Advances in alcoholic liver disease

Abstract

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.

Fig. 1

Mechanisms for alcoholic liver disease (ALD) are multiple and often interactive

Fig. 2

Fibrin metabolism. Activation of the coagulation cascade through thrombin initiates cross-linked fibrin deposition. Plasminogen activator inhibitor 1 (PAI-1) inhibits the activity of the plasminogen activators uPA and tPA by blocking the activation of plasmin. This process results in blunting fibrinolysis of fibrin matrices to fibrin degradation products (FDP)