The effect of sodium taurocholate on the hepatic metabolism of sulfobromophthalein sodium (BSP). The role of bile flow.

The influence of bile salts on the hepatic metabolism of sulfobromophthalein sodium (BSP) was studied in the perfused rat liver. During sodium taurocholate infusions, hepatic uptake of BSP from plasma was increased and appeared to be related to an enhanced transit of BSP from liver into bile. BSP-glutathione conjugation was not affected by the bile salt infusions, although bile salts inhibited the enzyme system in vitro. The major effect of bile salts was to increase the BSP transport maximum (Tm). When sodium taurocholate was infused in saline at a rate of 30 mumoles/hr, both bile flow and the BSP Tm increased, and remained at peak levels of 1.5 +/-0.12 mul/min per g liver and 21 +/-3.0 mug/min per g liver, respectively. In contrast, during saline infusion alone both levels were significantly lower (1.06 +/-0.17 mul/min per g liver and 15.8 +/-4.16 mug/min per g liver, respectively), and both fell progressively after the 2nd hr of perfusion. This decline in bile flow and BSP Tm was associated with a decrease in biliary bile salt excretion and was reversed by adding bile salts to the perfusate. Since the biliary concentration of BSP remained within a narrow range in all experiments, the BSP Tm was primarily determined by the rate of bile flow. Dependence of BSP Tm on the rate of bile production was further confirmed by changing the temperature of the perfusate during a constant infusion of taurocholate. BSP Tm paralleled temperature-induced changes in bile flow irrespective of changes in the level of bile salt excretion. Since the biliary concentration of BSP remained within a narrow range in all experiments, the concentrating capacity for BSP in bile may be the major limiting factor in BSP transport. Thus two independent factors appear to determine the BSP Tm: the bile BSP concentration, and the rate of bile production. Because taurocholate enhanced BSP transport only when it increased bile production, its effect on the BSP Tm appears to be attributable to its choleretic properties.

Serum bile acids in primary biliary cirrhosis.

Fasting serum bile acid levels were measured by gas-liquid chromatography in 56 patients with primary biliary cirrhosis. Of these, 52 (93%) had increased levels (greater than 2mug/ml), including 14 of the 18 with normal serum bilirubin concentrations. The four patients with normal bile acid levels had early lesions as judged by histological and clinical criteria. With progression of the disease, as indicated by the histological features of the lesions, total bile acid levels increased, and the ratio of serum cholic-to-chenodeoxycholic acid decreased. Ratios of serum cholic-to-chenodeoxycholic acid below 1 occurred predominantly in patients with advanced or terminal disease. These studies suggest that serial measurement of serum bile acids may aid in the evaluation of primary biliary cirrhosis.

Hepatic disease in erythropoietic protoporphyria.

Two sisters had erythropoietic protoporphyria and a spectrum of liver disease. One (F.B.) died in hepatic failure within 3 months after the development of jaundice. Only 10 months before she died, she had exhibited only bromsulfalein retention and a borderline increase in serum transaminase. Surgical exploration because of the jaundice revealed patency of the bile ducts which was confirmed at autopsy. Wedge biopsy and autopsy specimens of liver showed an active cirrhosis with massive amounts of protoporphyrin in Kupffer cells, portal histiocytes, bile canaliculi and parenchymal cytoplasm. The other sister (L.R.) had never had symptomatic liver disease and only a slight increase in serum transaminase and bromsulfalein retention. On needle biopsy, the liver specimen showed portal inflammation with erosion of limiting plates, occasional bridging between triads and central areas of cell dropout. Protoporphyrin pigment was present in portal histiocytes, areas of central collapse and, more rarely, in parenchymal cytoplasm. These studies demonstrate that significant, progressive hepatic disease may occur insidiously in erythropoietic protoporphyria, and that once jaundice appears it may be followed rapidly by fatal hepatic failure.

Hepatic granulomata: problems in interpretation.

Granulomata occur in the liver not only in patients with systemic granulomatous disease, but also in a variable number with underlying liver disease and in a heterogeneous group of disorders that appear to be neither hepatic nor granulomatous in nature. The hepatic granulomata found in association with liver disease are rarely attributable to complicating systemic granulomatous disease, and probably represent a nonspecific response to the underlying hepatic disease. In the heterogeneous group of diseases that appear to be neither hepatic nor granulomatous in nature, hepatic granulomata may (in some instances) represent a nonspecific response to such conditions as intraabdominal malignancy and ulcerative bowel disease. However, in others, particularly those with unexplained prolonged fever, hepatic granulomata may be attributable to specific agents that are overlooked or escape detection by currently available diagnostic measures. The etiology of hepatic granulomata can seldom be established on histological grounds alone, and usually requires collateral clinical and laboratory evidence for identification.

Persistent HB antigenemia: associated clinical manifestations and hepatic lesions.

The clinical, biochemical and histological features in nine asymptomatic HBs Ag carriers, 15 patients with symptomatic HBs Ag-positive chronic active hepatitis (CAH), and 29 patients with HBs antigenemia persistent for five months or longer following a documented attack of acute viral hepatitis were compared, and contrasted with those in 67 patients with HBs Ag-negative CAH. The findings were remarkably similar in all groups. However, young males predominated in all three HBs Ag-positive groups, whereas most HBs Ag-negative cases of CAH were in middle-aged women. Moreover, in the latter group, the lesions tended to be more extensive and more commonly were accompanied by smooth muscle antibody, antinuclear antibody and LE cells, and extrahepatic manifestations, such as ulcerative colitis, arthritis, pleurisy and pericarditis.

Asymptomatic primary biliary cirrhosis. A progress report on long-term follow-up and natural history.

Thirty-six patients presenting with asymptomatic primary biliary cirrhosis have been followed for a median period of 11.4 yr, extending by 5 yr a previously reported median follow-up study of 6 yr. Life table survival analysis indicates that the overall survival of this subgroup of patients with primary biliary cirrhosis continues to remain similar to that of the general population (p = 0.91). Over this period, 15 patients developed symptoms and 8 patients died, 6 from liver disease; 21 patients remained in an asymptomatic state. Portal granulomas on initial liver biopsy were the only finding that correlated with a normal survival and a continued asymptomatic state (p = 0.03). In contrast, associated autoimmune disorders (thyroiditis, sicca syndrome, CRST syndrome, Raynaud's phenomenon) correlated with decreased survival (p = 0.01). No other clinical, laboratory, or histologic features correlated with survival or the development of symptoms. This extended follow-up study (median 11.4 yr) indicates that many patients with asymptomatic primary biliary cirrhosis have a benign outcome. Although 42% developed signs or symptoms of progressive disease at variable times up to 14 yr from presentation, the group survival remained similar to the general population.

Effects of prolonged ingestion of glucose or ethanol on tissue lipid composition and lipid biosynthesis in rat.

The effects on lipid metabolism of long-term feeding of large amounts of ethanol or glucose differed from those that have been reported in short-term experiments. Three groups of male rats were investigated. The first was fed lab chow and 15% (v/v) ethanol ad lib.; the second was pair-fed with the first and given isocaloric amounts of glucose in lieu of ethanol; the third was fed lab chow and water ad lib. All three groups consumed nearly the same number of calories, and about 30% of the calories in the first group were derived from ethanol. Neither glucose nor ethanol added to a nutritionally adequate diet promoted the development of a fatty liver, although both stimulated acetate-(14)C utilization for hepatic lipid synthesis. In all three groups more than 80% of the label in hepatic lipid was found in fatty acids, and the distribution of label amongst the fatty acids of different chain lengths was virtually the same. Ethanol decreased while glucose increased the quantity of lipid in fat depots, and each altered the fatty acid composition of the lipids in adipose tissue, kidney, liver, and hepatic subcellular fractions in a different manner. The most striking of these changes was the relative increase in monounsaturated fatty acids and the decrease in essential fatty acids produced by glucose.

Effects of prolonged ingestion of glucose or ethanol on fatty acid synthesis by mitochondria and cell sap of rat liver and adipose tissue.

Effects of prolonged ingestion of glucose and ethanol on the rate of fatty acid synthesis by liver and adipose tissue have been investigated in male rats. Ethanol significantly enhanced the rate of fatty acid synthesis from malonyl-2-(14)C CoA in liver cell sap; glucose feeding enhanced the rate of fatty acid synthesis from both malonyl-2-(14)C and acetyl-1-(14)C CoA. Neither dietary supplement modified the types of fatty acid synthesized in this enzyme system. Palmitic acid was the principal product synthesized from a mixture of malonyl and acetyl CoA, whereas myristic and palmitic acids were the predominant products formed from acetyl CoA alone. Neither glucose nor ethanol affected fatty acid synthesis by adipose tissue cell sap. Mitochondria derived from liver and adipose tissue of control, glucose-fed, and ethanol-fed animals all incorporated acetyl-1-(14)C CoA into lipid at about the same rate, but did not utilize malonyl CoA for lipid synthesis to any significant degree. The label appeared in fatty acids, one-half of which were contained in phospholipid. Both unsaturated and saturated fatty acids synthesized by mitochondria contained isotope, most of which was present in the carboxyl groups. Ethanol and glucose feeding stimulated the labeling of monoenoic fatty acids in liver mitochondria, but only glucose did so for adipose tissue. These findings agree with results previously obtained when lipogenesis was measured with acetate-(14)C in vivo.

Identification of lymphocytes in percutaneous liver biopsy cores. Different T:B cell ratio in HB sAg-positive and -negative hepatitis.

The lymphocytes infiltrating the liver were isolated and characterized as T or B cells in three groups of patients: 20 patients with hepatitis B surface antigen (HB sAg)-positive acute and chronic hepatitis, 8 patients with HBsAg-negative chronic hepatitis with prior evidence for hepatitis B virus (HBV) infection, and 5 patients with HBsAg-negative chronic hepatitis without prior evidence for HBV infection. The predominant cell infiltrating the liver was shown to be a T cell in all categories; however, the ratio of T:B cells was significantly lower (1.96) in the patients without evidence for HBV infection than in the patients who were HBsAg-positive at (7.86), or before (8.85) the time of study. The significantly (P less than 0.001) higher number of B cells in the patients with chronic hepatitis of unknown etiology suggests that a different immunopathogenetic mechanism is operative in this group. A peripheral T lymphocytopenia was observed in patients with both antecedent and existent HBs-antigenemia, but not in the patients without evidence for HBV infection.

Inhibitory effects of scillaren and dinitrophenol on bilirubin excretion by the isolated perfused rat liver.

The effects of scillaren and dinitrophenol on bilirubin excretion by the perfused rat liver were studied. Both compounds inhibited bile flow, scillaren by 20 to 40%, and dinitrophenol by 60 to 80%. Bilirubin excretion was also impaired. However, the effect of scillaren on bilirubin excretion was less than that on bile flow, as indicated by an increase in the bile bilirubin concentration, whereas dinitrophenol had a greater effect on bilirubin excretion than on bile flow. Dinitrophenol also inhibited the hepatic removal of unconjugated bilirubin from the perfusate, probably because it impaired the initial uptake and/or storage of unconjugated bilirubin by the perfused liver.

Elevations in skin tissue levels of bile acids in human cholestasis: relation to serum levels and topruritus.

To define the relationship of bile acid retention to the pruritus of cholestasis, we quantified individual bile acids in serum, acetone swabs of skin, and skin tissue in 13 patients with cholestasis undergoing laparotomy and in 8 controls. There was no consistent relationship between pruritus and concentrations of either total or individual bile acids in serum. Skin tissue concentrations of bile acids were elevated in patients with cholestasis, were linearly related to serum levels, and did not differentiate between those patients with and those without pruritus. Concentrations of bile acids on the skin surface, which were lower than those reported by others, did not correlate with pruritus, and were decreased by simple soap and water washing. These data indicate that the pruritus of cholestasis is not directly related to the skin tissue concentration of any of the major bile acids, although a relationship to a particular molecular form of bile acids could not be excluded.