Alcohol and the liver

Ira R. Willnera and Adrian Reubenb

Purpose of review Introduction

To highlight salient recent discoveries and results of clinical Fermentation of sugar into alcohol, which occurs in nature
trials in alcoholic liver disease (ALD). The burden of care for through contact with airborne yeast, was undoubtedly
ALD patients is hefty and the prevalence of alcohol abuse stumbled upon by early hominids who ate rotting fruit,
may be increasing in both the developed and the by chance, and reveled in the after-effects. Indulgence
underdeveloped world. in alcohol probably only began in earnest with the dawn
Recent findings of agriculture when fermentable substrates, specifically
Molecular mechanisms of alcoholism are being identified sugars and starches, first appeared in abundance. It has
but not of the predisposition to alcoholic liver injury, except even been suggested that the demand for beer actually in-
perhaps for polymorphism of a cytotoxic T-cell antigen. The duced people to practice agriculture in the first place [1].
Mayo End-stage Liver Disease (MELD) score performs well Not surprisingly, the societal ill consequences of overin-
in assessing the prognosis of ALD; serological biomarkers dulgence were noticed soon after palm date wine was first
for predicting ALD outcome are of uncertain value. brewed in Mesopotamia and the first beer was concocted
Concomitant liver disease (e.g., obesity, hepatitis C, and in Ancient Egypt, as evidenced by the continuing expres-
iron overload) aggravates the severity of ALD; conversely, sion of abstinence by Muslims, Brahmin Hindus, Bud-
alcohol abuse may be a cryptic co-factor in some cases of dhists, and many others who espouse temperance. In
non-alcoholic fatty liver. For alcoholic hepatitis, nutritional contrast, as reviewed recently [2], the deleterious effects
support is the mainstay of treatment; steroids are of alcohol on the liver, namely cirrhosis, steatosis, and al-
considered by some (but not all) as safe and effective coholic hepatitis, were recognized only from the late 18th
therapy, whereas manipulations of tumor necrosis factor-alpha Century onwards, and the dominant role of the liver in the
activity have been disappointing, or of unproven benefit at metabolism of alcohol was only discovered as recently as
best. In liver transplantation for ALD, methods are being the late 1930s. Nonetheless, excess alcohol consumption
devised to monitor recidivism and to ameliorate its risk and remains a leading cause of preventable death in the United
that of co-morbid psychiatric conditions. States [3] and alcoholic cirrhosis is among the commonest
Summary indications for liver transplantation in the United States
Much of the pathogenesis of ALD has been identified and [4•], Europe [5], and elsewhere.
headway has been made in predicting its prognosis.
However, much remains to be done to elucidate the The current review will focus on the most important
molecular genetics of the risk of developing ALD and in articles published about alcohol and the liver over the past
formulating safe, effective therapies for alcoholic hepatitis. two years, concentrating on the pathogenesis of alcoholic
liver disease (ALD) and its treatment.
Keywords
alcoholic liver disease, genetics of alcoholism, hepatitis C,
liver transplantation, tumor necrosis factor Epidemiology and pathogenesis
In a recent detailed review [6], the authors point out that
—330. ª 2005 Lippincott Williams & Wilkins.
Curr Opin Gastroenterol 21:323— the classic studies on the epidemiology of ALD, from the
1950s to the 1980s, must be re-examined with attention to
a
Gastroenterology/Hepatology Training Program Medical Director, Liver the impact in the alcoholic of hepatitis B and C [6]. The
Transplantation Division of Gastroenterology/Hepatology Medical University of
South Carolina Charleston, South Carolina and bLiver Service Medical University of same is likely to be true for obesity, alpha1antitrypsin de-
South Carolina Charleston, South Carolina, USA ficiency, and other co-morbidities, the influence of which
we are only starting to appreciate. The decline in alcoholic
Correspondence to Ira R. Willner, Medical University of South Carolina, 96
Jonathan Lucas Street, Suite 210, PO Box 250327, Charleston, SC 29425, USA cirrhosis-related mortality that occurred in many countries
Tel: 843 792 6901; fax: 843 792 5187; e-mail: [email protected] from the 1970s onwards, has either stabilized or reversed
Current Opinion in Gastroenterology 2005, 21:323—
—330 recently. The extent of the global problem of people
drinking themselves to death was highlighted graphically
ª 2005 Lippincott Williams & Wilkins. by Pearson last year, in a brief report [7] that cited several
0267-1379 useful references. Worrisome increases in alcohol con-
sumption are being reported worldwide, in both devel-
oped and developing countries [8–10]. It has been
generally recognized that fatty liver occurs in up to 90%
of alcoholics [11], of whom 10–35% have alcoholic
323
324 Liver

hepatitis on liver biopsy [11,12]. Though there is agree- basis too [21,22], but this has been difficult to substanti-
ment that the risk of developing cirrhosis increases with ate. Efforts to find candidate genes for a predisposition to
higher levels of alcohol ingestion, the precise dose re- ALD have focused on four main targets: (1) genes that en-
quired is not known. Moreover, in only a relatively small code enzymes of alcohol metabolism, namely ADH and
proportion of individuals, drinking typically in excess of ALDH, respectively, which constitutively catalyze the for-
60–80 g of alcohol per day in men and greater than 20 g mation of acetaldehyde and acetate from relatively low cir-
per day in women, will cirrhosis occur. A recent report culating levels of ethanol, and the microsomal cytochrome
from China highlights the variability among ethnic groups P450 2E1 (CYP2E1) system, which is induced by chronic
of ALD prevalence in relation to alcohol dose [13•]. ingestion of relatively large amounts of alcohol and con-
Among almost 1300 alcohol drinkers, the risk threshold verts ethanol to acetaldehyde [2]; (2) genes that affect
for ALD was only 20 g alcohol daily for 5 years, with a greater endotoxin-derived inflammation in ALD, namely tumor
risk when alcohol was taken on an empty stomach, es- necrosis factor-alpha (TNFa) and other pro-inflammatory
pecially hard liquor. Even though individuals of normal cytokines, such as interleukin-1 (IL-1) and interleukin-6
body weight (BMI <25) drank more than those who were (IL-6); (3) genes that are implicated in hepatic fibrosis,
overweight (BMI >25), the latter group showed increased especially when there are polymorphisms of transforming
ALD morbidity. In a complementary study from Denmark growth factor-beta (TGF-b); and (4) certain genes of the
[14], data gathered prospectively from over 30,000 sub- immune response, specifically cytotoxic T-lymphocyte
jects showed that an intake of more than five drinks daily antigen-4 (CTLA-4). CTLA-4 is a T-cell surface molecule
gave a relative risk of 14–20 for developing cirrhosis, ex- that inhibits the immune response by its interaction, in
cept for wine drinkers in whom the relative risks was sub- competition with the co-stimulatory molecule CD28, with
stantially lower (RR 0.3). Further, the results of a case- ligand B27 on antigen presenting cells.
control study of nutrient intakes and nutritional patterns
among Italian patients with alcohol cirrhosis, suggested Before reporting on a few new observations made over the
that vegetables and fruits in the diet were beneficial, com- past 2–3 years on the genetic susceptibility to ALD, we
pared with animal and non-fruit sugar products [15]. The direct the readers’ attention to the many contemporary
finding that serum gamma-glutamyltransferase levels reviews of various facets of the multifactorial pathogenesis
are higher in African-American drinkers compared with of ALD. Recent reviews have dealt specifically with the
Caucasians, was taken to support the hypothesis that there role of intestinal permeability and endotoxemia [23], the
is greater hepatic vulnerability to alcohol injury among consequences of ethanol metabolism on the redox poten-
African-Americans than for whites [16]. Yet, even when tial in the liver [24], and the associated topics of oxidant
racial and ethnic differences in alcohol use and its ill effects stress [25,26], mitochondrial perturbations [27,28],
appear to be well explored, the data must be interpreted hyperhomocysteinemia [29] and iron overload [30] and
cautiously with due accounting for prevailing social fac- their contributions to oxidant stress [29,31,32], and the
tors. As a chilling reminder of the evils of bigotry in the activation of specific signal transduction pathways [33] in-
apartheid era in South Africa, the profiling of Africans as cluding redox sensitive nuclear factor kappa-B (NF-*B)
heavy drinkers was used by the state to justify its sale and the mitogen-activated protein kinase family mem-
of hard liquor to African men while denying the need bers. The disturbances that occur in cytokine metabolism,
for rehabilitation in the event of alcohol dependence [17•]. notably of TNFa and TNFaÿinducible cytokines and
chemokines, and their role in mitochondrial damage and
Ebrii gignunt ebrios, or ‘One drunkard begets another’, is a the injury and fibrosis of ALD, continue to attract reviewers’
much quoted phrase that Richard Burton, in his own 17th attention [34] as does the deleterious up-regulation of
Century masterpiece The Anatomy of Melancholy [18], at- endothelial adhesion molecules [35], the down-regulation
tributed to Plutarch. This aphorism is often used to show of S-adenosylmethionine production [36], and monocyte-
that this great Greek historian and philosopher was among macrophage activation [37]. The role of the immune
the first to point out that alcoholism is familial. Although system [38–40], including that of activated CD8+ T lym-
it is still debated whether Mestrius Plutarchus in the 2nd phocytes [41] and the aberrant recruitment and retention
Century CE was referring to environmental or hereditary of lymphocytes in the liver [42], have been well chroni-
influences [19], it is well accepted that there is a strong cled recently. Finally, the previously overlooked topic of
genetic component to alcoholism. A recent review [20] apoptosis as a mechanism of cell death in ALD is emerg-
comprehensively covered the evidence in favor of various ing as a subject of interest [43,44] with potential thera-
candidate genes for drinking behavior and alcohol depen- peutic implications. In fact, in two histologic studies of
dence, specifically those that code for alcohol and acetal- both alcoholic and non-alcoholic steatohepatitis (NASH)
dehyde dehydrogenases (ADH and ALDH, respectively), [45,46•], using the TUNEL (terminal deoxynucleotidyl-
dopamine receptors and transporters, serotonin trans- transferase-mediated dUTP nick end labeling) assay that
porters, and neuropeptide Y. Results of earlier studies sug- detects nuclear DNA fragments, apoptosis was found to
gested that susceptibility to ALD might have a genetic be prominent – more so in NASH than alcoholic hepatitis
 Alcohol and the liver Willner and Reuben 325

– in association with the expression of death receptors and atitis cirrhosis [54•], suggesting that the CC genotype
active NF-kB. increases the risk of hepatocellular carcinoma in those
who consume a high alcohol diet.
To date, results relating genetic variations of ethanol-
metabolizing enzymes with the development of ALD have Prognosis and outcome of alcoholic
been inconclusive. In an earlier study from Italy [47], het- liver disease
erozygosity for the c2 allele of CYP2E1 and homozygosity The outcome of ALD depends, among other factors, on
for allele ADH3*2 of ADH3, were thought to be indepen- whether the patient continues to imbibe, whether addi-
dent risk factors for ALD in alcoholics. Conversely, no re- tional causes of liver injury besides alcohol are present
lation to alcoholism or susceptibility to ALD was found in (such as viral hepatitis, obesity, hemochromatosis, etc.),
a large cohort of Spanish men with and without liver dis- the degree of hepatic injury and fibrosis already present,
ease, consisting of 264 alcoholics and 255 non-alcoholic and the response to improved nutrition and treatments
controls, with respect to genetic polymorphisms of that are available for the liver disease and its complica-
ADH2, ADH3, and the c1, c2, d1, and d2 alleles of the tions. Over many decades there have been numerous
CYP2E1 genes [48•]. Further, there was no relation be- attempts to devise ways to assess the prognosis of patients
tween the presence of genotypes of ADH2, ADH3, and with ALD, particularly those with alcoholic hepatitis and
ALDH2 and mortality risk of liver disease among 130 cirrhosis. Various prognostic indices have been formulated
males with alcohol dependence, from Taiwan [49]. In con- based on clinical, laboratory and/or imaging findings, and
trast, in several hundred Japanese the low activity occasionally from histologic data too. Of these, the Child-
ADH2*1 allele of the ADH2 gene was associated with Turcotte-Pugh (CTP) score has best stood the test of time
an increased risk of alcohol dependence, amnesia, alcohol [55]. CTP was the index most used in clinical practice and
withdrawal syndrome, and upper gastrointestinal tract research until it was superseded, to a large extent, by the
cancer, while the inactive ALDH2*2 allele was associated Mayo End-stage Liver Disease (MELD) score, which was
with decreased alcohol dependence and alcoholic poly- adopted in February 2003 by the United Network for
neuropathy; ALD was not assessed [50]. In conflict with Organ Sharing (UNOS) as the chief means of prioritizing
previous conclusions, polymorphisms of TNFa and IL-10 patients who are listed for liver transplantation in the
were not clearly related to the risk of ALD in a study of United States. When the MELD and CTP scores were ap-
147 patients and 355 healthy controls in Spain [51]. plied to a cohort of 1611 patients with chronic liver dis-
The evidence that genetic factors sway immune reactions ease, who had been retrospectively selected from a pool
in ALD is more promising than the role of genetic varia- of 2859 patients seen at the University of Wisconsin-
tion in alcohol metabolism. In a study from Italy and Great Madison [56••] over an 8-year interval, both scores were found
Britain [52] of patients with ALD, heavy drinkers with to be good predictors of 1-year mortality, and of 3- and 6-
steatosis only or without ALD, and healthy controls, Vidali month mortality in a subset of patients with alcoholic hep-
et al. found that chronic antigen stimulation by CYP2E1 atitis. In this large retrospective analysis, encephalopathy
that had been modified endogenously (by hydroxyethyl was a strong and independent predictor of mortality,
free radicals), in the presence of impaired control of T-cell which probably explains the independent predictive abil-
proliferation by CTLA-4 mutation, promoted the develop- ity of the CTP score (of which encephalopathy is a compo-
ment of anti-CYP2E1 autoantibodies that could contribute nent). These results were similar to those reported
to ALD pathogenesis. Valenti et al., in another study from recently from Europe [57]. Active tobacco use was a signif-
Italy [53], found that homozygosity for A49G CTLA-4 icant independent predictor of mortality and the long-
polymorphism was significantly more represented in standing observations concerning the deleterious effect
patients with ALD than in patients with chronic hepatitis of continued alcohol use were reiterated in the Wisconsin
C, non-alcoholic fatty liver disease (NAFLD), heavy study by the significantly higher mortality risk in ALD
drinkers without liver disease and healthy subjects, giving patients who did not achieve sobriety. Efforts continue
an odds ratio of 3.5 for the risk of cirrhosis. The patient to find other variables for prognostication, especially
with alcoholic cirrhosis is at risk for the development of serum markers of fibrosis, such as hyaluronate [58], YKL-
hepatocellular carcinoma. To the list of candidate genes 40 (a glycohydrolase growth factor of connective tissue
that have a weak link with primary liver cancer, must and endothelial cells), and PIIINP [59], the aminoter-
now be added C677T polymorphism of the methylenete- minal propeptide cleavage product of type III procollagen.
trahydrofolate reductase (MTHFR) gene, which has Whereas these markers show reasonable correlation with
already been known to be associated with a predisposition the degree of fibrosis, especially if advanced, their clinical
to colorectal cancer in patients who consume large utility has yet to be established. Meanwhile the search for
amounts of alcohol. In a study from France of 300 liver the ideal prognostic tool in alcoholic hepatitis goes on. A
transplant patients, the relative risk for hepatocellular car- 5-year retrospective analysis from Texas [60] of 89 patients
cinoma in patients with alcoholic cirrhosis was 2.03 for the with alcoholic hepatitis who did not receive steroids,
CC MTHFR genotype but only 0.7 for chronic viral hep- confirmed that a high discriminant function (>32) was
326 Liver

moderately sensitive (67%) and specific (62%) in pre- and cirrhosis, and may accelerate fibrogenesis, is well
dicting 28-day mortality (39%). But since patients with known, but the synergistic mechanism is obscure. The in-
a low discriminant function (<32) had significant short- teraction between alcohol and CHC has been reviewed
term mortality too, approaching 17%, a reevaluation of cur- thoroughly recently in articles that address the prevalence
rent criteria for assessing severity in alcoholic hepatitis is of CHC among alcoholics, what is known about the effect
needed. In fact, the MELD score performs as well or bet- of low-dose alcohol consumption, the possible pathogenic
ter than the discriminant function [61]. The sensitivity mechanism, and the effect of alcohol on the management
and specificity of MELD >11 were 86% and 81%, respec- of CHC [66,67]. Popular concepts to explain the damag-
tively, while the presence of ascites and bilirubin >8 mg/dL ing interaction between alcohol and hepatitis C include
had sensitivity and specificity of 71% and 96%, respec- increased hepatitis C viral replication and mutation, in-
tively. Spahr et al. [62] studied 108 cirrhotic patients with creased hepatocyte apoptosis, alcoholic fatty liver, alcohol-
alcoholic hepatitis and found that an elevated serum sol- induced iron overload, and increased oxidative stress. With
uble TNFa receptor-1 level on admission was an indepen- respect to the latter, in hepatitis C patients who con-
dent predictor of mortality, but the CTP score, the sumed moderate amounts of alcohol compared with those
discriminant function, serum levels of creatinine, TNFa, who drank less, Riggamonti et al. [68] found evidence for
and lipopolysaccharide binding protein and CD14 (medi- increased oxidative stress in the liver and this was associ-
ators of endotoxin action on target cells) were not related ated with more inflammation, necrosis, and fibrosis. In
to survival. Despite these encouraging results, measure- fact, even though heavy alcohol use exerts a greater effect
ment of novel serological biomarkers has yet to be widely on fibrosis than light or moderate use, there does appear to
validated. Similarly, though hepatic venous pressures and be a range of fibrosis for each level of alcohol intake [69•].
invasive hemodynamic measurements have proven value Thus, many of us advocate complete or almost complete
in the elucidation of the pathophysiology of portal hyper- alcohol abstention for hepatitis C patients, who now con-
tension, and perhaps in its pharmacological management stitute a sizable proportion of patients seen in specialist
too, it lacks usefulness in the prognostic assessment of pa- hepatologic practice. Of 1611 liver disease patients re-
tients with severe alcoholic cirrhosis, even in the hands of ferred to a university tertiary care center between 1994
experts [63], and cannot be recommended as a substitute and 2001 [70], two thirds had ALD and/or CHC, of whom
for scoring systems that are currently in practice. 21% had both. Since the addition of CHC to ALD in
patients with cirrhosis did not affect survival in this large
Irrespective of which prognostic method is used to predict retrospective survey, whereas liver decompensation and
the outcome of ALD, most of the studies reported deal continuing alcohol abuse did, the authors concluded that
with relatively short-term follow-up, of days, months, or alcoholism was the driving force for mortality. There is
a year or so, as we have seen. The long-term natural history emerging evidence, however, that there may be differ-
of ALD is harder to come by. This deficiency is now rem- ences in liver disease expression in patients infected with
edied by a 15-year follow-up study of a cohort of 100 different genotypes of hepatitis C. In a study of CHC and
patients with alcoholic cirrhosis, who were admitted to alcohol from northern Italy [71•], the authors found as
a single unit in Norway [64••]. The mortality of patients expected that alcohol was an important co-factor for both
with advanced cirrhosis was extremely high, 71% and 90% steatosis and fibrosis. Yet though greater steatosis correlated
at 5 and 15 years, respectively. Bleeding and hepatic fail- with the stage of fibrosis in CHC patients infected with
ure or a combination of these two conditions with hepato- genotypes 1, 2, and 4, and this relation was driven by
cellular carcinoma (which developed in almost 10% of alcohol consumption, no such relation was seen in patients
patients) accounted for almost 70% of the deaths, and al- with genotype 3a, despite more severe steatosis in the
most 50% died within 1 year (in the pretransplant era). latter group. Host, viral, and environmental factors have
Low ethanol consumption, younger age, and low serum al- intricate interactions.
kaline phosphatase were independent predictors of in-
creased survival. In this context, it is of interest that Compared with the great interest shown in the interplay
even patients with alcoholic steatosis without inflamma- of CHC and ALD, relatively little attention has been given
tion or fibrosis, have a relatively poor prognosis. Compared to the mutual deleterious effects of alcohol and hepa-
with 109 patients with NAFLD of whom only 1 developed titis B. In at least two studies of patients with alcoholic
cirrhosis, 22 of 106 patients with alcoholic steatosis devel- cirrhosis, the addition of hepatitis B was as bad [72] or
oped cirrhosis during a median follow-up period of 16.7 worse [73] than the addition of hepatitis C in compromis-
years, and 20 of the 22 died of liver disease [65]. ing patient survival, whereas in a small retrospective sur-
vey from Taiwan of the mortality of patients with alcohol
Impact of co-morbid liver disease on dependence [49], no difference was seen between HBsAg
alcoholic liver disease positive and negative patients. Given the threefold higher
That heavy alcohol consumption in patients with chronic prevalence of hepatitis B worldwide, compared with hep-
hepatitis C (CHC) increases the risk of advanced fibrosis atitis C, this certainly deserves further analysis. Two other
 Alcohol and the liver Willner and Reuben 327

co-morbid states that impact ALD are iron overload and Other rational therapies for alcoholic hepatitis have either
obesity. Both the pathogenesis of iron overload [30] and proved to be disappointing or remain indeterminate. In
the potential mechanism of its role in fibrogenesis in the first category are propylthiouracil [82] and anabolic-
ALD [31] have been discussed in detail recently, as has androgenic steroids [83]. Also, polyenylphosphatidylcho-
the observation that the quantitative hepatic iron content line that had been shown to prevent alcohol-induced
is predictive of death in alcoholic patients but not those fibrosis and cirrhosis in baboons, failed to affect the
with CHC alone [74]. The synergy between iron and al- progression of liver fibrosis when tested in a randomized
cohol is exemplified by the observation in hereditary he- placebo controlled trial in 789 alcoholics in a Veterans’
mochromatosis of an increased prevalence of alcohol Affairs cooperative study [84]. Complementary and alter-
abuse, which leads to more severe liver damage at lower native medicine agents, such as S-adenosylmethionine,
levels of hepatic iron content [75]. As interest in the met- which does have a biochemical rationale [36], have not
abolic syndrome epidemic grows, so does appreciation of yet proved to be effective.
the synergism between (metabolic) NAFLD and many
causes of liver disease. Body mass index is an independent Given the role that TNFa and other pro-inflammatory
risk factor for ALD [13•,76]. In a very small but important cytokines have in the pathogenesis of alcoholic hepatitis
study [77••], Hiyashi et al. evaluated the drinking habits of and its complications, this is an obvious target for therapy.
NAFLD patients, using a tool that allows the investigator The early promise of pentoxifylline, a nonselective phos-
to assess the total lifetime alcohol intake. Three of 23 ap- phodiesterase inhibitor that inhibits TNFa production,
parently bona fide NAFLD patients had lifetime alcohol has yet to be realized. Treatment with infliximab, an anti-
intakes of greater than 100 g (equivalent to 30 g daily TNF monoclonal antibody, has given mixed results in pre-
for 10 years, and thought by some to be the threshold liminary trials. In an uncontrolled trial of infliximab alone,
for cirrhosis), which was overlooked in prior physician- there appeared to be clinical, biochemical, and histologic
obtained alcohol histories. These results suggest not only improvement without misadventure [85], yet when used
that some NAFLD is ALD but also that physicians need with prednisolone in a double-blind randomized placebo
schooling in taking alcohol histories. controlled trial, no benefit was derived and the trial was
stopped because of a higher frequency of infection in
the infliximab group [86]. Nonetheless, it has been sug-
Treatment of alcoholic liver disease gested that a large randomized trial of infliximab is still
Lifestyle changes form the bedrock of therapy for ALD warranted after adequate discussion and review of all avail-
and these should include not only total abstinence of al- able data [87]. In a study of alcoholic cirrhotic patients
cohol and intense counseling, but also cessation of ciga- with ascites, TNFa expression by activated monocytes
rette smoking and weight reduction for obesity, where could be ameliorated by oral norfloxacin treatment, prob-
appropriate. Correction of malnutrition can restore well- ably by reducing bacterial and endotoxin translocation
being and muscle bulk, abrogate ascites formation, and re- from the gut [88], which may prove to be safe and effec-
verse some other complications of advanced ALD. Correc- tive adjunctive therapy. In contrast, therapy with etaner-
tion of trace nutrient deficiency is mandatory too. Many cept, a p75-soluble TNF receptor:FC fusion protein, in an
therapies have been introduced for the management of al- open-label pilot trial [89], was complicated by adverse
coholic hepatitis, which is the form of ALD with the most events in 23% of the patients. Even though 30-day survival
immediate lethality. Therapy for alcoholic hepatitis still was 92% on an intention-to-treat basis, it remains to be
includes simple oral nutrition that has been shown in a seen whether such therapy will prove feasible in this very
prospective pilot study to improve markers of malnutri- ill patient population.
tion and the CTP score [78•]. Steroid therapy has been
the most studied form of management for alcoholic hep- We close with a consideration of liver transplantation for
atitis for more than 30 years, but it remains controversial. alcoholic liver disease and the thorny pursuit of assessing
Individual data analysis of three recent randomized placebo- sobriety and risk of recidivism. Jauhar et al. [90•] found
controlled double blind trials led to the conclusion that that a family history of alcoholism was an independent risk
corticosteroids do improve short-term survival of alcoholic factor for relapse after liver transplantation whereas dura-
hepatitis patients with a discriminate function of greater tion of abstinence was not, which is in conflict with results
than 32, by approximately 30%, with age and serum creat- from France [91]. Six months sobriety is still the threshold
inine as independent prognostic factors [79]. It has been in most programs [92]. Beresford et al. [93•] developed
suggested that low-grade steatosis (<20%) on liver biopsy a brief interview technique to monitor return to alcohol
and major changes in portal blood flow are independently use following transplantation. This approach was well ac-
associated with poor survival in steroid-treated patients cepted by the patients and therefore may be applicable to
[80], as is the absence of an early fall in serum bilirubin the long-term monitoring of alcohol use among alcohol-
[81] (i.e., to a level at 7 days less than that at the begin- dependent liver graft recipients. It is of interest that
ning of treatment). DiMartini et al. from Pittsburgh [94••] found that a
328 Liver

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