of poor posttransplant outcome. We reviewed our experience with seven liver transplantations using very old donor livers. We found that the results in terms of graft function and patient survival are adequate. Interestingly, the majority of these donors originated from a single referring donor unit (of more than 20 units who belong to our donor network) that systematically refers all brain-dead donors to the transplant center, independent of the age of the potential donor. This implies that many of these donors are left undetected in other units. In conclusion, very old donors should be referred to transplant centers since results of transplantation with these grafts are favorable.

Diagnosis and treatment of autoimmune hepatitis at age 65 and older.

AIM: To study features in older patients with autoimmune hepatitis, as this was considered mainly a disease of young females. METHODS: Analysis of 28 patients diagnosed at age > or =65 years compared with 84 younger patients. RESULTS: The incidence was similar at all age decades. The ratio M:F was 1:3 (> or =65 years) vs. 1:2 (<65 years). Presenting symptoms were not different when compared with younger patients and consisted of general malaise and fatigue (36%), jaundice +/- other symptoms (50%), or ascites (11%). Antinuclear antibodies (ANA) > or = 1/80 were positive in 93%, smooth muscle antibodies (SMA) > 1/40 in 50%, anti-liver kidney microsomes (anti-LKM) proved always negative. Histology showed acute necrotizing hepatitis in 19%, severe interphase hepatitis in 15%, chronic hepatitis with plasmo-lymphocytic infiltrate in 30%, cirrhosis in 29% (with active inflammation in one-third); biopsy was refused in 11%. The elderly responded very well to low doses of methylprednisolone (< or =8 mg) and azathioprine (1 mg/kg). This schedule obviates side-effects such as infections seen with higher dosages. CONCLUSION: Autoimmune hepatitis has to be also looked for in the elderly with acute and chronic hepatitis. The steroid therapy should be individualized but kept at a low dose.

Treatment of acute hepatitis C with interferon alpha-2b: early initiation of treatment is the most effective predictive factor of sustained viral response.

AIM: To evaluate the efficacy of early interferon alpha-2b in non-post-transfusion acute hepatitis C virus: a prospective study with historical comparison. PATIENTS: Group A: 28 patients prospectively treated for acute hepatitis C virus with daily regimen of interferon 5 million units for 2 months. Group B: historical series of 16 patients with untreated acute hepatitis C virus. RESULTS: There was no significant difference between the two groups with regard to gender, age, icterus, alanine aminotransferase, or genotypes. In group B, hepatitis spontaneously resolved in three of 16 (19%) patients (follow-up 1-7 years). In group A, 21 of 25 patients became sustained viral responders (75%; P = 0.0003 vs. group B). Factors include not predictive of sustained viral response: age, gender, sources of infection, presence of icterus, alanine aminotransferase peak, bilirubin peak, incubation period, presence of hepatitis C virus antibodies at presentation, or genotypes. The time from presentation to the start of therapy was, however, significantly shorter in sustained viral responders (43 +/- 31 days) than in relapsers or non-responders (88 +/- 52 days) (P = 0.016). CONCLUSIONS: Early treatment of acute hepatitis C virus with interferon prevents chronicity. A short waiting time from presentation to treatment appears as the most relevant predictive factor for sustained response.

Aggregated colon cancer cells have a higher metastatic efficiency in the liver compared with nonaggregated cells: an experimental study.

BACKGROUND: It remains unclear whether aggregated colon cancer cells have a higher tendency for metastasis formation than nonaggregated cells. Also, the absolute number of cancer cells required for hepatic metastasis remains undefined. The aim of the present study was to compare in the liver the metastatic efficiency of viable nonaggregated colon cancer cells versus cell aggregates for equivalent numbers of cancer cells. MATERIALS AND METHODS: DHD/K12/TRb colon cancer cells were administered through the portal vein in syngeneic male BD IX rats. Surgical exploration was performed 8 weeks after injection. Four groups of rats were injected with 0.25 or 0.5 x 10(6) DHD/K12/TRb viable cancer cells, either as single nonaggregated cells or as cell aggregates. RESULTS: Hepatic metastases were observed in 81% of the rats after intraportal injection of cell aggregates equivalent to 0.5 x 10(6) cancer cells. A significant lower metastatic efficiency was found after the injection of 0.5 x 10(6) non-aggregated, and 0.25 x 10(6) aggregated or nonaggregated cancer cells i.e., 16%, 32%, and 27%, respectively. CONCLUSION: Aggregated colon cancer cells have a higher metastatic efficiency in the liver compared with non-aggregated cells, although a critical number of cancer cells are necessary.

Oxidative breakdown of octanoic acid is maintained in patients with cirrhosis despite advanced disease.

As an octanoic acid 13CO2 breath test is frequently used to test gastric emptying of solid food, the purpose of the present study was to study whether oxidative breakdown of octanoic acid is affected by severe liver disease. The design of our study was twofold. First, cirrhotic patients (n = 82) of varying severity were compared with healthy controls (n = 17). Values of half-time, time point of maximal expiration and cumulative recovery of octanoic acid breath tests (OBT) were not significantly different between them. Secondly, cirrhotic patients (n = 10) were studied before placement of transjugular intrahepatic portosystemic shunt, 4-7 days later and 1-2 months later. Values of half-time, time point of maximal expiration and cumulative recovery of consecutive OBTs did not change significantly. The OBT may therefore be a suitable test in the future to detect delayed gastric emptying of solids in cirrhotic patients with reduced liver function and portal hypertension.

Hepatic osteodystrophy in rats results mainly from portasystemic shunting.

BACKGROUND AND AIMS: In chronic liver disease, bone disease frequently develops. The contributions of the different features of liver disease such as parenchymal inflammation, portal hypertension, and portasystemic shunting on bone metabolism have not been systematically studied. The aim of this study was to identify the features of liver disease contributing to bone disease using rat models. METHODS: Parenchymal liver disease was induced by carbon tetrachloride administration, portal hypertension by partial portal vein ligation, and portasystemic shunting by end to side anastomosis of the portal vein to the inferior vena cava. Normal and sham operated surgical animals served as controls. Serum calcium, 25-hydroxy vitamin D (25-OH vit D), and osteocalcin levels, and urinary deoxypyridinoline excretion were analysed. Testosterone and oestradiol levels were determined in male and female rats, respectively. Interleukin 1, interleukin 6, and tumour necrosis factor alpha (TNF-alpha) were determined in serum. Bone density was measured in all groups and in addition, in the surgical groups, histomorphometry was performed on undecalcified specimens of the proximal tibia. The calcium content of the femurs, removed at termination and ashed, was determined. RESULTS: Early parenchymal disease and portal hypertension did not affect bone metabolism or body mass. Portasystemic shunting increased bone resorption, decreased bone formation, bone density, and trabecular bone volume which were commensurate with a reduction in body mass. TNF-alpha levels were elevated and testosterone levels were low in male portasystemic shunted rats. CONCLUSIONS: Portasystemic shunting in the rat adversely affects bone metabolism as part of a generalised catabolic state where high TNF-alpha and low testosterone and 25-OH vit D levels may play a role.

Noniatrogenic haemochromatosis in congenital dyserythropoietic anaemia type II is not related to C282Y and H63D mutations in the HFE gene: report on two brothers.

BACKGROUND: The discovery of the gene responsible for most cases of hereditary haemochromatosis has made it possible to evaluate the role of this gene in iron accumulation in other conditions. Previous observations in patients with various inherited anaemias are suggestive of a role of the haemochromatosis gene in the noniatrogenic form of iron overload that may occur in these conditions. METHODS: We studied two brothers with congenital dyserythropoietic anaemia type II, presenting with marked noniatrogenic iron overload. Young age, familial occurrence, concordance of iron overload, and histology were all suggestive of a genetic basis for the iron overload. A search for C282Y, H63D, S65C, and IVS3 + 1G?T mutations was performed by polymerase chain reaction after extraction of genomic DNA from whole blood. RESULTS: A search for the C282Y, H63D, S65C, and IVS3 + 1G?T mutations in the HFE gene proved to be negative. Despite the existence of ineffective erythropoiesis with mild anaemia, both patients were treated with regular phlebotomies in order to prevent long-term complications of their iron-overload. This treatment was well tolerated. CONCLUSIONS: 1. C282Y, H63D, S65C, and IVS3 + 1G?T mutations were negative in two brothers with congenital dyserythropoietic anaemia, in whom young age, familial occurrence, concordance of iron overload, and the histological pattern were all suggestive of hereditary haemochromatosis. 2. Treatment with regular phlebotomies, in order to prevent complications of iron overload, was well tolerated despite the existence of mild haemolytic anaemia.

In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats.

BACKGROUND: Portal hypertension in cirrhosis results from enhanced intrahepatic resistance to an augmented inflow. The former is partly due to an imbalance between intrahepatic vasoconstriction and vasodilatation. Enhanced endothelin-1 and decreased activity of hepatic constitutive endothelial nitric oxide synthase (NOS 3) was reported in carbon tetrachloride (CCl(4)) cirrhotic rat liver. AIMS: To study whether an increase in hepatic NOS 3 could be obtained in the CCl(4) cirrhotic rat liver by in vivo cDNA transfer and to investigate a possible effect on portal pressure. METHODS: Hepatic NOS 3 immunohistochemistry and western blotting were used to measure the amount of NOS 3 protein. Recombinant adenovirus, carrying cDNA encoding human NOS 3, was injected into the portal vein of CCl(4) cirrhotic rats. Cirrhotic controls received carrier buffer, naked adenovirus, or adenovirus carrying the lac Z gene. RESULTS: NOS 3 immunoreactivity and amount of protein (western blotting) were significantly decreased in CCl(4) cirrhotic livers. Following cDNA transfer, NOS 3 expression and the amount of protein were partially restored. Portal pressure was 11.4 (1.6) mm Hg in untreated cirrhotic (n=9) and 11.8 (0.6) in lac Z transfected (n=4) cirrhotic rats but was reduced to 7.8 (1.0) mm Hg (n=9) five days after NOS 3 cDNA transfer. No changes were observed in systemic haemodynamics, in liver tests or urinary nitrates, or in NOS 3 expression in lung or kidney, indicating a highly selective transfer. CONCLUSIONS: NOS 3 cDNA transfer to cirrhotic rat liver is feasible and the increase in hepatic NOS 3 leads to a marked decrease in portal hypertension without systemic effects. These data indicate a major haemodynamic role of intrahepatic NOS 3 in the pathogenesis of portal hypertension in CCl(4) cirrhosis.