Modern Approach to Alcoholic Liver Disease R. K. ZE’ITERMAN Section of Digestive Diseases and Nutrition, University of Nebraska Medical Center, Omaha, Nebraska, USA Zetterman RK. Modern approach to alcoholic liver disease. Scand J Gastroenterol 1992;27 Suppl
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The pathogenesis of alcoholic liver disease is unclear. The recent literature on pathogenic factors, including direct effects of ethanol and its proximate metabolite acetaldehyde, associated nutritional factors, the formation of acetaldehyde-protein adducts, associated immune alterations, and the potential for liver injury due to coexisting hepatitis virus infection, is highlighted. The therapy of patients with advanced alcoholic liver injury, especially alcoholic hepatitis, is also controversial. It seems reasonable that all patients should receive adequate nutrition even if parenteral or enteral supplementation is required. Corticosteroid administration may benefit those patients with alcoholic hepatitis who have coexisting spontaneous hepatic encephalopathy and no gastrointestinal bleeding. For patients with complications from end-stage alcoholic cirrhosis, liver transplantation should be considered, as the patient with alcoholic cirrhosis does as well after liver transplantation as those patients with other forms of end-stage liver disease. Key words: Acetaldehyde; acetaldehydedehydrogenase;acetaldehyde-protein adducts; alcohol dehydrogenase; cirrhosis, alcoholic; ethanol; hepatitis, alcoholic; immune mechanisms; liver disease, alcoholic; liver transplantation Rowen K. Zetterman, M. D., Section of Digestive Diseases and Nutrition, University of Nebraska Medical Center, 600 S. 42nd St., Omaha, N E 68198-2000, USA
With sustained ethanol consumption, alcoholic liver disease (ALD) may develop. It is characteristically observed as one of three histologic manifestations, including fatty liver, alcoholic hepatitis, or alcoholic (Laennec’s) cirrhosis. Alcoholic hepatitis, with its centrilobular hepatocellular necrosis, polymorphonuclear inflammatory infiltrate, and alcoholic (Mallory’s) hyalin, is considered by many to be the intermediate step in the development of alcoholic cirrhosis. However, explanations of why only 1 5 2 0 % of chronic alcoholics develop alcoholic hepatitis, the mechanism(s) that results in its formation, and the appropriate therapy for patients with this disorder continue to elude the clinician. In this brief review, information from the past 2 years on pathogenesis, medical therapy, and liver transplantation will be highlighted. PATHOGENESIS
Ethanol metabolism The quantity of ethanol consumed is important in the development of advanced alcoholic liver disease. In epidemiologic surveys, males who consume the equivalent of 160g absolute ethanol or more daily for greater than 10 years are at greatest risk of developing cirrhosis (1). Women seem to be at greater risk for development of cirrhosis than men ( 2 ) , and the intake of just 80 g or more daily seems to put women at high risk (1). Although a definitive relationship for development of alcoholic hepatitis to blood alcohol level has not been established, women do have higher blood
alcohol levels than men after equivalent doses of oral ethanol. Ethanol is principally metabolized within the hepatocyte by the NAD-dependent cytosolic enzyme alcohol dehydrogenase (ADH) to its proximate metabolite acetaldehyde. Acetaldehyde is principally metabolized by mitochondria1 acetaldehyde dehydrogenase (ALDH) to acetate, which is largely utilized by peripheral tissues. Ethanol metabolism may be initiated by the ADH present in gastric mucosa. In women, a reduction of gastric A D H may limit initial ethanol metabolism by the stomach and result in increased systemic bioavailability of ethanol. Furthermore, ethanol will be delivered directly to the liver of women, potentially resulting in the formation of greater quantities of acetaldehyde within the liver. Acetaldehyde is a highly reactive molecule, and increased levels in the hepatocyte may enhance adduct formation (see below). These alterations may account for the increased risk of development of alcoholic liver disease in women despite smaller quantities of ethanol consumption. Medications may also reduce gastric ADH activity, including some histamine-2 receptor antagonists (4,s) and aspirin (6). This raises a question for chronic alcohol consumers of the safety of long-term use of medications that may alter ethanol metabolism by the stomach. Hepatocyte alcohol dehydrogenase activity is not altered by alcohol intake (7) but is reduced with increasing severity of liver disease (7,8), as is low K,,, acetaldehyde dehydrogenase activity (8,9). Both of these enzymes are polymorphic in humans, resulting in enzymes with various
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biologic activities. One commonly observed alteration is the deficiency of the class-I1 isoenzyme of aldehyde dehydrogenase (ALDH2) in Orientals, which results in an ‘alcohol flush reaction’ because of increased acetaldehyde levels. These enzyme alterations have been nicely reviewed by others (10). Because of differences in ethanol and acetaldehyde metabolism, it has been postulated that polymorphism of ADH and ALDH may also contribute to the development of alcoholic liver disease. If either enhanced ADH activity and/or reduced ALDH activity could increase the concentration of acetaldehyde within liver cells, greater liver cell injury due to acetaldehyde might be observed. However, studies to date have not identified a greater frequency of either ADH isoenzymes that enhance ethanol metabolism (11) or of ALDH isoenzymes that limit acetaldehyde clearance (12, 13) in patients with alcoholic cirrhosis. Of 47 Japanese patients with alcoholic liver disease, 40 were homozygous for normal ALDH2, and 7 patients (15) were heterozygous for the abnormal ALDH2 (12). In 20 normal controls, 9 heterozygotes (45%) for abnormal ALDH2 were observed. The reduced frequency of ADLH2 in those with ALD suggests the presence of impaired acetaldehyde metabolism may even be protective due to the symptoms associated with acetaldehyde accumulation. The lack of alteration of ALDH2 activity has also been observed in patients with alcoholic cirrhosis in England (13). In this study, however, a trend toward a greater frequency of ALDH3, which enables faster metabolism of ethanol, was observed. ADH activity has been thought to be principally contained in zone-3 hepatocytes of the hepatic acinus (perivenous region). However, a recent study suggests that the location and level of activity of ADH in the liver may vary between men and women (14). Overall, in those subjects less than 50 years of age, women tended to have greater ADH activity (22% more) than men. Above the age of 50, no difference of activity was observed. Furthermore, ADH was distributed differently along the acinus, with greater activity in the perivenous region of women and a more intermediate zonal distribution in men. ALDH activities were similar in both groups. It is unclear whether these differences in ADH activity or distribution could contribute to the increased risk of developing liver disease in women. Perhaps the increased ADH activity of perivenous hepatocytes results in even greater exposure of the hepatic acinar cells to acetaldehyde to produce liver damage. However, whether women really are at greater risk than men for liver damage from ethanol has been questioned. In a study of Danish alcoholics followed up for 5 years, no difference in survival of men or women or of increased susceptibility of women to alcoholic liver disease was observed ( 5 ) . Nutrition In early clinical studies nutrition was assigned a dominant role in the development of alcoholic liver disease. This was
principally due to the observation of advanced liver disease in the severely malnourished ‘skid row’ alcoholic and the presumption that alcoholic cirrhosis was not being observed in the well-fed alcoholic. We now know that nutrition alone is not the dominant factor and that alcoholic hepatitis and cirrhosis can occur in the presence of an adequate caloric intake. New studies of ethanol and dietary feeding in animal models are again addressing nutritional issues in the pathogenesis of alcoholic liver disease. By means of a continuous intragastric feeding tube model, Wistar rats were fed diets containing various amounts of dietary fat or protein plus ethanol. Since the animals were continuously infused, they received a diet throughout the day. In a study of the quantity of dietary fat and developing alcoholic liver injury, animals were infused in a pair-fed fashion with a high-fat (corn oil), low-protein diet with or without ethanol (46% of calories as ethanol or as an isocaloric substitution with dextrose, respectively (16). Animals were infused for up to 6 months. At 1 month, fatty change in the liver was greatest in the group receiving ethanol and a high-fat, low-protein diet. At 6 months, those animals who had the greatest degree of fatty liver at 1 month had the greatest degree of fibrosis, hepatocellular necrosis, and inflammation. In addition, the type of dietary fat may be important. Rats fed beef fat (lard or tallow) plus ethanol did not develop features of alcoholic liver injury (17), possibly as a consequence of the reduction of linoleic acid in beef tallow. In a preliminary report addition of omega-3 fatty acids to this model resulted in a greater degree of alcohol injury than animals receiving ethanol alone (18). However, even the gastric perfusion model of ethanol feeding cannot reproduce the full spectrum of alcoholic liver injury seen in man. This continues to limit the conclusions of these studies. Acetaldehyde-protein adducts Acetaldehyde is a highly reactive metabolite of ethanol which can bind to lysine residues on proteins to form stable and unstable protein-acetaldehyde adducts. Adducts could produce liver injury by either an impairment of a critical hepatocyte function or by an immune response directed against the adduct. Binding of acetaldehyde to proteins often occurs at the critical lysine moiety, interfering with their function as seen with tubulin polymerization (19). This may interfere with protein trafficking, with impairment of secretion of glycoproteins. Glycoproteins are seen to accumulate within the Golgi apparatus of alcohol-fed animals (20). When rats are chronically fed ethanol (21) or rat hepatocytes are maintained in primary culture and exposed to ethanol in vitro (22), a characteristic 37-kilodalton (kD) cytosolic proteinacetaldehyde adduct has been observed. Alteration of acetaldehyde levels also appeared to affect formation of the adduct. Supplementation of the diet of ethanol-fed rats with the alcohol dehydrogenase inhibitor pyrazole prevented the formation of the 37-kD adduct, whereas the potentiation
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of acetaldehyde concentration by addition of the aldehyde dehydrogenase inhibitor cyanamide enhanced its formation. These studies indicate that protein-acetaldehyde adducts can form during ethanol oxidation and that adducts have the potential to harm specific hepatocyte functions. Circulating protein-acetaldehyde adducts can also be observed in the serum of chronic alcoholics (23). Utilizing an enzyme-linked immunosorbent assay (ELISA) with antibodies directed against either hemocyanin-acetaldehyde adducts or myoglobin-acetaldehyde adducts, high titers of circulating protein-acetaldehyde adducts are seen in most alcoholics. In an additional study of human volunteers, ingestion of 1.3-2.9 g ethanol/kg body weight resulted in formation of hemoglobin-acetaldehyde adducts that persisted for up to 7 days (24). Protein-acetaldehyde adducts have also been observed in the liver of chronic alcoholics (25). Using a rabbit polyclonal antibody that recognized several acetaldehyde adducts, intracellular hepatocyte adducts were identified by immunohistochemical staining of liver biopsy specimens of chronic alcoholics but not nondrinking controls. There did not appear to be a relationship to the severity of histologic injury but, rather, to the prior ethanol consumption. The protein-acetaldehyde adduct data are interesting and seem to account for some of the alterations of hepatocyte function seen with acute and chronic ethanol consumption. However, it appears we should all make adducts on ethanol consumption. If so, how do we escape the hepatic injury they seem capable of causing? Circulating antibodies to protein-acetaldehyde adducts also develop in patients with chronic alcohol consumption (26). In this study, circulating antibodies were seen in 73% of alcoholics but only 39% of control patients and seemed to correlate in patients with the increased severity of underlying alcoholic liver disease. Another study has suggested the presence of these antibodies indicates a greater likelihood for histologic progression of liver disease (27). In patients with both alcoholic and non-alcoholic liver disease, IgM antibodies to protein-acetaldehyde adducts were seen, whereas IgA antibodies were seen only in alcoholic liver disease. This suggests that circulating IgA antibodies to protein-acetaldehyde adducts may be useful as a marker for the underlying etiology of unexplained chronic liver disease (28). Immune mechanisms
At first thought, it seems unlikely that immune mechanisms should have any role in the development of alcoholic liver disease. However, the rapid redevelopment of alcoholic hepatitis with resumption of ethanol consumption despite prior histologic and clinical recovery, the progression of liver injury despite cessation of ethanol intake, associated hypergammaglobulinemia and autoantibody formation, and the apparent chronic hepatitis that occur in selected alcoholics suggests an immunologic role for its pathogenesis.
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Selected immunologic features are highlighted to draw attention to recent studies. Autoantibodies have been described in patients with advanced alcoholic liver disease (29,30). In a recent evaluation of patients with ALD and autoimmune chronic hepatitis (CAH), antinuclear antibodies (ANA) were seen in 22% of ALD and 73% of CAH patients (31). Antibodies to single-stranded and double-stranded DNA were seen in 60% of patients with ALD. When the presence of all three antibodies was determined in patients with ALD and CAH, they were seen in 25.5% and 32%, respectively. In addition, other evidence of enhanced humoral immunity has been observed in patients with advanced alcoholic liver disease including hypergammaglobulinemia (32), circulating immune complexes (33), immune complex glomerulonephritis (34), and hepatic perisinusoidal deposition of IgA (35). These results are suggestive of ongoing immune reactivity in the presence of alcoholic liver disease and seems indicative of a potential role of humoral immune events in its pathogenesis. Alterations of in vivo and in vitro cell-mediated immune events are also frequently observed in patients with alcoholic liver disease, especially those with alcoholic hepatitis (36). Various hepatocyte epitopes have been considered candidate antigens for initiation of this activity, including liver specific proteins (37), alcoholic hyalin (38), ethanol-altered membrane epitopes (39), and protein-acetaldehyde adducts (40). Although reactivity against these antigens has been observed in vitro, their role in vivo is less clear. Does such reactivity have a pathogenic significance or is it just an epiphenomena that occurs in patients with alcoholic liver disease? The lack of an appropriate animal model continues to hamper investigation. Only with such a model can the role of immune reactivity be assessed as the immune status of the animal is perturbed. Recent interest has centered on the potential role of cytokines in the manifestations of alcoholic hepatitis. Tumor necrosis factor alpha (TNFa) is secreted by mononuclear cells and possesses immunoregulatory and inflammatory properties. TNFa may be the mediator of the effects of endotoxemia and account for the acute-phase reactions seen with inflammatory disorders, including leukocytosis, fever, hypoalbuminemia, and anorexia. Its immunoregulatory activities appear to include T- and B-cell activation, natural killer (NK) cell activation, and release of cytokines including interleukin-6 (IL-6) (41). Both serum TNFa (42-46) and IL6 (45-48) levels are increased in patients with alcoholic hepatitis. Similar elevations have not been consistently observed in other stages of alcoholic liver disease. No correlation with circulating endotoxin levels seems to exist in patients with alcoholic hepatitis (44,46), although circulating, TNFa levels may correlate with the presence of coexisting infection (44). Elevated serum TNFa levels do correlate with mortality in patients with alcoholic hepatitis (43,44). TNFa levels may also persist for up to 6 months
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after a diagnosis of alcoholic hepatitis has been established, although IL-6 levels return to normal with clinical recovery (46). IL-6 levels may also be indicative of greater mortality. In a study of 58 alcoholic hepatitis patients, serum IL-6 levels were highest in those who died and in those with significant hepatic decompensation such as hepatic encephalopathy, hyperbilirubinemia, and hypoprothrombinemia (48). Whether cytokines like TNF and IL-6 play a direct role in the mortality of alcoholic hepatitis patients or are simply increased because of the severity of the underlying liver disease is unclear from these observations. They do suggest that cytokines such as TNF and IL-6 at least have pathophysiologic roles in the clinical manifestations of patients with alcoholic hepatitis.
of HCV RNA is also observed and correlates with the advanced nature of alcoholic liver injury (56). In this study sera from 40% of patients with alcoholic hepatitis and 61% of those with alcoholic cirrhosis were HCV RNA-positive. Does this indicate that HCV has a role in the development of alcoholic cirrhosis? Obviously, this will be a very difficult question to answer. However, it may shed additional light on some aspects of alcoholic liver disease. Previous studies have indicated that alcohol intake may lead to a state of chronic hepatitis-like liver injury that is progressive despite cessation of ethanol consumption (58,59). However, studies of HCV coexistence in the chronic alcoholic indicate that these changes may be due to HCV infection, as patients who are anti-HCV-positive tend to have histologic changes more characteristic of chronic viral than alcoholic injury (50). Additional studies will be required to clarify this issue. When Japanese alcoholic patients with chronic hepatitislike histology were evaluated, an HBV and HCV markernegative subgroup was still identified which had improvement of serum aminotransferases with abstinence, suggesting ethanol alone had a direct role in the pathogenesis of a chronic hepatitis-like lesion (54).
Viral hepatitis Although hepatotrophic viruses may not have a direct role in the pathogenesis of alcoholic liver disease, their frequent concurrence and coexisting manifestations of chronic viral hepatitis with alcoholic liver disease warrant its inclusion in this section. Hepatitis B virus (HBV). In Alaskan natives, seropositivity for markers of prior B virus infection was seen in 34% of chronic alcoholics, compared with 12% of controls, THERAPY OF ALCOHOLIC LIVER DISEASE of which 3.1% and 1.7%, respectively, were currently hepatitis B surface antigen (HBsAg)-positive (49). Similarly, in The difficulty of treating the patient with alcoholic hepatitis a Veterans Administration cooperative treatment trial for is recognized when one reviews the different therapies and patients with alcoholic hepatitis, antibodies to HBsAg or the number of trials that have been reported. One of the hepatitis B core antigen (HBcAg) were identified in 29% of difficulties in assessing therapies is the lack of uniformity of patients (50). HBsAg was not observed in this study, as its patients studied, including their principal diagnosis presence was an exclusion criteria, for entry into the study. (alcoholic hepatitis or decompensated cirrhosis) and the In a histologic study 54 chronic alcoholics who were also severity of clinical illness (prognosis) of patients who are hepatitis B virus carriers were evaluated by liver biopsy (51). entered into clinical trials. In this section, recent studies will Half had changes principally due to HBV, 13% had changes be discussed. For an overview of treatment of alcoholic due to alcoholic liver disease, and 8% had both (51). The hepatitis, another recent review is suggested (60). remainder had nonspecific histologic findings. When biopsy specimens were evaluated by electron microscopy, both Nutritional supplementation In a study of 35 severely malnourished patients with HBV and alcoholic hyalin were observed within the same alcoholic cirrhosis, the use of total enteral nutrition (TEN) hepatocyte. Do these studies imply a pathogenic role for HBV in alcoholic liver disease? Although the data are incon- for at least 3 weeks significantly improved survival rates clusive, it seems likely that these findings simply reflect that when compared with an ad lib standard low-sodium hospital alcoholics also engage in behavior that puts them at risk for diet (61). The enteral diet was a specially prepared diet supplying 2115 kcal, with 71 g protein (as whole protein HBV infection. Hepatitis C virus (HCV). The interrelation of hepatitis C supplemented with branched-chain amino acids), 38 g fat, virus with alcoholic liver disease (ALD) is complex. Dep- and 367 g carbohydrate. There were only 2 deaths (1 sponending on the country of origin and the type of underlying taneous bacterial peritonitis (SBD), 1 upper gastrointestinal ALD, up to 48% of patients may have detectabie anti-HCV bleeding) in 16 patients receiving TEN, as compared with 9 (50,52-57). It does not appear to require ‘high-risk’behavior deaths (4 SBP, 3 upper GI bleeding, and 2 liver failure) in by patients with alcoholic liver disease to acquire markers 19 patients on a standard diet. Serum albumin and Child’s for HCV (55). Anti-HCV is more common in alcoholic score were also significantly improved by TEN. No compatients with cirrhosis (53,56,57) but may, in part, be a plications directly due to the diet or its infusion were consequence of false-positive reactions in the presence of observed. Whether or not these results hold up in larger hypergammaglobulinemia (53). However, when HCV ribo- trials, this study at least indicates that TEN is safe and nucleic acid (RNA) is determined in sera by means of potentially of great benefit to the malnourished patient with polymerase chain reaction (PCR), an increased frequency advanced ALD.
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Alcoholic Liver Disease
A trial of parenteral supplementation in patients with alcoholic hepatitis has also been reported (62). Fifty-four patients with clinical variables indicative of alcoholic hepatitis were randomized to receive either 2 I/day of parenteral dextrose (65 g) supplementation with (28 patients) or without (26 patients) 51.6 g amino acids as Freeamine I1 (Kendall McGraw, Irvine, Calif., USA). Although there was no difference in mortality, there was significant improvement in the nitrogen balance and biochemical variables of liver injury (serum bilirubin, aminotransferases, and prothrombin level), which continued even after cessation of infusion in those receiving amino acid supplementation. No deaths as a consequence of intravenous access were reported. These studies indicate the need to supplement the diet of the patient admitted to the hospital with advanced alcoholic liver disease. The simple use of a hospital diet may be inadequate in many because of anorexia, gastric displacement by ascites, and the severity of underlying malnutrition. Patients can still receive an oral diet as tolerated even if receiving enteral or parenteral supplementation. Anabolic steroids plus nutritional supplementation Anabolic steroids have been suggested to improve the outcome of patients with alcoholic hepatitis (63), perhaps by improving protein synthesis and positive nitrogen balance in patients with severe hepatic dysfunction. In a study of 39 patients with alcoholic hepatitis, patients were assigned to 21 days of a standard hospital diet; standard diet plus oxandrolone, 80 mg/day, in divided doses; standard diet plus peripheral venous parenteral supplementation; or standard diet plus oxandrolone plus peripheral venous parenteral supplementation (64,65). Parenteral supplementation included electrolytes, 100 g carbohydrate as dextrose, and 70 g amino acids (Aminosyn 11, Abbott Laboratories, Chicago, Ill., USA). There were significant improvements of serum albumin, transferrin, and prothrombin level in patients receiving parenteral supplementation with or without the addition of oxandrolone when compared with standard hospital diet, again suggesting the importance of adequate dietary intake in the management of patients with alcoholic hepatitis. Insulin-glucagotr infusions Two trials assessed the value of simultaneous infusions of insulin and glucagon in patients with alcoholic hepatitis (66,67). A role for insulin and glucagon has been suggested in hepatic regeneration, and prior studies in small groups of subjects with alcoholic hepatitis have indicated a potential benefit for insulin-glucagon in the management of such patients (68,69). In both of these studies patients with clinical (83 patients) (66) or biopsy (72 patients) (67) evidence of alcoholic hepatitis were randomized to 3 weeks of infusions of either 60 units insulin and 6 mg glucagon/day or to placebo infusion. There was no improvement in shortterm or long-term survival with insulin-glucagon infusion.
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These trials in large numbers of patients would seem to put to rest any consideration of insulin-glucagon infusions in the therapy of patients with alcoholic hepatitis. Corticosteroids There have been many trials of corticosteroids in patients with various degrees of severity of alcoholic hepatitis. Rather than repeat the results of these trials, a review of the metaanalysis of the use of corticosteroid trials will be discussed (70). Eleven randomized trials of hospitalized patients from a total of 30 published studies were included, based on similarity of inclusion and exclusion criteria, prognostic factors at entry into the trials, and ancillary and principal therapies. A total of 562 patients were included, of which 45% were encephalopathic. The effect of corticosteroids on short-term (60 day) mortality was determined. Corticosteroids appear to improve outcome significantly, with a reduction of the relative risk of death to 0.63. This was especially true for trials that excluded GI bleeding as an entry criterion. When only trials with a high quality score that excluded GI bleeding were combined, the relative risk of mortality was further reduced to 0.36. Hepatic encephalopathy was an additional important variable. In those alcoholic hepatitis patients with hepatic encephalopathy, corticosteroids reduced the relative risk of short-term mortality to 0.66 while having no effect on those without encephalopathy. This meta-analysis suggests that corticosteroids should be considered part of the treatment of patients with alcoholic hepatitis who have encephalopathy in the absence of gastrointestinal bleeding. What should be the therapeutic approach to patients with alcoholic hepatitis? It seems clear that all patients who present with alcoholic hepatitis should receive dietary supplementation with enteral or parenteral amino acidcontaining solutions. In those with encephalopathy, corticosteroids seem to be of benefit as well. The use of oxandrolone deserves additional study but should probably be reserved for those patients who can be included in a controlled trial.
LIVER TRANSPLANTATION OF ALCOHOLIC CIRRHOSIS The controversy regarding liver transplantation for the patient with end-stage alcoholic liver disease continues to pose problems for the clinician. Issues include clinical questions such as the short-term and long-term clinical outcome of patients with alcoholic cirrhosis after transplantation, the presence of coexisting diseases also due to alcoholism (for example, cardiomyopathy) which will put the patient at risk from the operation, the potential for recidivism, the need to maintain follow-up, and the ability of the alcoholic to return to a ‘useful’ existence in the workplace. Ethical issues have also been raised, including whether people who have developed an avoidable disease by engaging in self-destructive
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behavior deserve to be given a valuable resource (donor liver) while potentially depriving another person of this same resource (71-77). Furthermore, a little-spoken concern is the outcome decision for potential donors when they learn their (or their next of kin) liver may go t o an alcoholic. The decision to transplant any patients with alcoholic liver disease is only relatively recent in most centers. As essentially all transplant centers have demanded a prolonged period of ethanol abstinence before consideration of transplantation, patients with acute alcoholic hepatitis have been eliminated from consideration. In published studies to date the short- and long-term outcome of patients with alcoholic cirrhosis who receive a liver transplant is similar t o that of patients transplanted with other forms of liver disease (78-81). In the larger of these reports (79), 73 patients with end-stage alcoholic liver disease received a liver transplant. The mean age of the recipients was 48 years, 73% were male, and most were Child’s class B (32%) or C (64%). At 1 year after liver transplantation, overall survival was 74% and comparable to that of patients undergoing transplantation for other hepatic diseases. Furthermore, only 6 of 52 survivors (11.5%) returned to any form of ethanol consumption, of which 4 were described as social (consumption on holidays and special occasions) and 2 were moderate drinkers (three or fewer drinks per week). Recidivism did correlate with length of preoperative abstinence. In those who had been abstinent for 6 months o r longer, only 7% resumed ethanol consumption, compared 43% of those who had been abstinent for less than 6 months. When ability to return to work was assessed, only 21% were unable to return to work after operation. These data would suggest that the patient with endstage alcoholic liver disease who has stopped drinking for 6 months before transplantation is a good candidate for liver transplantation. The clinical arguments against consideration, such as survival rates, recidivism, failure of follow-up, or a lack of a return to work have been countered by available studies. Any concern about coexisting diseases that should preclude transplantation can be alleviated by careful preoperative evaluation. In fact, some disorders such as glomerulonephritis related to alcoholic cirrhosis may improve after liver transplantation (82). However, current studies d o not address the outcome of transplantation for patients with acute alcoholic hepatitis, as these patients have essentially been excluded from transplantation by the requirement for prolonged ethanol abstinence. Should we transplant these patients? This is a difficult question in view of the potential risks of redrinking and of even higher intraoperative mortality, as has been observed for other operations in alcoholic hepatitis patients in the past. If this step is considered, it must be in the context of a controlled trial with careful preoperative assessment of the patient for both medical and psychologic aspects of their disease.
SUMMARY Alcoholic liver disease remains a difficult problem for the clinician-investigator. Despite extensive research, beyond recognizing that excessive ethanol consumption is potentially harmful, the mechanisms involved in the pathogenesis of alcoholic hepatitis and cirrhosis continue to elude us. The potential role of protein-acetaldehyde adducts is intriguing because of their possibilities for both a direct injurious effect on hepatocyte function and the initiation of immune sensitization. There seems little question that several immunologic alterations occur in the patient with advanced alcoholic liver disease. However, whether these changes are the initiating mechanisms involved in the pathogenesis, simply epiphenomena of an injured liver, o r the resulting mechanisms that cause the sequelae of alcoholic liver disease remains unclear. Similarly, therapy for the patient with alcoholic hepatitis beyond ethanol abstinence is unresolved. Provision of adequate nutrition including amino acid supplementation is important. However, the role of pharmacologic intervention is less clear. Corticosteroids may be of benefit in those patients with alcoholic hepatitis who have hepatic encephalopathy in the absence of upper gastrointestinal bleeding. It seems that many of these issues could be resolved if an adequate animal model was available. We need, therefore, to continue to evaluate new animal models of alcoholic liver disease to allow us to test new ideas with regard to pathogenesis and therapy.
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hepatic alcohol and aldehyde dehydrogenases. Gastroenterology 1989;97:70%14. 9. Takase S , Takada A, Yasuhara, Tsutsumi M. Hepatic aldehyde dehydrogenaseactivity in liver diseases, with particular emphasis on alcoholic liver disease. Hepatology 1989;9:704-9. 10. Ehrig T, Bosron WF, Li T-K. Alcohol and aldehyde dehydrogenase. Alcohol Alcoholism 1990;25:106-15. 11. Couzigou P, Fleury B, Groppi A, et al. Role of alcohol dehydrogenase polymorphismin ethanol metabolism and alcohol-related diseases. Adv Exp Med Biol 1991;284:263-70. 12. Enomoto N, Takase S , Takada N, Takada A. Alcoholic liver
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Alcoholic Liver Disease disease in heterozygotes of mutant and normal aldehyde dehydrogenase-2 genes. Hepatology 1991;13:1071-5. 13. Day CP, Bashir R, James OFW, et al. Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage. Hepatology 1991;14:79%801. 14. Maly IP, Sasse D. lntraacinar profiles of alcohol dehydrogenase and aldehyde dehydrogenase activities in human liver. Gastroenterology 1991;101 :1716-23, 15. Milman N, Graudal N , Stram P, Franzmann M-B. Alcoholic hepatitis in females. Acta Med Scand 1988;223:11%24. 16. Nanji AA, Tsukamotoo H, French SW. Relationship between fatty liver and subsequent development of necrosis, inflammation and fibrosis in experimental alcoholic liver disease. Exp Mol Pathol 1989;51:141-8. 17. Nanji AA, Mendenhall CL, French SW. Beef fat prevents alcoholic liver disease in the rat. Alcohol Clin Res 1989;13:159. 18. Degli-Esposti S, Frizell E, He 0, et al. Improved rat model of alcoholic liver disease: omega-3-fatty acids plus ethanol administration [abstract]. Hepatology 1991;14:132A. 19. Smith SL, Jennett RB, Sorrel1 MF, et al. Acetaldehyde stochiometrically inhibits neurotuhulin polymerization. J Clin Invest 1989;84:337-41. 20. Matsuda Y. Takada A, Takase S, Sat0 H. Accumulation of glycoprotein in the golgi apparatus of hepatocytes in alcoholic liver injuries. Am J Gastroenterol 1991;86:85460. 21. Lin RC Lumeng L. Formation of 37KD protein-acetaldehyde adduct in liver during alcohol treatment is dependent on alcohol dehydrogenase activity. Alcohol Clin Exp Res 1990;14:766-70. 22. Lin RC, Fillenwarth J, Minter R , Lumeng L. Formation of the 37-kD protein-acetaldehyde adduct in primary cultured rat hepatocytes exposed to alcohol. Hepatology 1990;11:401-7. 23. Lin RC, Lumeng L, Shahidi S, et al. Protein-acetaldehyde adducts in serum of alcoholic patients. Alcohol Clin Exp Res 1990;14:438-43. 24. Niemela 0, Israel Y, Mizoi Y, et al. Hemoglobin-acetaldehyde adducts in human volunteers following acute ethanol ingestion. Alcohol Clin Exp Res 1990;14:838-41. 25. Niemela 0, Juvonen T, Parkkila S. lmmunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption. J Clin Invest 1991;87:1367-74. 26. Hoerner M, Behrens UJ, Worner TM, et al. The role of alcoholism and liver disease in the appearance of serum antibodies against acetaldehyde adducts. Hepatology 1988;8:569-74. 27. Izumi N , Sakai Y, Koyama W, Hasumura Y. Clinical significance of serum antibodies against alcohol-altered hepatocyte membrane in alcoholic liver disease. Alcohol Clin Exp Res 1989;13:762-5. 28. Worrall S, De Jersey J , Shanley BC, Wilce PA. Antibodies against acetaldehyde-modified epitopes: an elevated IgA response in alcoholics. Eur J Clin Invest 1991;21:9@5. 29. Bailey RJ,Krasner N, Feddleston AL, et al. Histocompatibility antigens, autoantibodies, and immunoglobulins in alcoholic liver disease. Br Med J 1976;2:727-9. 30. Gluud C, Tage-Jensen U, Rubinstein E, Henriksen JH. Autoantibodies and immunoglobulins in patients with alcoholic cirrhosis. Digestion 1984;30:1-6. 31. Laskin CA, Vidins E, Blendis LM, Soloninka CA. Autoantibodies in alcoholic liver disease. Am J Med 1990;89:129-33. 32. Gluud C, Tage-Jensen U. Autoantibodies and immunoglobulins in alcoholic steatosis and cirrhosis. Acta Med Scand 1983; 214:614. 33. Gluud C, Jans H. Circulating immune complexes and complement concentrations in patients with alcoholic liver disease. J Clin Pathol 1982;35:380-4. 34. Lomax-Smith JD, Zabrowarny LA, Howarth GS, et al. The immunochemical characterization of mesangial IgA deposits. Am J Pathol 1983;113:359-64. 35. Van de Wiel A, Van Hattum J , Schuurman H-J, Kater L. Immunoglobulin A in the diagnosis of alcoholic liver disease. Gastroenterology 1988;94:457-62. 36, Zetterman RK. Autoimmune manifestations of alcoholic liver
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disease. In: Krawitt EL, Wiesner RH, editors. Autoimmune liver iseases. New York: Raven Press, 1991;247-60. 37. Perperas A, Tsantoulas D, Portmann B, Feddleston AL, Williams R. Autoimmunity to a liver membrane lipoprotein and liver damage in alcoholic liver disease. Gut 1981;22: 149-52. 38. Zetterman RK, Luisada-Opper A, Leevy CM. Alcoholic hepatitis: cell-mediated immunologic response to alcoholic hyalin. Gastroenterology 1976;70:3824. 39. Izumi N, Sakai Y, Koyama W, Hasumura Y. Clinical significance of serum antibodies against alcohol-altered hepatocyte membrane in alcoholic liver disease. Alcohol Clin Exp Res 1989;13~762-5. 40. Trudell JR, Ardies CM, Anderson WR. Cross-reactivity of antibodies raised against acetaldehyde adducts of protein with acetaldehyde adducts of phosphatidyl-ethanolamine:possible role in alcoholic cirrhosis. Mol Pharm 1990;38:587-93. 41. Thiele DL. Tumor necrosis factor, the acute phase response and the pathogenesis of alcoholic liver disease. Hepatology 1989;91497-9. 42. McClain CJ, Cohen DA. Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology 1989;9:349-5 1. 43. Felver ME, Mezey E, McGuire M, et al. Plasma tumor necrosis factor apredicts decreased long-term survival in severe alcoholic hepatitis. Alcohol Clin Exp Res 1990;14:255-9. 44. Bird GLA, Sheron N, Goka AKJ, Alexander GJ, Williams RS. Increased plasma tumor necrosis factor in severe alcoholic, hepatitis. Ann Intern Med 1990;112:917-20. 45. Deviere J, Content J , Denys C, et al. Excessive in vitro bacterial lipopolysaccharide-induced production of monokines in cirrhosis. Hepatology 1990;4:628-34. 46. Khoruts A, Stahnke L, McClain CJ, et al. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrationb in chronic alcoholic patients. Hepatology 1991;13:267-76. 47. Deviere J, Content J, Denys C. et al. High interleukin-6 serum levels and increased production by leucocytes in alcoholic liver cirrhosis. Correlation with IgA serum levels and lymphokines production. Clin Exp Immunol 1989;77:221-5. 48. Sheron N, Bird G , Goka J , et al. Elevated plasma interleukin6 and increased severity and mortality in alcoholic hepatitis. Clin Exp Immunol 1991;84:449-53. 49. McMahon BJ, Wainwright K, Bulkow L, et al. Response to hepatitis B vaccine in Alaska natives with chronic alcohlism compared with non-alcoholic control subjects. Am J Med 1990;88:460-4. 50. Mendenhall CL, Seeff L, Diehl AM, et al. Antibodies to hepatitis B virus and hepatitis C virus in alcoholic hepatitis and cirrhosis: their prevalence and clinical relevance. Hepatology 1991;14:581-9. 51. Takahashi T, Kamimura T, Asakura H, Ichida F. Hepatic lesions in alcoholic HBV carriers. Dig Dis Sci 1991;36:1234-42. 52. Estaban JI, Estaban R, Viladomiu L, et al. Hepatitis C virus antibodies among high risk groups in Spain. Lancet 1989;2:2946. 53. Bode JC, Biermann J , Kohse KP, et al. High incidence of antibodies to hepatitis C virus in alcoholic cirrhosis: fact or fiction? Alcohol Alcoholism 1991;26:1114. 54. Takase S, Takada N. Enomoto N, et al. Different types of chronic hepatitis in alcoholic patients: does chronic hepatitis induced by alcohol exist? Hepatology 1991;13:87681. 55. Caldwell SH, Jeffers U.Ditomaso A, et al. Antibody to hepatitis C is common among patients with alcoholic liver disease with and without risk factors. Am J Gastroenterol 1991;86:121923. 56. Nishiguchi S, Kuroki T, YabusakoT, et al. Detection of hepatitis C virus antibodies and hepatitis C virus RNA in patients with alcoholic liver disease. Hepatology 1991;14:985-9. 57. Pares A, Barrera JM, Caballeria J, et al. Hepatitis C virus antibodies in chronic alcoholic patients: association with severity of liver injury. Hepatology 1990;12:1295-9. 58. Goldberg SJ, Mendenhall CL, Connell AM, et al. ‘Nonalcoholic’ chronic hepatitis in the alcoholic. Gastroenterology 1977;72:598-604.
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59. Nei J , Matsuda Y, Takada A. Chronic hepatitis induced by alcohol. Dig Dis Sci 1983;28:207-15. 60. Bird GLA, Williams R. Treatment of advanced alcoholic liver disease. Alcohol Alcoholism 1990;25:197-206. 61. Cabre E, Gonzalez-Huix F, Abad-Lacruz A, et al. Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics. Gastroenterology 1990;98:715-20. 62. Mezey E, Caballeria J, Mitchell MC. Effect of parenteral amino acid supplementation on short-term and long-term outcomes in severe alcoholic hepatitis: a randomized controlled trial. Hepatology 1991;14:1090-6. 63. Mendenhall CL, Anderson S, Garcia-Pont P, et al. Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med 1984;311: 1464-70. 64. Bonkovsky HL, Fiellin DA, Smith GS, et al. A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. I. Short-term effects on liver function. Am J Gastroenterol 1991;86:120&8. 65. Bonkovsky HL, Singh RH, Jafri IH, et al. A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. 11. Short-term effects on nitrogen metabolism, metabolic balance, and nutrition. Am J Gastroenterol 1991;86:1209-18. 66. Bird G, Lau JYN, Koskinas J , et al. Insulin and glucagon infusion in acute alcoholic hepatitis: a prospective randomized controlled trial. Hepatology 1991;14:1097-101. 67. Trinchet J-C, Balkau B, Poupon RE, et al. Treatment of severe alcoholic hepatitis by infusion of insulin and glucagon: a multicenter sequential trial. Hepatology 1992;15:76-81. 68. Baker AL, Jaspan JB, Haines NW, et al. A randomized clinical trial of insulin and glucagon infusion for treatment of alcoholic hepatitis: a progress report in 50 patients. Gastroenterology 1981 $0: 1410-14. 69. Feher J, Cornides A, Romany A, et al. A prospective multicentre study of insulin and glucagon infusion therapy of acute
alcoholic hepatitis. J Hepatol 1987;5:224-31. 70. Imperiale TF, McCullough AJ. Do corticosteroids reduce mortality from alcoholic hepatitis? Ann Intern Med 1990;113:29% 307. 71. Schwartzman K. In vino veritas? Alcoholics and liver transplantation. Can J Med 1989;141:1262-1265. 72. Schenker S. Should patients with end-stage alcoholic liver disease have a new liver? Hepatology 1990;11:314-9. 73. Moss AH, Siegler M. Should alcoholics compete equally for liver transplantation? JAMA 1991;265:1295-8. 74. Cohen C, Benjamin M. Alcoholics and liver transplantation. JAMA 1991;265:1299-301. 75. Van Thiel DH, Gavaler JS, Tarter RE, et al. Liver transplantation for alcoholic liver disease: a consideration of reasons for and against. Alcohol Clin Exp Res 1989;13:181-4. 76. Neuberger JM. Transplantation for alcoholic liver disease. Br Med J 1989;299:693-4. 77. BeresfordTP,Turcotte JG, Merion R, et al. A rational approach to liver transplantation for the alcoholic patient. Psychosomatics 199O;31:241-54. 78. Doffoel M, Wolf P, Ellero B, et al. Results of orthotopic liver transplantation (OLT) in alcoholic cirrhosis. J Hepatol 1989;9 Suppl 1527. 79. Kumar S, Stauber RE, Gavaler JS, et al. Orthotopic liver transplantation for alcoholic liver disease. Hepatology 1990;11:159-64. 80. Stevens L, Piper J, Emond J, et al. Liver transplantation for controversial indications: alcoholic liver disease, hepatic cancers, and viral hepatitis. Transplantation Proc 1991;23:19156. 81. Van Thiel DH, Carr B, Iwatsuki S, et al. Liver transplantation for alcoholic liver disease, viral hepatitis, and hepatic neoplasms. Transplantation Proc 1991;23:1917-21. 82. Ghabra N, Piraino B, Greenberg, Banner B. Resolution of cirrhotic glomerulonephritis following successful liver transplantation. Clin Nephrol 1991;35:69.
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The pathogenesis of alcoholic liver disease is unclear. The recent literature on pathogenic factors, including direct effects of ethanol and its proximate metabolite acetaldehyde, associated nutritional factors, the formation of acetaldehyde-protein adducts, associated immune alterations, and the potential for liver injury due to coexisting hepatitis virus infection, is highlighted. The therapy of patients with advanced alcoholic liver injury, especially alcoholic hepatitis, is also controversial. It seems reasonable that all patients should receive adequate nutrition even if parenteral or enteral supplementation is required. Corticosteroid administration may benefit those patients with alcoholic hepatitis who have coexisting spontaneous hepatic encephalopathy and no gastrointestinal bleeding. For patients with complications from end-stage alcoholic cirrhosis, liver transplantation should be considered, as the patient with alcoholic cirrhosis does as well after liver transplantation as those patients with other forms of end-stage liver disease. Key words: Acetaldehyde; acetaldehydedehydrogenase;acetaldehyde-protein adducts; alcohol dehydrogenase; cirrhosis, alcoholic; ethanol; hepatitis, alcoholic; immune mechanisms; liver disease, alcoholic; liver transplantation Rowen K. Zetterman, M. D., Section of Digestive Diseases and Nutrition, University of Nebraska Medical Center, 600 S. 42nd St., Omaha, N E 68198-2000, USA
With sustained ethanol consumption, alcoholic liver disease (ALD) may develop. It is characteristically observed as one of three histologic manifestations, including fatty liver, alcoholic hepatitis, or alcoholic (Laennec’s) cirrhosis. Alcoholic hepatitis, with its centrilobular hepatocellular necrosis, polymorphonuclear inflammatory infiltrate, and alcoholic (Mallory’s) hyalin, is considered by many to be the intermediate step in the development of alcoholic cirrhosis. However, explanations of why only 1 5 2 0 % of chronic alcoholics develop alcoholic hepatitis, the mechanism(s) that results in its formation, and the appropriate therapy for patients with this disorder continue to elude the clinician. In this brief review, information from the past 2 years on pathogenesis, medical therapy, and liver transplantation will be highlighted. PATHOGENESIS
Ethanol metabolism The quantity of ethanol consumed is important in the development of advanced alcoholic liver disease. In epidemiologic surveys, males who consume the equivalent of 160g absolute ethanol or more daily for greater than 10 years are at greatest risk of developing cirrhosis (1). Women seem to be at greater risk for development of cirrhosis than men ( 2 ) , and the intake of just 80 g or more daily seems to put women at high risk (1). Although a definitive relationship for development of alcoholic hepatitis to blood alcohol level has not been established, women do have higher blood
alcohol levels than men after equivalent doses of oral ethanol. Ethanol is principally metabolized within the hepatocyte by the NAD-dependent cytosolic enzyme alcohol dehydrogenase (ADH) to its proximate metabolite acetaldehyde. Acetaldehyde is principally metabolized by mitochondria1 acetaldehyde dehydrogenase (ALDH) to acetate, which is largely utilized by peripheral tissues. Ethanol metabolism may be initiated by the ADH present in gastric mucosa. In women, a reduction of gastric A D H may limit initial ethanol metabolism by the stomach and result in increased systemic bioavailability of ethanol. Furthermore, ethanol will be delivered directly to the liver of women, potentially resulting in the formation of greater quantities of acetaldehyde within the liver. Acetaldehyde is a highly reactive molecule, and increased levels in the hepatocyte may enhance adduct formation (see below). These alterations may account for the increased risk of development of alcoholic liver disease in women despite smaller quantities of ethanol consumption. Medications may also reduce gastric ADH activity, including some histamine-2 receptor antagonists (4,s) and aspirin (6). This raises a question for chronic alcohol consumers of the safety of long-term use of medications that may alter ethanol metabolism by the stomach. Hepatocyte alcohol dehydrogenase activity is not altered by alcohol intake (7) but is reduced with increasing severity of liver disease (7,8), as is low K,,, acetaldehyde dehydrogenase activity (8,9). Both of these enzymes are polymorphic in humans, resulting in enzymes with various
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biologic activities. One commonly observed alteration is the deficiency of the class-I1 isoenzyme of aldehyde dehydrogenase (ALDH2) in Orientals, which results in an ‘alcohol flush reaction’ because of increased acetaldehyde levels. These enzyme alterations have been nicely reviewed by others (10). Because of differences in ethanol and acetaldehyde metabolism, it has been postulated that polymorphism of ADH and ALDH may also contribute to the development of alcoholic liver disease. If either enhanced ADH activity and/or reduced ALDH activity could increase the concentration of acetaldehyde within liver cells, greater liver cell injury due to acetaldehyde might be observed. However, studies to date have not identified a greater frequency of either ADH isoenzymes that enhance ethanol metabolism (11) or of ALDH isoenzymes that limit acetaldehyde clearance (12, 13) in patients with alcoholic cirrhosis. Of 47 Japanese patients with alcoholic liver disease, 40 were homozygous for normal ALDH2, and 7 patients (15) were heterozygous for the abnormal ALDH2 (12). In 20 normal controls, 9 heterozygotes (45%) for abnormal ALDH2 were observed. The reduced frequency of ADLH2 in those with ALD suggests the presence of impaired acetaldehyde metabolism may even be protective due to the symptoms associated with acetaldehyde accumulation. The lack of alteration of ALDH2 activity has also been observed in patients with alcoholic cirrhosis in England (13). In this study, however, a trend toward a greater frequency of ALDH3, which enables faster metabolism of ethanol, was observed. ADH activity has been thought to be principally contained in zone-3 hepatocytes of the hepatic acinus (perivenous region). However, a recent study suggests that the location and level of activity of ADH in the liver may vary between men and women (14). Overall, in those subjects less than 50 years of age, women tended to have greater ADH activity (22% more) than men. Above the age of 50, no difference of activity was observed. Furthermore, ADH was distributed differently along the acinus, with greater activity in the perivenous region of women and a more intermediate zonal distribution in men. ALDH activities were similar in both groups. It is unclear whether these differences in ADH activity or distribution could contribute to the increased risk of developing liver disease in women. Perhaps the increased ADH activity of perivenous hepatocytes results in even greater exposure of the hepatic acinar cells to acetaldehyde to produce liver damage. However, whether women really are at greater risk than men for liver damage from ethanol has been questioned. In a study of Danish alcoholics followed up for 5 years, no difference in survival of men or women or of increased susceptibility of women to alcoholic liver disease was observed ( 5 ) . Nutrition In early clinical studies nutrition was assigned a dominant role in the development of alcoholic liver disease. This was
principally due to the observation of advanced liver disease in the severely malnourished ‘skid row’ alcoholic and the presumption that alcoholic cirrhosis was not being observed in the well-fed alcoholic. We now know that nutrition alone is not the dominant factor and that alcoholic hepatitis and cirrhosis can occur in the presence of an adequate caloric intake. New studies of ethanol and dietary feeding in animal models are again addressing nutritional issues in the pathogenesis of alcoholic liver disease. By means of a continuous intragastric feeding tube model, Wistar rats were fed diets containing various amounts of dietary fat or protein plus ethanol. Since the animals were continuously infused, they received a diet throughout the day. In a study of the quantity of dietary fat and developing alcoholic liver injury, animals were infused in a pair-fed fashion with a high-fat (corn oil), low-protein diet with or without ethanol (46% of calories as ethanol or as an isocaloric substitution with dextrose, respectively (16). Animals were infused for up to 6 months. At 1 month, fatty change in the liver was greatest in the group receiving ethanol and a high-fat, low-protein diet. At 6 months, those animals who had the greatest degree of fatty liver at 1 month had the greatest degree of fibrosis, hepatocellular necrosis, and inflammation. In addition, the type of dietary fat may be important. Rats fed beef fat (lard or tallow) plus ethanol did not develop features of alcoholic liver injury (17), possibly as a consequence of the reduction of linoleic acid in beef tallow. In a preliminary report addition of omega-3 fatty acids to this model resulted in a greater degree of alcohol injury than animals receiving ethanol alone (18). However, even the gastric perfusion model of ethanol feeding cannot reproduce the full spectrum of alcoholic liver injury seen in man. This continues to limit the conclusions of these studies. Acetaldehyde-protein adducts Acetaldehyde is a highly reactive metabolite of ethanol which can bind to lysine residues on proteins to form stable and unstable protein-acetaldehyde adducts. Adducts could produce liver injury by either an impairment of a critical hepatocyte function or by an immune response directed against the adduct. Binding of acetaldehyde to proteins often occurs at the critical lysine moiety, interfering with their function as seen with tubulin polymerization (19). This may interfere with protein trafficking, with impairment of secretion of glycoproteins. Glycoproteins are seen to accumulate within the Golgi apparatus of alcohol-fed animals (20). When rats are chronically fed ethanol (21) or rat hepatocytes are maintained in primary culture and exposed to ethanol in vitro (22), a characteristic 37-kilodalton (kD) cytosolic proteinacetaldehyde adduct has been observed. Alteration of acetaldehyde levels also appeared to affect formation of the adduct. Supplementation of the diet of ethanol-fed rats with the alcohol dehydrogenase inhibitor pyrazole prevented the formation of the 37-kD adduct, whereas the potentiation
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Alcoholic Liver DCease
of acetaldehyde concentration by addition of the aldehyde dehydrogenase inhibitor cyanamide enhanced its formation. These studies indicate that protein-acetaldehyde adducts can form during ethanol oxidation and that adducts have the potential to harm specific hepatocyte functions. Circulating protein-acetaldehyde adducts can also be observed in the serum of chronic alcoholics (23). Utilizing an enzyme-linked immunosorbent assay (ELISA) with antibodies directed against either hemocyanin-acetaldehyde adducts or myoglobin-acetaldehyde adducts, high titers of circulating protein-acetaldehyde adducts are seen in most alcoholics. In an additional study of human volunteers, ingestion of 1.3-2.9 g ethanol/kg body weight resulted in formation of hemoglobin-acetaldehyde adducts that persisted for up to 7 days (24). Protein-acetaldehyde adducts have also been observed in the liver of chronic alcoholics (25). Using a rabbit polyclonal antibody that recognized several acetaldehyde adducts, intracellular hepatocyte adducts were identified by immunohistochemical staining of liver biopsy specimens of chronic alcoholics but not nondrinking controls. There did not appear to be a relationship to the severity of histologic injury but, rather, to the prior ethanol consumption. The protein-acetaldehyde adduct data are interesting and seem to account for some of the alterations of hepatocyte function seen with acute and chronic ethanol consumption. However, it appears we should all make adducts on ethanol consumption. If so, how do we escape the hepatic injury they seem capable of causing? Circulating antibodies to protein-acetaldehyde adducts also develop in patients with chronic alcohol consumption (26). In this study, circulating antibodies were seen in 73% of alcoholics but only 39% of control patients and seemed to correlate in patients with the increased severity of underlying alcoholic liver disease. Another study has suggested the presence of these antibodies indicates a greater likelihood for histologic progression of liver disease (27). In patients with both alcoholic and non-alcoholic liver disease, IgM antibodies to protein-acetaldehyde adducts were seen, whereas IgA antibodies were seen only in alcoholic liver disease. This suggests that circulating IgA antibodies to protein-acetaldehyde adducts may be useful as a marker for the underlying etiology of unexplained chronic liver disease (28). Immune mechanisms
At first thought, it seems unlikely that immune mechanisms should have any role in the development of alcoholic liver disease. However, the rapid redevelopment of alcoholic hepatitis with resumption of ethanol consumption despite prior histologic and clinical recovery, the progression of liver injury despite cessation of ethanol intake, associated hypergammaglobulinemia and autoantibody formation, and the apparent chronic hepatitis that occur in selected alcoholics suggests an immunologic role for its pathogenesis.
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Selected immunologic features are highlighted to draw attention to recent studies. Autoantibodies have been described in patients with advanced alcoholic liver disease (29,30). In a recent evaluation of patients with ALD and autoimmune chronic hepatitis (CAH), antinuclear antibodies (ANA) were seen in 22% of ALD and 73% of CAH patients (31). Antibodies to single-stranded and double-stranded DNA were seen in 60% of patients with ALD. When the presence of all three antibodies was determined in patients with ALD and CAH, they were seen in 25.5% and 32%, respectively. In addition, other evidence of enhanced humoral immunity has been observed in patients with advanced alcoholic liver disease including hypergammaglobulinemia (32), circulating immune complexes (33), immune complex glomerulonephritis (34), and hepatic perisinusoidal deposition of IgA (35). These results are suggestive of ongoing immune reactivity in the presence of alcoholic liver disease and seems indicative of a potential role of humoral immune events in its pathogenesis. Alterations of in vivo and in vitro cell-mediated immune events are also frequently observed in patients with alcoholic liver disease, especially those with alcoholic hepatitis (36). Various hepatocyte epitopes have been considered candidate antigens for initiation of this activity, including liver specific proteins (37), alcoholic hyalin (38), ethanol-altered membrane epitopes (39), and protein-acetaldehyde adducts (40). Although reactivity against these antigens has been observed in vitro, their role in vivo is less clear. Does such reactivity have a pathogenic significance or is it just an epiphenomena that occurs in patients with alcoholic liver disease? The lack of an appropriate animal model continues to hamper investigation. Only with such a model can the role of immune reactivity be assessed as the immune status of the animal is perturbed. Recent interest has centered on the potential role of cytokines in the manifestations of alcoholic hepatitis. Tumor necrosis factor alpha (TNFa) is secreted by mononuclear cells and possesses immunoregulatory and inflammatory properties. TNFa may be the mediator of the effects of endotoxemia and account for the acute-phase reactions seen with inflammatory disorders, including leukocytosis, fever, hypoalbuminemia, and anorexia. Its immunoregulatory activities appear to include T- and B-cell activation, natural killer (NK) cell activation, and release of cytokines including interleukin-6 (IL-6) (41). Both serum TNFa (42-46) and IL6 (45-48) levels are increased in patients with alcoholic hepatitis. Similar elevations have not been consistently observed in other stages of alcoholic liver disease. No correlation with circulating endotoxin levels seems to exist in patients with alcoholic hepatitis (44,46), although circulating, TNFa levels may correlate with the presence of coexisting infection (44). Elevated serum TNFa levels do correlate with mortality in patients with alcoholic hepatitis (43,44). TNFa levels may also persist for up to 6 months
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after a diagnosis of alcoholic hepatitis has been established, although IL-6 levels return to normal with clinical recovery (46). IL-6 levels may also be indicative of greater mortality. In a study of 58 alcoholic hepatitis patients, serum IL-6 levels were highest in those who died and in those with significant hepatic decompensation such as hepatic encephalopathy, hyperbilirubinemia, and hypoprothrombinemia (48). Whether cytokines like TNF and IL-6 play a direct role in the mortality of alcoholic hepatitis patients or are simply increased because of the severity of the underlying liver disease is unclear from these observations. They do suggest that cytokines such as TNF and IL-6 at least have pathophysiologic roles in the clinical manifestations of patients with alcoholic hepatitis.
of HCV RNA is also observed and correlates with the advanced nature of alcoholic liver injury (56). In this study sera from 40% of patients with alcoholic hepatitis and 61% of those with alcoholic cirrhosis were HCV RNA-positive. Does this indicate that HCV has a role in the development of alcoholic cirrhosis? Obviously, this will be a very difficult question to answer. However, it may shed additional light on some aspects of alcoholic liver disease. Previous studies have indicated that alcohol intake may lead to a state of chronic hepatitis-like liver injury that is progressive despite cessation of ethanol consumption (58,59). However, studies of HCV coexistence in the chronic alcoholic indicate that these changes may be due to HCV infection, as patients who are anti-HCV-positive tend to have histologic changes more characteristic of chronic viral than alcoholic injury (50). Additional studies will be required to clarify this issue. When Japanese alcoholic patients with chronic hepatitislike histology were evaluated, an HBV and HCV markernegative subgroup was still identified which had improvement of serum aminotransferases with abstinence, suggesting ethanol alone had a direct role in the pathogenesis of a chronic hepatitis-like lesion (54).
Viral hepatitis Although hepatotrophic viruses may not have a direct role in the pathogenesis of alcoholic liver disease, their frequent concurrence and coexisting manifestations of chronic viral hepatitis with alcoholic liver disease warrant its inclusion in this section. Hepatitis B virus (HBV). In Alaskan natives, seropositivity for markers of prior B virus infection was seen in 34% of chronic alcoholics, compared with 12% of controls, THERAPY OF ALCOHOLIC LIVER DISEASE of which 3.1% and 1.7%, respectively, were currently hepatitis B surface antigen (HBsAg)-positive (49). Similarly, in The difficulty of treating the patient with alcoholic hepatitis a Veterans Administration cooperative treatment trial for is recognized when one reviews the different therapies and patients with alcoholic hepatitis, antibodies to HBsAg or the number of trials that have been reported. One of the hepatitis B core antigen (HBcAg) were identified in 29% of difficulties in assessing therapies is the lack of uniformity of patients (50). HBsAg was not observed in this study, as its patients studied, including their principal diagnosis presence was an exclusion criteria, for entry into the study. (alcoholic hepatitis or decompensated cirrhosis) and the In a histologic study 54 chronic alcoholics who were also severity of clinical illness (prognosis) of patients who are hepatitis B virus carriers were evaluated by liver biopsy (51). entered into clinical trials. In this section, recent studies will Half had changes principally due to HBV, 13% had changes be discussed. For an overview of treatment of alcoholic due to alcoholic liver disease, and 8% had both (51). The hepatitis, another recent review is suggested (60). remainder had nonspecific histologic findings. When biopsy specimens were evaluated by electron microscopy, both Nutritional supplementation In a study of 35 severely malnourished patients with HBV and alcoholic hyalin were observed within the same alcoholic cirrhosis, the use of total enteral nutrition (TEN) hepatocyte. Do these studies imply a pathogenic role for HBV in alcoholic liver disease? Although the data are incon- for at least 3 weeks significantly improved survival rates clusive, it seems likely that these findings simply reflect that when compared with an ad lib standard low-sodium hospital alcoholics also engage in behavior that puts them at risk for diet (61). The enteral diet was a specially prepared diet supplying 2115 kcal, with 71 g protein (as whole protein HBV infection. Hepatitis C virus (HCV). The interrelation of hepatitis C supplemented with branched-chain amino acids), 38 g fat, virus with alcoholic liver disease (ALD) is complex. Dep- and 367 g carbohydrate. There were only 2 deaths (1 sponending on the country of origin and the type of underlying taneous bacterial peritonitis (SBD), 1 upper gastrointestinal ALD, up to 48% of patients may have detectabie anti-HCV bleeding) in 16 patients receiving TEN, as compared with 9 (50,52-57). It does not appear to require ‘high-risk’behavior deaths (4 SBP, 3 upper GI bleeding, and 2 liver failure) in by patients with alcoholic liver disease to acquire markers 19 patients on a standard diet. Serum albumin and Child’s for HCV (55). Anti-HCV is more common in alcoholic score were also significantly improved by TEN. No compatients with cirrhosis (53,56,57) but may, in part, be a plications directly due to the diet or its infusion were consequence of false-positive reactions in the presence of observed. Whether or not these results hold up in larger hypergammaglobulinemia (53). However, when HCV ribo- trials, this study at least indicates that TEN is safe and nucleic acid (RNA) is determined in sera by means of potentially of great benefit to the malnourished patient with polymerase chain reaction (PCR), an increased frequency advanced ALD.
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Alcoholic Liver Disease
A trial of parenteral supplementation in patients with alcoholic hepatitis has also been reported (62). Fifty-four patients with clinical variables indicative of alcoholic hepatitis were randomized to receive either 2 I/day of parenteral dextrose (65 g) supplementation with (28 patients) or without (26 patients) 51.6 g amino acids as Freeamine I1 (Kendall McGraw, Irvine, Calif., USA). Although there was no difference in mortality, there was significant improvement in the nitrogen balance and biochemical variables of liver injury (serum bilirubin, aminotransferases, and prothrombin level), which continued even after cessation of infusion in those receiving amino acid supplementation. No deaths as a consequence of intravenous access were reported. These studies indicate the need to supplement the diet of the patient admitted to the hospital with advanced alcoholic liver disease. The simple use of a hospital diet may be inadequate in many because of anorexia, gastric displacement by ascites, and the severity of underlying malnutrition. Patients can still receive an oral diet as tolerated even if receiving enteral or parenteral supplementation. Anabolic steroids plus nutritional supplementation Anabolic steroids have been suggested to improve the outcome of patients with alcoholic hepatitis (63), perhaps by improving protein synthesis and positive nitrogen balance in patients with severe hepatic dysfunction. In a study of 39 patients with alcoholic hepatitis, patients were assigned to 21 days of a standard hospital diet; standard diet plus oxandrolone, 80 mg/day, in divided doses; standard diet plus peripheral venous parenteral supplementation; or standard diet plus oxandrolone plus peripheral venous parenteral supplementation (64,65). Parenteral supplementation included electrolytes, 100 g carbohydrate as dextrose, and 70 g amino acids (Aminosyn 11, Abbott Laboratories, Chicago, Ill., USA). There were significant improvements of serum albumin, transferrin, and prothrombin level in patients receiving parenteral supplementation with or without the addition of oxandrolone when compared with standard hospital diet, again suggesting the importance of adequate dietary intake in the management of patients with alcoholic hepatitis. Insulin-glucagotr infusions Two trials assessed the value of simultaneous infusions of insulin and glucagon in patients with alcoholic hepatitis (66,67). A role for insulin and glucagon has been suggested in hepatic regeneration, and prior studies in small groups of subjects with alcoholic hepatitis have indicated a potential benefit for insulin-glucagon in the management of such patients (68,69). In both of these studies patients with clinical (83 patients) (66) or biopsy (72 patients) (67) evidence of alcoholic hepatitis were randomized to 3 weeks of infusions of either 60 units insulin and 6 mg glucagon/day or to placebo infusion. There was no improvement in shortterm or long-term survival with insulin-glucagon infusion.
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These trials in large numbers of patients would seem to put to rest any consideration of insulin-glucagon infusions in the therapy of patients with alcoholic hepatitis. Corticosteroids There have been many trials of corticosteroids in patients with various degrees of severity of alcoholic hepatitis. Rather than repeat the results of these trials, a review of the metaanalysis of the use of corticosteroid trials will be discussed (70). Eleven randomized trials of hospitalized patients from a total of 30 published studies were included, based on similarity of inclusion and exclusion criteria, prognostic factors at entry into the trials, and ancillary and principal therapies. A total of 562 patients were included, of which 45% were encephalopathic. The effect of corticosteroids on short-term (60 day) mortality was determined. Corticosteroids appear to improve outcome significantly, with a reduction of the relative risk of death to 0.63. This was especially true for trials that excluded GI bleeding as an entry criterion. When only trials with a high quality score that excluded GI bleeding were combined, the relative risk of mortality was further reduced to 0.36. Hepatic encephalopathy was an additional important variable. In those alcoholic hepatitis patients with hepatic encephalopathy, corticosteroids reduced the relative risk of short-term mortality to 0.66 while having no effect on those without encephalopathy. This meta-analysis suggests that corticosteroids should be considered part of the treatment of patients with alcoholic hepatitis who have encephalopathy in the absence of gastrointestinal bleeding. What should be the therapeutic approach to patients with alcoholic hepatitis? It seems clear that all patients who present with alcoholic hepatitis should receive dietary supplementation with enteral or parenteral amino acidcontaining solutions. In those with encephalopathy, corticosteroids seem to be of benefit as well. The use of oxandrolone deserves additional study but should probably be reserved for those patients who can be included in a controlled trial.
LIVER TRANSPLANTATION OF ALCOHOLIC CIRRHOSIS The controversy regarding liver transplantation for the patient with end-stage alcoholic liver disease continues to pose problems for the clinician. Issues include clinical questions such as the short-term and long-term clinical outcome of patients with alcoholic cirrhosis after transplantation, the presence of coexisting diseases also due to alcoholism (for example, cardiomyopathy) which will put the patient at risk from the operation, the potential for recidivism, the need to maintain follow-up, and the ability of the alcoholic to return to a ‘useful’ existence in the workplace. Ethical issues have also been raised, including whether people who have developed an avoidable disease by engaging in self-destructive
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R. K . Zetterman
behavior deserve to be given a valuable resource (donor liver) while potentially depriving another person of this same resource (71-77). Furthermore, a little-spoken concern is the outcome decision for potential donors when they learn their (or their next of kin) liver may go t o an alcoholic. The decision to transplant any patients with alcoholic liver disease is only relatively recent in most centers. As essentially all transplant centers have demanded a prolonged period of ethanol abstinence before consideration of transplantation, patients with acute alcoholic hepatitis have been eliminated from consideration. In published studies to date the short- and long-term outcome of patients with alcoholic cirrhosis who receive a liver transplant is similar t o that of patients transplanted with other forms of liver disease (78-81). In the larger of these reports (79), 73 patients with end-stage alcoholic liver disease received a liver transplant. The mean age of the recipients was 48 years, 73% were male, and most were Child’s class B (32%) or C (64%). At 1 year after liver transplantation, overall survival was 74% and comparable to that of patients undergoing transplantation for other hepatic diseases. Furthermore, only 6 of 52 survivors (11.5%) returned to any form of ethanol consumption, of which 4 were described as social (consumption on holidays and special occasions) and 2 were moderate drinkers (three or fewer drinks per week). Recidivism did correlate with length of preoperative abstinence. In those who had been abstinent for 6 months o r longer, only 7% resumed ethanol consumption, compared 43% of those who had been abstinent for less than 6 months. When ability to return to work was assessed, only 21% were unable to return to work after operation. These data would suggest that the patient with endstage alcoholic liver disease who has stopped drinking for 6 months before transplantation is a good candidate for liver transplantation. The clinical arguments against consideration, such as survival rates, recidivism, failure of follow-up, or a lack of a return to work have been countered by available studies. Any concern about coexisting diseases that should preclude transplantation can be alleviated by careful preoperative evaluation. In fact, some disorders such as glomerulonephritis related to alcoholic cirrhosis may improve after liver transplantation (82). However, current studies d o not address the outcome of transplantation for patients with acute alcoholic hepatitis, as these patients have essentially been excluded from transplantation by the requirement for prolonged ethanol abstinence. Should we transplant these patients? This is a difficult question in view of the potential risks of redrinking and of even higher intraoperative mortality, as has been observed for other operations in alcoholic hepatitis patients in the past. If this step is considered, it must be in the context of a controlled trial with careful preoperative assessment of the patient for both medical and psychologic aspects of their disease.
SUMMARY Alcoholic liver disease remains a difficult problem for the clinician-investigator. Despite extensive research, beyond recognizing that excessive ethanol consumption is potentially harmful, the mechanisms involved in the pathogenesis of alcoholic hepatitis and cirrhosis continue to elude us. The potential role of protein-acetaldehyde adducts is intriguing because of their possibilities for both a direct injurious effect on hepatocyte function and the initiation of immune sensitization. There seems little question that several immunologic alterations occur in the patient with advanced alcoholic liver disease. However, whether these changes are the initiating mechanisms involved in the pathogenesis, simply epiphenomena of an injured liver, o r the resulting mechanisms that cause the sequelae of alcoholic liver disease remains unclear. Similarly, therapy for the patient with alcoholic hepatitis beyond ethanol abstinence is unresolved. Provision of adequate nutrition including amino acid supplementation is important. However, the role of pharmacologic intervention is less clear. Corticosteroids may be of benefit in those patients with alcoholic hepatitis who have hepatic encephalopathy in the absence of upper gastrointestinal bleeding. It seems that many of these issues could be resolved if an adequate animal model was available. We need, therefore, to continue to evaluate new animal models of alcoholic liver disease to allow us to test new ideas with regard to pathogenesis and therapy.
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