Leslie J. Schoenfield

Observer error and sampling variability tested in evaluation of hepatitis and cirrhosis by liver biopsy

In 50 patients with chronic active liver disease, observer and sampling error in histologically evaluating hepatitis and cirrhosis after blind-needle biopsy of the liver was assessed from coded tissue. This was done by repeated readings of the same specimens by the same pathologist, by sequential biopsies from the same patients with cirrhosis, and by multiple simultaneous biopsies from adjacent areas of the liver. Observer error was small. The consistency of grading the individual histologic characteristics of hepatitis was 90%, and the reproducibility of the degree of either hepatitis or cirrhosis was 94%. Sampling error was also trivial in hepatitis, indicating that a single needle biopsy accurately reflects the type and degree of inflammation and necrosis in adjacent areas of the liver. By contrast, sampling error was of considerable magnitude when the presence of cirrhosis in patients known to have the lesion was sought, since confirmation by simultaneous or sequential biopsies was made in only 33% of the cases.

Chronic active liver disease: The range of histologic lesions, their response to treatment, and evolution

Abstract Histologic study of serial biopsy specimens in a prospective, controlled, double blind, randomized trial of treatment involving 63 patients with predefined clinical and biochemical criteria of severe chronic active liver disease revealed five different histologic patterns of hepatic injury on initial biopsy: chronic persistent hepatitis, chronic aggressive hepatitis, subacute hepatitis with bridging, subacute hepatitis with multilobular necrosis, and cirrhosis. The initial biopsies in the fatal cases revealed cirrhosis, subacute hepatitis with multilobular necrosis, or subacute hepatitis with bridging. Patients with subacute hepatitis with bridging and with multilobular necrosis more frequently revealed stigmata of viral hepatitis and more frequently developed cirrhosis than chronic aggressive hepatitis, regardless of treatment. The severe forms of hepatitis more frequently remitted to the histologic features of chronic persistent hepatitis in patients treated with prednisone and a combination of prednisone and azathio-prine than with azathioprine or placebo alone. Serial biopsy specimens frequently revealed changes in the histologic pattern before remission to chronic persistent hepatitis. Histologic progression to cirrhosis may occur by bouts of intralobular and multilobular necrosis as well as by piecemeal necrosis. Sampling error in needle biopsy of cirrhosis is so great that the condition either may be missed or may be impossible to accurately classify into portal and postnecrotic cirrhosis. Observations at autopsy always revealed postnecrotic cirrhosis characterized by extensive parenchymal loss and incomplete regeneration. We conclude that the evolution of any lesion is influenced by at least two factors: the original histologic pattern and the therapy applied.

Effects of meals and interruption of enterohepatic circulation on flow, lipid composition, and cholesterol saturation of bile in man after cholecystectomy

In 4 patients studied after cholecystectomy and common-duct exploration for cholesterol gallstones, bile salt (BS) and phospholipid (PL) output and bile flow increased significantly in response to breakfast, but cholesterol (Ch) output was unaltered. Simultaneously, Ch concentration decreased while PL and BS concentrations did not change. The degree of Ch saturation of bile, [BS+PL]/[Ch], decreased in each study, whether or not the original ratio indicated Ch supersaturation; in 3 of 5 studies, an initially supersaturated bile became unsaturated with Ch in response to breakfast. No significant changes were noted after lunch. During interruption of enterohepatic circulation (EHC), studies with radiolabeled bile acids indicated that the increased bile acid output in response to meals was secondary to increased recirculation of intestinal bile acids rather than tode novo bile acid synthesis. This mechanism may account for the adequate delivery of BS and for the decreased degree of Ch saturation of bile postprandially in cholecystectomized patients.

Identification of extrahepatic bilirubin monoglucuronide and its conversion to pigment 2 by isolated liver.

Summary and Conclusions The pigment obtained by reversed-phase partition chromatography from the plasma of the hepatectomized dog has been shown to be bilirubin monoglucuronide (pigment 1). In the experiments performed, pigment 1 was of extrahepatic origin. The isolated perfused rat liver converts bilirubin monoglucuronide to bilirubin diglucuronide and excretes the diconjugate in the bile.

Further studies on the nature and source of the conjugated bile pigments.

Summary and conclusions Rat-fistula bile, isolated rat liver, liver slices incubated with bilirubin, and the hepatectomized dog were utilized to study the nature and sources of conjugated bile pigment. The technics of reverse-phase column chromatography, chemical-partition chromatography, and paper chromatography were employed and molar ratios were calculated. Probably pigment 1 is formed solely in extrahepatic sites. The evidence favors a bilirubin monoglucuronide structure for pigment 1 rather than a complex of bilirubin and pigment 2. In the dog, pigment 2 probably is formed only within the liver. It is suggested that bilirubin diglucuronide may be formed intrahepatically from bilirubin directly, as well as from part of the extrahepatic pigment 1.

Hepatic lipid secretion and cholelithiasis

SummaryRecent work has suggested that secretion of lithogenic hepatic bile is a major factor in the etiology, and a prerequisite abnormality to the growth and maturation of cholesterol gallstones. Cholesterol is normally solubilized in bile by mixed micelles of bile acids and lecithin. A decreased bile acid pool or a decrease in the ratio of bile acid and lecithin to cholesterol characterizes lithogenic bile. These observations have stimulated investigation of biliary lipid secretion, relevant to pursuing the genesis of the alterations. This review summarizes current knowledge of the individual and interrelated biosynthesis, kinetics, biliary secretion, and regulation of cholesterol, bile acid and lecithin. Investigations of induced alterations by drugs, hormones and diet are also reviewed. The lithogenic potential of bile can be decreased by chenodeoxycholic acid, but more work is needed, in particular, to define the hepatic enzymatic abnormality that causes the secretion of lithogenic bile.

Increased Serum Conjugated Bilirubin in Hemolytic Anemia

Rarely is conjugated hyperbilirubinemia associated with hemolytic anemia. This article describes three patients with hemolytic anemia (two autoimmune acquired and one congenital spherocytic) in whom an increase in the conjugated bilirubin fraction occurred. The increase subsided after amelioration or control of the hemolytic process.

Plasminogen Activator in Bile Stimulated by Sodium Taurocholate in Isolated Hamster Livers

Summary Plasminogen activator activity (bilokinase) was demonstrated for the first time in fistula bile of the hamster as well as in the bile of isolated hamster liver. Sodium taurocholate was shown to stimulate the release of bilokinase into bile. Bilokinase in bile is analogous to urokinase in urine, but its role in coagulation homeostasis or in gallstone formation remains to be determined. Acknowledgment is made of the expert assistance of Mr. Emery Van Hook in preparing the isolated liver system and of Miss Linda L. Livingston in laboratory determinations.