Pathogenesis of Alcoholic Liver Damage and New Treatment Aspects

Key Learning Objective

At the end of the session, the participants will be able to:

  • to translate new knowledge acquired in the understanding of the pathogenesis of alcoholic liver disease into better treatment

Abstract

It was believed before that liver disease in the alcoholic is due exclusively to malnutrition, but it is now established that ethanol is hepatotoxic: in the absence of dietary deficiencies, and even in the presence of protein, vitamin and mineral enriched diets, ethanol produces a fatty liver, with striking ultrastructural lesions, both in rats and in human volunteers, and fibrosis with cirrhosis in non-human primates. In some patients, necrosis and inflammation (alcoholic hepatitis) hasten the fibrosis, but even in the absence of alcoholic hepatitis, tissue damage may result from alcohol’s direct toxic effects, linked to its metabolism (Lieber, 1992; 1998). The main pathway involves alcohol dehydrogenase which catalyzes the oxidation of ethanol to the toxic acetaldehyde (with a shift to a more reduced state) and which produces metabolic disturbances (hyperlactacidemia, acidosis, hypoglycemia, hyperuricemia and fatty liver) (Figure 1).

(Modified from Lieber, 1995)

Malnutrition, whether primary or secondary, can be differentiated from metabolic changes or direct toxicity, resulting partly from ADH (alcohol dehydrogenase) mediated redox changes, or effects secondary to microsomal (especially CYP2E1) induction, including increased acetaldehyde production by both pathways.

Even more severe toxic manifestations result from an accessory pathway, the microsomal ethanol oxidizing system involving an ethanol-inducible cytochrome P450 (CYP2E1). After chronic ethanol consumption, there is a five to ten fold induction of CYP2E1, associated with increased acetaldehyde generation and activation of xenobiotics to toxic metabolites, which explains the increased vulnerability of the heavy drinker to solvents commonly used in industry, anaesthetic agents, medications (isoniazid), over the counter analgesics (acetaminophen), illicit drugs (cocaine), chemical carcinogens, and even vitamins such as retinol and its precursor, b-carotene (Leo, et al, 1992; 1997). Furthermore, enhanced microsomal degradation of retinoids (together with increased hepatic mobilization) promotes their depletion and associated pathology (Leo and Lieber 1999). Acetaldehyde forms adducts with proteins, resulting in antibody production, enzyme inactivation, decreased DNA repair, impaired utilization of oxygen, glutathione depletion, and increased collagen synthesis.

Most important is the association of alcoholic liver disease with hepatitis C: a quarter of all patients with alcoholic liver disease have also markers of HCV infection (Koff and Dienstag, 1995), with an even higher incidence in urban areas. We found that even in the absence of risk factors such as intravenous drug abuse, portal or lobular inflammation is strongly associated with the hepatitis C virus in alcoholics (Rosman, et al, 1993), suggesting that alcohol may favor the acquisition replication, or persistence of the virus. It was also clear that alcoholism is associated with hepatitis C but not hepatitis B in that population (Rosman, et al, 1996). Alcohol consumption is clearly a risk factor for the progression of liver disease caused by HCV (Schiff, 1997; Ostapowicz, et al, 1998). Furthermore, fibrosis correlates significantly with alcohol consumption, and even low alcohol intake increases viremia and hepatic fibrosis (Pessione, et al, 1998). Wiley et al (1998) who examined the effect of moderate alcohol intake on HCV infection, concluded that alcohol intake is an independent risk factor in the clinical and histologic progression of HCV infection. Specifically, there was a two to three fold greater risk of liver cirrhosis and decompensated liver disease in the alcoholic and the development of cirrhosis was faster in the alcohol group. Thus, HCV infection multiplies the alcohol-associated risk of cirrhosis (Corrao and Arico, 1998) and alcohol and HCV together accelerate the development of hepatocellular carcinoma (HCC) (Tsutsumi, et al, 1996). In these patients, the incidence of HCC exceeded 50%.

The insight gained in pathogenesis is yielding new therapies, including adenosylmethionine, which attenuated mitochondrial lesions in baboons and replenished glutathione (Lieber, et al, 1990), and has now been shown to significantly reduce mortality in patients with child A or B cirrhosis (Mato, et al, 1999; Lieber, 1999). Oxidant stress is also opposed by polyenylphosphatidylcholine (PPC) which corrects the ethanol-induced hepatic phospholipid depletion as well as the decreased phosphatidylethanolamine methyltransferase activity (Lieber, et al, 1994a) and deactivates hepatic lipocytes, whereas its dilinoleoyl species increases collagenase activity resulting in full prevention of ethanol-induced septal fibrosis and cirrhosis in the baboon (Lieber, et al, 1994b).

Increased free radical generation and accelerated acetaldehyde production by ethanol-induced microsomes, resulting in enhanced lipid peroxidation and reduced glutathione (GSH) depletion. Metabolic blocks caused by alcoholic liver disease or folate deficiency are also illustrated, with a resulting depletion in S-adenosylmethionine, phosphatidylcholine, and GSH.

Current clinical trials with PPC are targeted on susceptible populations: heavy drinkers detected by markers (i.e., carbohydrate deficient transferrin; Rosman and Lieber, 1994) at pre-cirrhotic stages, characterized by perivenular fibrosis (Worner and Lieber, 1985). Since PPC appears to promote the breakdown of collagen, it might affect not only the progression of the disease, but it may also reverse preexisting fibrosis, as demonstrated for CCl4-induced cirrhosis in the rat (Ma, et al, 1996). In addition, PPC may be useful for the management of non-alcoholic liver diseases: it has been shown for instance to reduce transaminases in patients with hepatitis C (Niederau, et al, 1998). Other antioxidants (such as silymarin,¬†a-tocopherol, and selenium) and anti-inflammatory medications (corticosteroids, colchicine) are also being used (Figure 4) and agents that interfere with collagen synthesis, such as inhibitors of prolyl-4-hydroxylase, are being tested experimentally, as well as anticytokines (Lieber, 1997). Transplantation is now accepted treatment in alcoholics who have brought their alcoholism under control and who benefit from adequate social support, but the rate limiting factor is still the vastly insufficient donor supply and the prejudice against using this scarce resource in patients with “self inflicted” disease. Finally, abstinence from excessive drinking is always indicated; it is difficult to achieve but some agents that oppose alcohol craving, such as naltrexone (Volpicelli, et al, 1992), are now available and may be useful. In conclusion, elucidation of the biochemical effects of ethanol now provides prospects for improved diagnosis and therapy.

Figure : Therapeutic agents under evaluation or recently approved for the prevention and/or treatment of alcoholic liver damage.

 

 

Nutrients & Antioxidants

 

Anti-inflammatory & Antifibrotics

SilymarinColchicine
Vitamin ESteroids
SeleniumPTU
SAMeAnticytokines
Thioctic AcidThioctic Acid
PPC, DLPCPPC, DLPC

SAMe: S-adenosylmethionine. PPC: Polyenylphosphatidylcholine.

DLPC: dilinoleoylphosphatidylcholine. PTU: Propylthiouracil

Charles S. Lieber, MD

Professor of Medicine & Pathology

Suggested Reading

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