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This study examined the role of decreased nitric oxide (NO) in the microcirculatory obstruction of hepatic sinusoidal obstruction syndrome (SOS). SOS was induced in rats with monocrotaline. Monocrotaline caused hepatic vein NO to decrease by 30% at 24 hours and by 70% at 72 hours; this decrease persisted throughout late SOS. N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, exacerbated monocrotaline toxicity, whereas V-PYRRO/NO, a liver-selective NO donor prodrug, restored NO levels, preserved sinusoidal endothelial cell (SEC) integrity and sinusoidal perfusion as assessed by in vivo microscopy and electron microscopy, and prevented clinical and histologic evidence of SOS. NO production in vitro by SEC and Kupffer cells, the 2 major liver cell sources of NO, decreases largely in parallel with loss of cell viability after exposure to monocrotaline. Increased matrix metalloproteinase (MMP) activity increases early on in SOS and this increase in activity has been implicated in initiating SOS. Infusion of V-PYRRO-NO prevented the monocrotaline-induced increase in MMP-9. In conclusion, decreased hepatic NO production contributes to the development of SOS. Infusion of an NO donor preserves SEC integrity and prevents development of SOS. These findings show that a decrease in NO contributes to SOS by allowing up-regulation of MMP activity, loss of sinusoidal integrity, and subsequent disruption of sinusoidal perfusion.

Lack of a reproducible animal model has hampered progress in understanding hepatic veno-occlusive disease (HVOD). This article characterizes a reproducible model of HVOD. Rats gavaged with monocrotaline, 160 mg/kg, were killed between days 1 and 10. Sections were evaluated by light microscopy with a standardized scoring system, by immunoperoxidase staining with ED-1 (monocytes, macrophages) and ED-2 (Kupffer cells) antibodies, and by transmission (TEM) and scanning electron microscopy (SEM). On days 1 and 2, the earliest manifestations were progressive injury to the sinusoidal wall with loss of sinusoidal lining cells, sinusoidal hemorrhage, and mild damage to central vein (CV) endothelium. On days 3 through 5 ("early HVOD"), there was centrilobular coagulative necrosis, severe injury to sinusoids, severe sinusoidal hemorrhage, and severe CV endothelial damage; inflammation with ED-1-positive cells was most marked on these days. Days 6 and 7 ("late HVOD") were characterized by subendothelial and advential fibrosis of CVs, damage of the CV endothelium with subendothelial hemorrhage, and some restoration of the sinusoidal wall. Between days 8 and 10, sections showed interindividual variation ranging from mild, residual fibrosis to severe, late HVOD. From days 1 through 10, ED-2-positive cells were decreased in number, and the number of ED-1-positive cells was increased. Sinusoidal damage is the earliest change in HVOD. Coagulative necrosis follows sinusoidal injury and resolves with improvement in sinusoidal endothelial cell (SEC) morphology. Moderate-to-severe CV fibrosis occurs after reappearance of sinusoidal lining cells and resolution of hepatocyte necrosis. The inflammatory response within the lobule and CVs is a result of recruitment of monocytes, whereas Kupffer cells are decreased in number.

Liver-specific and non-liver-specific methionine adenosyltransferase (MAT) are products of two genes, MAT1A and MAT2A, respectively, that catalyze the formation of S-adenosylmethionine (SAM), the principal methyl donor. Mature liver expresses mainly MAT1A. We showed a switch from MAT1A to MAT2A gene expression in human liver cancer cells that may offer a growth advantage. To gain a better understanding of the chronology and significance of the change in MAT expression, we examined changes in hepatic MAT expression after acute treatment of rats with a hepatocarcinogen, thioacetamide (TAA). TAA treatment for 3 weeks did not change the MAT1A mRNA level but reduced the liver-specific MAT protein level to below 30% of control. TAA also acutely reduced the activity of liver-specific MAT when added to normal liver homogenates. In contrast, both the mRNA and protein levels of non-liver-specific MAT were induced. Because liver-specific MAT exhibits a much higher Km for methionine (mmol/L) than non-liver-specific MAT ( approximately 10 micromol/L), MAT activity was decreased at 5 mmol/L but increased at 20 micromol/L methionine concentration. The SAM level, SAM-to-S-adenosylhomocysteine (SAH) ratio, and DNA methylation all fell during treatment. In summary, TAA treatment induced differential changes in hepatic MAT expression. The reduction in liver-specific MAT protein level represents a novel mechanism of inactivation of liver-specific MAT. This along with induction in MAT2A contributed to a fall in the SAM-to-SAH ratio. The resulting DNA hypomethylation may be important in the process of hepatocarcinogenesis.

The significance of antibodies to hepatitis C virus in patients with chronic alcoholic liver disease is unclear. Prior studies have utilized the first-generation enzyme-linked immunosorbent assay, which is limited by problems with sensitivity and specificity. Hepatitis C virus infection in 137 patients with biopsy-proven alcoholic liver disease was assessed with second-generation hepatitis C virus antibody assays and reverse transcription-polymerase chain reaction for detection of hepatitis C virus RNA in the serum. The patients were categorized into three groups according to results of serological testing. Discriminant-function analysis was used to determine which factors (risk, biochemical and histological) could best differentiate the three groups. Thirty-three patients were reactive on secondgeneration enzyme-linked immunosorbent assay/second-generation recombinant immunoblot assay and RNA positive (group 1). Twelve were reactive on second-generation enzyme-linked immunosorbent assay/second-generation recombinant immunoblot assay but RNA negative (group 2). Eighty-six were nonreactive on second-generation enzyme-linked immunosorbent assay, and six were reactive on second-generation enzyme-linked immunosorbent assay but negative on second-generation recombinant immunoblot assay and negative for hepatitis C virus RNA (group 3). Seventy-six percent of patients in group 1 and 58 in group 2 had parenteral risk factors, compared with only 1 in group 3 (p < 0.00001). The mean ALT level was higher in group 1 patients (p < 0.05). The mean histologic activity index was significantly higher in group 1 (p = 0.0007). Periportal and bridging necrosis and portal inflammation were significantly increased in group 1 (p = 0.0004 and p = 0.002, respectively). We found no significant difference in intralobular degeneration and focal necrosis or fibrosis among the three groups. The histological and biochemical features of groups 2 and 3 were similar. Most patients with alcoholic liver disease with concomitant hepatitis C infection have an identifiable parenteral risk factor. Patients with viremia have histological evidence of chronic hepatitis superimposed on alcoholic liver disease. The histological features of hepatitis C virus antibody-reactive patients without viremia resemble those of patients without serological evidence of hepatitis C virus infection. (Hepatology 1994;19:554–557).

The hepatorenal syndrome, a primary cause of death from acute and chronic liver disease, consists of a functional renal failure whereby examination of the kidney has previously shown no distinct or specific morphologic change. We describe an unusual renal lesion consisting of the reflux of proximal convoluted tubular epithelium into Bowman's space. An autopsy series shows this glomerular change to be present in 71.4% of cases with the hepatorenal syndrome, while only present in 0 to 27.3% in other autopsy categories (p less than 0.001). Since this lesion has been previously described with experimental renal ischemic change and terminal hypotension, it is possible that it is caused in part by the decreased or altered renal blood flow known to be associated with the hepatorenal syndrome.

We examined beta 2-microglobulin (B2MG) excretion, an index of tubular function, in patients with hepatorenal syndrome, in whom tubular function is generally regarded as normal. Urine B2MG was significantly higher in these patients than in control patients with normal serum creatinine concentration. Patients with high urine B2MG concentration had markedly higher serum bilirubin than did patients with normal values (31 +/- 3 vs. 10 +/- 8 mg%, p less than 0.001), whereas prothrombin activity, serum albumin and serum B2MG concentration were similar. A "threshold" serum bilirubin concentration of about 23 mg% differentiated patients with normal and high urine B2MG values. Renal morphology at autopsy was unremarkable in both groups. Tubular dysfunction, manifested by increased urinary excretion of B2MG, occurs in patients with hepatorenal syndrome and deep jaundice. This measurement cannot, therefore, be used to make a diagnosis of acute tubular injury, as due to aminoglycosides, in such patients.

A urinary sodium concentration [U(Na)] of less than 10 mmoles per liter is considered important in differentiating hepatorenal syndrome from other causes of progressive renal impairment in patients with liver disease. However, occasionally, patients with hepatorenal syndrome have been recognized in whom the U(Na) is consistently greater than 10 mmoles per liter. Eight such patients, in all of whom there was no clinical or laboratory evidence to implicate other causes of progressive renal impairment, were identified. The clinical features, hepatic and renal status and hospital course were compared with eight other patients who had hepatorenal syndrome and a U(Na) consistently less than 10 mmoles per liter. The mean U(Na) was 24 +/- 4 mmoles per liter in the high U(Na) group and 3.7 +/- 1.8 mmoles per liter in the low U(Na) group. All patients in both groups had acutely decompensated alcoholic hepatitis of similar severity and activity. The high U(Na) group had significantly less clinical ascites and peripheral edema and higher serum levels of sodium and chloride both at the onset of the hepatorenal syndrome and throughout the clinical course. Significant differences in the serum potassium and blood urea nitrogen levels became apparent between the two groups of patients as renal failure progressed, and the mean average blood urea nitrogen to serum creatinine ratio was significantly higher (p less than 0.025) in the low U(Na) group (13.8 +/- 0.9 vs. 10.1 +/- 1.1). Mean urinary potassium concentration was significantly higher in the high U(Na) patients but urinary creatinine concentrations, specific gravity and sediment were similar in both groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)