Michael A. Gerber

Hepatocellular Hyalin in Cholestasis and Cirrhosis: Its Diagnostic Significance

Liver tissue of patients with various stages of alcoholic liver injury, with cholestatic liver diseases and with various types of cirrhosis, were examined for the presence of hyalin, mainly by light microscopy and, in selected instances, also by electron microscopy. Hyalin was detected in alcoholic liver disease and in prolonged cholestasis, mainly in primary biliary cirrhosis. It was not found in diseases in which cholestasis was of shorter duration and was predominantly central in location. Electron microscopically, hyalin was identical in alcoholic hepatitis and in primary biliary cirrhosis, although the pattern of injury of hepatocytic organelles was different in these diseases. A morphologic relation between hyalin and cholestasis or any other hepatocellular abnormalities could not be detected. Hyalin was also found in advanced nonalcoholic cirrhosis, in Wilsons disease, and in Indian childhood cirrhosis, and with the exception of the last, it was always associated with peripheral cholestasis. Centrolobular hyalin in specimens with intact lobular architecture is diagnostic for alcoholic liver injury. Peripheral hyalin in the absence of cirrhosis favors primary biliary cirrhosis over extrahepatic biliary obstruction. Hyalin throughout nodules in advanced cirrhosis does not necessarily indicate alcoholic liver disease, Wilsons disease, or Indian childhood cirrhosis, but also occurs in cryptogenic cirrhosis.

Relation between central canals and portal tracts in alcoholic hepatitis: A contribution to the pathogenesis of cirrhosis in alcoholics

Abstract The relation between central canals and portal tracts was determined in 42 biopsy and eight autopsy specimens with histologic signs of acute alcoholic hepatitis. Five stages were recognized. Acute alcoholic hepatitis in the absence of septa between central and portal areas was always centrolobular in the specimens examined. When necrosis associated with inflammation and fibrosis connected hepatic vein tributaries and portal tracts in a “bridge”-like fashion, hepatitic manifestations including alcoholic hyaline were also found in the periphery of the hepatic lobule. The presence of proliferated bile ductules in the “bridges” and thus in the vicinity of sclerosed central veins may create the impression that the main lesion is portal. This might explain the long delay in recognizing that alcoholic hepatitis is basically a central lesion. The collapse of the described bridge-like connections initiates cirrhosis development. This and the occasional massive necrosis occurring in alcoholic hepatitis explain the similarity of the architectural alteration in alcohol and viral hepatitis induced and cryptogenic liver cirrhosis, even if the initial cytologic characteristics are missing.

Acetaminophen associated hepatic injury, Report of two cases showing unusual portal tract reactions.

Two patients experienced acute transient hepatic and renal failure following ingestion of substantial but less than the usually toxic doses of acetaminophen, in both cases associated with heavy acute alcohol intake. One patient developed transient clinical features of chronic active liver disease one month later. Liver biopsy specimens from both patients taken after the acute episodes revealed, in addition to the well recognized centrilobular hepatic injury of acetaminophen, unusual portal tract lesions, which resembled chronic active hepatitis in one case. In some patients therapeutic doses of acetaminophen, if taken together with alcohol, may produce acute and chronic liver disease.

Precursor stage of hepatocellular neoplasm following long exposure to orally administered contraceptives

Hepatic neoplasms and peliosis are known to occur in women taking contraceptives orally. We observed hyperplasia of hepatocytes combined with hypertrophy of sinusoidal lining cells and sinusoidal dilatation with progression to peliosis in the liver of a patient who had been taking such contraceptives for 10 years. These changes resembled the precursor stage in the development of hepatic angiosarcoma induced by vinyl chloride, Thorotrast, and arsenic. In users of orally administered contraceptives these findings may precede the development of hepatocellular neoplasms.

Infantile hemangioendothelioma of heterotopic intrathoracic liver associated with diaphragmatic hernia

An autopsy of a six-hour-old term neonate, who died during surgery for repair of a left diaphragmatic hernia, revealed an infantile hemangioendothelioma type I arising in a heterotopic lobe of liver in the left thorax. The upper pole of the tumor was attached by fibrovascular tissue to the lower lobe of the left hypoplastic lung. A pedicle attached to the lower pole of the heterotopic liver pierced through the diaphragm to the left lobe of the normal liver. This case is an example of an unusual association of congenital malformation and putative neoplasm.

Observations on the core particle of hepatitis B virus and the DNA polymerase associated with hepatitis B antigen.

Several methods are presented for the purification of core particles of hepatitis B virus (HBV) from nuclei of infected human hepatocytes. No endogenous DNA polymerase activity was found in any of the preparations of core particles even when circular double and single stranded DNAs were used as exogenous templates. The DNA polymerase activity associated with serum HB Ag was not stimulated by circular DNAs. Sodium dodecyl sulfate (SDS) at concentrations of greater than or equal to 0.1% inhibited the DNA polymerase activity of serum HB Ag. Exogenous templates such as native and activated calf thymus and Micrococcus lysodeikticus DNAs did not stimulate the DNA polymerase of serum HB Ag even in the presence of low concentrations of SDS. It is suggested that the DNA polymerase associated the HB Ag is specific for its own DNA as template.

Characterization of RNA transcripts and virally coded proteins synthesized in mouse fibroblasts transfected with hepatitis B DNA: HBeAg synthesis in HBcAg-negative cells with active core-antigen genes

A line of mouse cells expressing hepatitis B virus (HBV) surface and ‘e’ antigens identical in their physico-chemical properties to antigens from patients infected with HBV was isolated after transfection of 3T3 ceils with cloned HBV DNA. The studies reported here indicate that the ceils contain uninterrupted copies of the entire HBV genome which are unmethylated on CCGG sites and have no gross deletions or rearrangements. The entire core region is transcribed into polyadenylated RNAs large enough to serve as messengers for production of viral core antigen (HBcAg) yet no HBcAg can be detected. This suggests that the ceils produce a primary translation product copied from the HBcAg messenger which either cannot assume the proper configuration for display of HBcAg determinants or is rapidly converted to HBeAg by proteolysis.

Radioimmunometric assay for hepatitis B surface antigen on the surface of infected cells

It has been difficult to differentiate hepatitis B surface antigen (HBsAg) on the cell surface from intracellular or intramembranous HBsAg that is not exposed to the host immune response. We describe here a radioimmunometric assay for HBsAg on the cell surface using HBsAg producing hepatocellular carcinoma cell lines and fibroblasts transfected with cloned hepatitis B virus DNA as models. The assay is sensitive, specific, simple and takes approximately 1 1/2 h. The procedure may be modified to compare quantitatively cell surface with intracellular HBsAg and to demonstrate other cell associated hepatitis B virus antigens such as HBcAg and HBeAg.