fibrin and Liver-Cirrhosis--Alcoholic

Plasminogen activator inhibitor-1 (PAI-1) is a major player in fibrinolysis due to its classical role of inhibiting plasminogen activators. Although increased fibrinolysis is common in alcoholic cirrhosis, decreased fibrinolysis (driven mostly by elevated levels of PAI-1) is common during the development of alcoholic liver disease (ALD). However, whether or not PAI-1 plays a causal role in the development of early ALD was unclear. Recent studies in experimental models have suggested that PAI-1 may contribute to the development of early (steatosis), intermediate (steatohepatitis) and late (fibrosis) stages of ALD. For example, fatty liver owing to both acute and chronic ethanol was blunted by the genetic inhibition of PAI-1. This effect of targeting PAI-1 appears to be mediated, at least in part, by an increase in very low-density lipoprotein (VLDL) synthesis in the genetic absence of this acute phase protein. Results from a two-hit model employing ethanol and lipopolysaccharide administration suggest that PAI-1 plays a critical role in hepatic inflammation, most likely due to its ability to cause fibrin accumulation, which subsequently sensitizes the liver to ensuing damaging insults. Lastly, the role of PAI-1 in hepatic fibrosis is less clear and appears that PAI-1 may serve a dual role in this pathological change, both protective (enhancing regeneration) and damaging (blocking matrix degradation). In summary, results from these studies suggest that PAI-1 may play multiple roles in the various stages of ALD, both protective and damaging. The latter effect is mediated by its influence on steatosis (i.e. decreasing VLDL synthesis), inflammation (i.e. impairing fibrinolysis) and fibrosis (i.e. blunting matrix degradation), whereas the former is mediated by maintaining hepatocyte division after an injury.

Topics: Animals; Disease Progression; Ethanol; Fatty Liver; Fibrin; Fibrinolysis; Humans; Lipopolysaccharides; Lipoproteins, VLDL; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Mice; Plasminogen Activator Inhibitor 1

Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States. In studies from the Veterans Administration, patients with cirrhosis and superimposed alcoholic hepatitis had greater than 60% mortality over a 4-year period, with most of those deaths occurring in the first month. Thus, the prognosis for this disease is more ominous than for many common types of cancer (eg, breast, prostate, and colon). Moreover, ALD imposes a significant economic burden from lost wages, health care costs, and lost productivity. Unfortunately, there is still no Food and Drug Administration-approved or widely accepted drug therapy for any stage of ALD. Thus, a pressing need exists for a more detailed understanding of mechanisms of liver injury. This article reviews recent advances in mechanisms and therapy related to five major areas of direct relevance to ALD: oxidative stress; gut-liver axis and cytokine signaling; malnutrition; fibrin/clotting; and stellate cell activation/fibrosis. We also review why therapies related to these mechanisms have performed well in experimental animals and in vitro systems, but have not necessarily translated into effective therapy for humans with ALD.

Topics: Blood Coagulation; Cytokines; Fibrin; Gastrointestinal Tract; Hepatic Stellate Cells; Humans; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Malnutrition; Oxidative Stress; Signal Transduction; Zinc

The autopsy data at the University of Southern California Liver Unit was studied during a 6-year period to investigate the relationship of fibrinous pericarditis with liver diseases. We found 18 cases of fibrinous pericarditis in 220 patients with alcoholic liver disease but none in 32 patients with fulminant and subacute hepatitis without alcoholism or in 39 patients with nonalcoholic cirrhosis. Although all the 18 patients with pericarditis had azotemia, 3 patients had pericarditis develop only in mild renal function impairment. These findings suggest that chronic alcoholism may precipitate pericarditis during the hepatorenal syndrome.

Topics: Adult; Aged; Aged, 80 and over; Fibrin; Hepatitis, Alcoholic; Humans; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Pericarditis; Retrospective Studies; Uremia