The effect of experimental bile-duct obstruction on critical biosynthetic functions of the liver

Abstract

SUMMARYUsing biosynthetic activities which have a maximum energy requirement, the effect of obstruction of the bile-duct has been studied in isolated perfused rat livers, and compared with controls undergoing 'sham' ligation and with normal animals. T h e maximum rate of gluconeogenesis from lactate was inhibited by 67 per cent after bile-duct ligation when compared with the normal value. The maximum rate of urea synthesis which occurred in the presence of ornithine was the same in the jaundiced and in the normal animals. ' Sham' operation, without ligation of the bile-duct, inhibited gluconeogenesis by less than 20 per cent but doubled the maximum rate of urea synthesis.It is concluded that complete biliary obstruction seriously impairs gluconeogenesis and prevents the normal increase of urea synthesis which occurs in response to trauma and that these changes develop earlier than might be expected after the onset of obstruction.Some possible mechanisms of these effects are discussed. If similar abnormalities of hepatocyte function are demonstrated in man it is suggested that surgical relief of obstructive jaundice is indicated at an early stage.THE chemical changes observed in the blood of a patient or animal after the bile-duct becomes obstructed are due to retention of bile rather than to a direct effect of the obstruction on the cells of the liver. Abnormalities of clinical liver-function tests are not marked unless the obstructive jaundice has been present for some time, and it is usually considered that hepatocyte function remains normal during the first few weeks after obstruction has taken place. However, most biochemical activities of the liver take place at such a rate that the standard clinical tests of function, which are relatively insensitive, remain normal until gross hepatic damage has occurred.Recently, perfusion techniques have been developed which allow a direct study of the biosynthetic reactions of the liver. The maximum rates of energyrequiring cellular activities are more sensitive tests of liver function than are the investigations usually employed. The synthesis of glucose from lactate (Meyerhof, 1930;Hems, Ross, Berry, and Krebs, 1966), of urea from ammonia (Cohen and Sallach, 1961), and possibly of protein, are the principal reactions which consume large quantities of ATP, and require the integrated action of both mitochondrial and cytoplasmic enzymes.I n the experiments recorded in this paper ligation of the bile-duct has been used to produce jaundice, and the maximum rates of gluconeogenesis and urea synthesis in the perfused livers of jaundiced animals were compared with those in both normal and control animals. A preliminary account of part of this work has been presented previously (Lee, ROSS, and Haines, 1971). MATERIALS AND METHODSMale albino Wistar rats weighing between 150 and 200g. were obtained from Messrs. Scientific Products Farm, Ash, Kent, and were fed on a standard 41B diet.Bile-duct Ligation.-Three groups of rats were prepared for liver perfusion. Group I consisted of t...

Lack of Control of Liver Gluconeogenesis in Cholestatic Rats With Reduced Portal Blood Flow

“…Lowered fasted glucose levels (31, possibly caused by reduced liver gluconeogenesis (41, have also been observed in rats with experimentally induced cholestasis. Histochemical measurements showing increased glycogen phosphorylase (5) and decreased phosphoenolpyruvate carboxykinase (PEPCK) activity (5,6) in livers from cholestatic rats are consistent with the observed increased glycogenolysis (5) and decreased gluconeogenesis (4).…”

Glycerol clearance in alcoholic liver disease.

“…Gluconeogenesis is also impaired in animal models of 262 liver disease such as diet-induced cirrhosis,47 galactosamine hepatitis,48 and bile duct ligation. 49 Glycerol infusion caused a minor rise in blood lactate concentrations and the ratio of lactate to pyruvate in peripheral blood in both alcoholics and controls. Metabolism of glycerol increases the lactate to pyruvate ratio in the liver50 reflecting a more reduced hepatic cystolic redox state, as dihydroxyacetone phosphate is formed from glycerol-3-phosphate and enters the glycolytic-gluconeogenic pathway.23 The change in lactate:pyruvateratio in peripheral blood may reflect these changes in the liver.…”

Amino Acid Incorporation into Liver Proteins during Extrahepatic Cholestasis in the Rat

“…Although a number of reports suggest a decreasing capacity in some functional systems during the progression of cholestasis [1,12,20,22,27,36,37], several investigations indicate elevated levels of cell function [1, 12, 15, 27, 28, 34-37, 39, 40, 45]. For example, the level of serum albumin remains relatively unaffected by cholestasis while the weight of the liver increases [22]. The concept of an increased re-gionalization within the liver lobule during cholestasis with respect to cell damage has been put forward [11,13].…”