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Hepatobiliary secretion of bile acids is an important liver function. Here, we quantified the hepatic transport kinetics of conjugated bile acids using the bile acid tracer [N-methyl-Nine healthy participants and eight patients with varying degrees of cholestasis were examined withResults are presented as median (range). The hepatic intrinsic clearance was 1.50 (1.20-1.76) ml blood/min/ml liver tissue in healthy participants and 0.46 (0.13-0.91) in patients. In healthy participants, the rate constant for secretion ofThis first in vivo quantification of individual steps involved in the hepatobiliary secretion of a conjugated bile acid in humans provided new insight into cholestatic disease.Positron emission tomography (PET) using the radiolabelled bile acid (The trial is registered at ClinicalTrials.gov (NCT01879735).

The kinetics of hepatic removal of protein-bound substances were studied in nine human subjects with various liver diseases by the use of indocyanine green as a model substance. Intrinsic hepatic clearance of indocyanine green was measured by means of a constant infusion of indocyanine green and concentration measurements of indocyanine green in arterial and hepatic venous plasma samples. During the indocyanine green infusion, 1-1.51 of dextran-70 was given whereby a stable dilution of the plasma protein concentration by a factor of 0.6-0.8 was obtained. In each of the subjects, the intrinsic clearance of indocyanine green increased after the protein dilution (range 11-64%). Elimination of ethanol (not protein bound), similarly assessed, was not significantly changed. The traditional hypothesis that unbound clearance (intrinsic clearance divided by the free fraction of the ligand) is independent of protein concentration was refuted since in each of the subjects the protein dilution was followed by a reduction of the unbound clearance of ICG (P0.005, n = 9). We examined whether these observations imply some special mechanism (e.g. a hepatocyte protein receptor) by which the unbound clearance is enhanced by the binding protein(s). The previously developed pseudofacilitation model--describing the effects of ligand-protein diffusion and dissociation in an unstirred plasma layer near the hepatocyte--was extended to the case of a mixture of binding proteins, and parameter-free bounds were derived to predict the response of intrinsic clearance to protein dilution. The observed changes of the intrinsic clearance values did not violate these bounds (P0.002, n = 9). Thus no facilitating mechanisms are necessary to account for the observed deviations from the traditional hypothesis.

In cirrhotic patients, insufficient redistribution of blood from splanchnic organs to the central circulation could limit blood supply to skeletal muscles and the brain during exercise.Eight cirrhotic patients performed incremental cycling to exhaustion (74 (49-123) W; median with range).Heart rate increased from 68 (62-88)beats/min at rest to 142 (116-163)beats/min, cardiac output from 5.1 (3.3-7.2) to 12.9 (8.5-15.9)l/min, and mean arterial pressure from 89 (75-104) to 115 (92-129)mmHg (P0.05), while the indocyanine green elimination determined hepatosplanchnic blood flow declined from 0.97 (0.55-1.46) to 0.62 (0.36-1.06)l/min (P0.05). As assessed by near-infrared spectrophotometry, cerebral oxygenation (NIRS) was 61% (48-85%) and increased to 72% (57-86%) during exercise (P0.05). The NIRS determined oxygenation of the vastus lateralis muscle also increased: the concentrations of oxygenated haemoglobin by 5.9 (0.57-9.47)micromol/l, deoxygenated haemoglobin by 7.2 (1.8-12.0)micromol/l, and thus total haemoglobin by 12.1 (3.6-21.5)micromol/l (P0.05).In patients with cirrhosis, exercise reduces hepatosplanchnic blood flow, while O(2) supply to muscle and brain appears to increase indicating that blood redistribution from splanchnic organs does not limit blood flow to working muscles and the brain.

In acute liver failure the liver has to regenerate, which may increase the consumption of essential fatty acids. Nutritional support consists mainly of infusion of glucose. It is therefore possible that essential fatty acid deficiency may develop in such patients.Plasma phospholipid composition was studied in healthy controls (n=11), in patients with acute liver failure, (n=10), in patients with stable cirrhosis (n=7), and in patients with acute on chronic liver disease with hepatic encephalopathy (n=6). The influence of 2 days of fat-free diet followed by infusion of glucose was studied in five healthy controls.The ratio between the sums of nonessential/ essential fatty acids, (n-7+n-9)/(n-3+n-6), was higher in patients with acute liver failure (0.73+/-0.17) compared to healthy controls (0.35+/-0.06, p0.001). The ratio was also higher in patients with acute on chronic liver disease (1.11+/-0.39) compared to patients with cirrhosis (0.61+/-0.18, p0.01). These differences were mainly due to low levels of linoleic acid and high levels of oleic acid in the patients with acute liver failure and acute on chronic liver disease. Two days of fat-free diet followed by infusion of glucose did not change this ratio (0.40+/-0.04 vs. 0.47+/-0.05, NS) in healthy controls. The essential fatty acid deficiency indicator eicosatrienoic acid was detectable in 2 out of 11 controls, in 5/10 with acute liver failure, in 7/7 with cirrhosis, and in 6/7 with acute on chronic liver disease.Acute severe deterioration of liver function was associated with changes in the fatty acid composition of plasma phospholipids suggestive of essential fatty acid deficiency.

Results: Treatment of hepatocytes with CA induced SHP upregulation and inhibited Cyp7a1 expression. When L-NAME was present in the incubation medium, CA increased SHP mRNA but was not able to inhibit Cyp7a1 expression. ChIP analysis showed that L-NAME significantly blocked the binding of SHP to the Cyp7a1 promoter upon CA administration. Interestingly, CA induced GAPDH nitrosylation and its nuclear translocation. Likewise, CA promoted nitrosylation of both Sirt1 and HDAC2, proteins which assemble with SHP to form the Cyp7a1 repressor complex. Nitrosylation of GAPDH, Sirt1 and HDAC2 were prevented by treatment of hepatocytes with L-NAME. Conclusions: BS induce NO production in hepatocytes leading to nitrosylation and nuclear translocation of GAPDH and nitrosylation of proteins that integrate the Cyp7a1 repressor complex. Blockade of NO synthesis prevented the binding of SHP to Cyp7a1 promoter impairing the ability of BS to control their own synthesis.