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Alcohol & Alcoholism, Vol. 31, No. 2, pp. 117-134. 1996
INVITED REVIEW
THE TREATMENT OF ALCOHOLIC HEPATITIS
MARSHA Y. MORGAN
Department of Medicine. The Royal Free Hospital. London NW3 2QG. UK
INTRODUCTION
required in individuals who present with severe
alcoholic hepatitis in whom the short-term mortality rate may be as high as 60% (Morgan, 1996).
A number of treatment options have been used
in this patient population, but with varying
degrees of success (Morgan, 1991; Mezey, 1993;
Morgan, 1993; Ramond et a/., 1993) (Table 1).
Alcoholic hepatitis develops in only a minority of
chronic alcohol abusers, even after decades of
abuse (Lelbach, 1966; Leevy, 1968). An unknown
percentage of individuals with this condition
remain asymptomatic and do not come to medical
attention; their liver injury may then heal in
response to abstinence from alcohol, or else may
evolve silently to alcoholic cirrhosis, over time,
particularly with continued drinking (Morgan,
1991). Individuals with alcoholic hepatitis may
come to medical attention when incidentally
found to have abnormal liver function tests or
asymptomatic hepatomegaly. Alternatively, they
may present with complications such as jaundice,
ascites, gastrointestinal bleeding and hepatic
encephalopathy (Morgan, 1991). Symptomatic
individuals show variable morbidity and mortality
both in the short- and long-term (Morgan, 1996).
Progression to cirrhosis is observed more commonly in women, in individuals who present with
severe disease and in those who continue to abuse
alcohol.
For individuals with mild to moderate alcoholic
hepatitis, the main therapeutic manoeuvres are
the removal of alcohol and the provision of
nutritional support. Further measures are
TREATMENT OPTIONS
Corticosteroids
Corticosteroids stimulate the appetite, increase
hepatic albumin production and inhibit the production of Type I and Type IV collagen. In addition, they possess both anti-inflammatory and
immunosuppressive properties. As such, they may
benefit patients with alcoholic hepatitis.
Table 1. Potential treatments for alcoholic hepatitis
Corticosteroids
Hyperalimentation
Anabolic steroids
Insulin/glucagon
Colchicine
Propylthiouracil
D-Penicillamine
Hepatoprotective agents
Hepatic transplantation
117
1996 Medical Council on Alcoholism
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Abstract — Alcoholic hepatitis is a precirrhotic lesion; it develops in only a minority of chronic alcohol
abusers even after decades of abuse The clinical spectrum of disease varies from asymptomatic
hepatomegaly to florid hepatocellular failure with gastrointestinal bleeding and hepatic encephalopathy.
Corresponding variation is observed both in morbidity and mortality. The majority of individuals with
mild to moderate alcoholic hepatitis improve significantly following abstinence from alcohol and the
provision of a diet sufficient to meet their nutritional requirements, their long-term outcome is
determined largely by their ability to maintain abstinence from alcohol. Individuals with severe alcoholic
hepatitis require intensive nutritional support and vigorous management of the complications of their
liver injury; their outcome is generally poor. A small, carefully selected subgroup of these very sick
patients may benefit, at least in the short-term, from treatment with corticosteroids; the place of
orthotopic hepatic transplantation. in this patient group, is still the subject of debate No other treatment
modalities have been shown to confer benefit consistently. A number of new therapeutic approaches
have been proposed and need to be explored
118
M. Y MORGAN
viduals biopsied had established cirrhosis.
Inclusion and exclusion criteria varied between
studies; histological proof of diagnosis was an
inclusion criterion in only three (Helman et al.,
1971; Bories et al., 1987; Ramond et al., 1992);
patients with gastrointestinal bleeding were
excluded in most studies. Treatment regimens
varied both in terms of the drugs used, the dosage
and reducing schedules and the time periods
employed (Table 2). However, the usual treatment regimen was prednisolone 40 mg daily for
4-6 weeks (Table 2). In all 13 studies the endpoint was death, usually in relation to the trial
period or the hospital inpatient stay, although
survival rates at 3 months or beyond were reported
in some series.
In the first study, undertaken by Helman et al.
(1971), 37 patients with alcoholic hepatitis, 27
(76%) of whom had underlying cirrhosis, were
randomized to treatment with either prednisolone,
40 mg daily, reducing over 6 weeks, or to a placebo
preparation. Details were not provided of the
mortality rates at 1 month; however, the 3-month
mortality rate was significantly lower in the steroid-treated patients (5%) than in the control
Table 2. Controlled trials of corticosteroids in patients with alcoholic hepatitis of all grades of severity
Control group
First author
Year
Daily drug dosage
Helman
Porter
1971
1971
Campra
Blitzer
Shumaker
1973
1977
1978
Lesesne
Maddrey
Depew
Theodossi
Mendenhall
Bories
Carithers
1978
1978
1980
1982
1984
1987
1989
Ramond
1992
40 mg prednisolone reducing
40 mg methylprednisolone i.v.
reducing oral
0.5 mg/kgprednisone reducing
40 mg prednisolone reducing
30 mg methylprednisolone i.v.
reducing oral
40 mg prednisolone reducing
40 mg prednisolone reducing
40 mg prednisolone reducing
1 g methylprednisolone i.v.
60 mg prednisolone reducing
40 mg prednisolone
32 mg methylprednisolone
oral/i.v. reducing
40 mg prednisolone
Treatment
period
42
10
35
42
26
4-7
21-24
44
28-32
42
3
30
30
42
28
Patients
n
Deaths*
n (%)
Steroid group
Patients
n
Deaths*
/,(%)
17
9
6(35)
7(78)
20
11
1 (5)t
6(55)
25
16
15
9(36)
2(13)
7(47)
20
12
12
7(35)
2(8)
6(50)
7
31
13
28
88
21
31
7 (100)
4(13)
7(54)
16 (57)
18 (20)
2(10)
11 (35)
7
24
15
27
90
24
35
2 (29)t
1 (4)
8(53)
17 (63)
19(21)*
1 (4)
2(6)t
29
16 (55)
32
4 (13)t
330
112 (34)
329
76 (23)§
*At end of trial period except Helman (3-month mortality rates) and Theodossi (30-day mortality rates).
tTrials in which treatment conferred significant benefit.
+Values extrapolated from trial data and other publications.
§Combined results suggest significant treatment effect.
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Between 1971 and 1992 the results of 13,
randomized, controlled trials of the effects of
corticosteroids, in patients with alcoholic
hepatitis, were published (Helman et al., 1971;
P o r t e r s a/., 1971; Campra elal., 1973; Blitzer et
al., 1977; Shumaker et al., 1978; Lesesne el al.,
1978; Maddrey et al., 1978; Depew et al., 1980;
Theodossi et al., 1982; Mendenhall et al., 1984;
Bories et al. ,1987; Carithers et al. ,1989; Ramond
et al., 1992). In addition, five separate meta-analyses of data from selected studies were undertaken and individually reported (Reynolds et al.,
1989; Imperiale and McCullough, 1990; Daures et
al., 1991; Poynard et al., 1991; Christensen and
Gluud, 1995). Nevertheless, there is still no clear
consensus as to the benefits of this form of treatment.
In the studies conducted to date, the severity of
the liver lesion varied considerably both within
and between study populations; this is reflected
in the short-term mortality rates in the control
patients, which ranged from 10 to 100% (Table
2). Histological confirmation of the diagnosis was
obtained from 30 to 100% of individuals in the
various series; between 50 and 93% of the indi-
TREATMENT OF ALCOHOLIC HEPATITIS
119
Table 3. Effect of treatment with corticosteroids in patients with severe alcoholic hepatitis and spontaneous hepatic
encephalopathy included in randomized, controlled, clinical trials
Control group
Year
Helman
Porter
Campra
Blitzer
Shumaker
Lesesne
Maddrey
Depew
Theodossi
Mendenhall
Carithers
Ramond
1971
1971
1973
1977
1978
1978
1978
1980
1982
1984
1989
1992
*At end of the trial period
tTrials in which treatment
^Values extrapolated from
§Combined results suggest
Patients
n
Deaths*
» (%)
Patients
n
Deaths*
/!(%)
6
8
10
2
6
7
10
13
14
58
19
10
6 (100)
7(88)
8(80)
1 (50)
4(67)
7 (100)
6 (60)
7(54)
10(71)
13 (22)
9(47)
6 (60)
9
7
8
3
6
7
5
15
20
61
14
9
l(ll)t
6(86)
4(50)
2(66)
2(33)
2 (29)t
1 (20)
8(53)
19 (95)
13 (21)*
1 (7)t
3 (33)t
163
84 (52)
164
62 (38)§
except Helman (3-month mortality rates) and Theodossi (30-day mortality rates).
conferred significant benefit.
trial data and other publications.
significant treatment effect.
subjects (35%) (P < 0.01). Maximum benefit was
observed in the most severely ill patients; thus
the mortality rate in patients with spontaneous
hepatic encephalopathy, given steroids, was 11%
compared with a mortality rate of 100% in their
counterparts given the placebo preparation (Table
3).
This study has been criticized for a number
of reasons, but particularly because oral energy
intakes in the patients who received the placebo
preparation were substantially less than in the
steroid-treated individuals. A second trial was,
therefore, undertaken by workers from the same
department, in which they ensured comparable
daily energy intakes in both the control and steroid-treated groups (Lesesne et al., 1978). In this
trial, the mortality rate at the end of the treatment
period was also significantly lower in the steroidtreated patients (29 vs 100%; P < 0.01) (Table 2).
However, although the two patient groups
appeared balanced at randomization, the steroidtreated patients were probably less severely ill
and were certainly significantly younger than the
patients in the control group; both these factors
will have affected outcome.
Between 1971 and 1987 a further nine studies
of the effects of corticosteroids in patients with
alcoholic hepatitis were published, none of which
showed benefit (Tables 2 and 3) (Porter et al.,
1971; Campra et al., 1973; Blitzer et al., 1977;
Shumaker et al., 1978; Maddrey et al., 1978;
Depew et al., 1980; Theodossi et al., 1982;
Mendenhall e/a/., 1984; Bones etal., 1987). Four
of these studies deserve separate mention.
Campra et al. (1973) randomized 45 patients
with alcoholic hepatitis to treatment with either
prednisolone, 0.5 mg/kg daily, reducing over 6
weeks, or to a placebo preparation. At the end of
the treatment period, the mortality rates in the
control group (36%) and in the steroid-treated
group (35%) were comparable (Table 2). However, patients with severe alcoholic hepatitis
complicated by the development of spontaneous
hepatic encephalopathy appeared to benefit
selectively from treatment; thus, in this subpopulation the mortality rates were 80% in the
control and 50% in the steroid-treated patients
(Table 3). This observation prompted workers
from the same department to undertake a second
study including only patients with severe alcoholic
hepatitis complicated by the presence of hepatic
encephalopathy (Depew et al., 1980). However,
treatment did not confer significant benefit; the
within-trial mortality rate was approximately
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First author
Steroid group
120
M. Y. MORGAN
50%, in both control and steroid-treated patients,
with deaths occurring at similar rates and for
similar reasons in both groups.
Maddrey et al. (1978) randomized 55 patients
with alcoholic hepatitis of varying severity to treatment with either prednisolone, 40 mg daily, or a
placebo preparation, for approximately 1 month.
The 30-day mortality rates in the control (13%)
and steroid-treated patients (4%) were comparable (Table 2), as were the hospital inpatient
mortality rates of 19% and 13%. Nevertheless, all
deaths occurred in the most severely ill patients
and discriminant function analysis showed that
treatment had a significant effect on survival.
Further, these authors found that the formula:
4.6 (prothrombin time — control time)(s)
serum bilirubin
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Discriminant function = 4.6 (prothrombin
time)(s) + serum bilirubin (mg/dl)
was useful in predicting survival; all deaths
occurred in patients in whom the discriminant
function exceeded 93 on entry into the study.
The largest study, to date, was undertaken by
Mendenhall et al. (1984), who randomized 178
patients with alcoholic hepatitis to treatment with
either prednisolone, 60 mg daily, reducing over
30 days, or a placebo preparation. The 30-day
mortality rates were comparable in both control
(20%) and steroid-treated (21%) groups (Table
2). Approximately two-thirds of the trial population had hepatic encephalopathy at the time
of enrollment and of these —20% died; again,
however, steroids had no effect on the outcome
in this subpopulation (Table 3).
In the last 6 years, two more carefully designed
and executed studies have been published (Carithers et al., 1989; Ramond et al., 1992), both of
which reported a significant effect of treatment
with corticosteroids on outcome. Carithers et al.
(1989) randomized 66 patients with alcoholic
hepatitis, recruited from four centres, to treatment with either 32 mg of methylprednisolone,
given orally or intravenously for 4 weeks, tapering
over a further 2 weeks, or a placebo preparation.
All patients had severe disease evidenced by the
presence of either spontaneous hepatic encephalopathy or a discriminant function of >32, calculated from the modified formula:
Discriminant function =
The 28-day mortality rate in the steroid-treated
patients (6%) was significantly lower than in the
patients receiving the placebo preparation (35%)
(P < 0.006) (Table 2). In the subgroup of patients
with spontaneous hepatic encephalopathy, the
mortality rate in the steroid-treated patients (7%)
was again significantly lower than in the control
group (47%) (P<0.02) (Table 3). This was a
well-conducted study, but it has been criticized
because the diagnosis of alcoholic hepatitis was
not confirmed histologically, nor were data provided on outcome beyond the study period.
The most recent study, undertaken in two
centres by Ramond et al. (1992), employed the
same inclusion criteria and utilized a similar
treatment regimen to that used by Carithers et al.
(1989). In addition, however, the diagnosis of
alcoholic hepatitis was confirmed histologically in
all patients and the follow-up period was prolonged beyond 6 months. Sixty-one patients were
randomized to treatment with either prednisolone
40 mg daily, or a placebo preparation, for 28 days.
During the study, there were significantly fewer
deaths among the steroid-treated patients (13%)
than among the patients receiving the placebo
preparation (55%) (P < 0.001) (Table 2).
Equally, the mean cumulative survival rates at 2
months and 6 months were significantly higher in
the steroid-treated patients (88% and 84%) than
in the patients who had received the placeo preparation (45% and 45%) (Fig. 1). Subgroup analysis showed that the use of steroids conferred
significant benefit, independently of the presence
of hepatic encephalopathy (Fig. 2).
Between 1989 and 1995, five separate metaanalyses of available studies were undertaken to
determine whether treatment with corticosteroids
affects short-term mortality in patients with
alcoholic hepatitis (Reynolds et al., 1989; Imperiale and McCullough, 1990; Daures et al., 1991;
Poynard et al., 1991; Christensen and Gluud,
1995). The results of these meta-analyses are conflicting. Thus, Imperiale and McCullough (1990)
concluded that, provided patients with gastrointestinal bleeding were excluded, steroids
reduced the short-term mortality in patients with
acute alcoholic hepatitis and hepatic encephalopathy. Poynard et al. (1991) concluded that
steroids significantly reduced mortality in patients
with severe alcoholic hepatitis independently of
the presence of hepatic encephalopathy, whereas
TREATMENT OF ALCOHOLIC HEPATITIS
100 —«i
121
Patient lost to follow-up
84 + 6%
45 + 9%
\
50 •
c
<u
u
Placebo
i_
0.
90
Days
180
Fig. 1. Survival in 61 patients with alcoholic hepatitis randomly assigned to receive either prednisolone 40 mg daily for
28 days or a placebo preparation (Ramond et al., 1992)
100
••_
Corticosteroids without encephalopathy
""
Corticosteroids with encephalopthy
I
Placebo without encephalopthy
Placebo with encephalopthy
0)
Q.
70
35
Days
Fig. 2. Survival in 61 patients with alcoholic hepatitis, randomly assigned to receive either prednisolone 40 mg daily for
25 days or a placebo preparation: relationship to the presence or absence of hepatic encephalopathy (Ramond et al.,
1992)
Christensen and Gluud (1995) concluded that
steroids have no significant effect on mortality in
patients with alcoholic hepatitis whether or not
they have hepatic encephalopathy.
The results of these meta-analyses must be
viewed with caution, bearing in mind the results
of the two best conducted studies to date (Carithers et al., 1989; Raymond et al., 1992). Thus,
overall, it would appear that corticosteroids do not
affect outcome in patients with mild to moderate
alcoholic hepatitis, although they may significantly improve outcome in a small subgroup of
patients with severe disease. These individuals
have a discriminant function in excess of 32 and
are free of gastrointestinal bleeding, bacterial
infection and significant renal failure.
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n
122
M. Y. MORGAN
Nutritional supplementation
Very little information is available on the
nutritional requirements of patients with alcoholic
hepatitis (Morgan, 1991; Miiller et al., 1994;
Nompleggi and Bonkovsky, 1994). In a study by
Weber and Reiser (1982), it was shown that these
patients need protein intakes in the region of 70100 g daily to ensure positive nitrogen balance. It
is also likely that their daily energy requirements
are increased, but this has not been documented,
to date. Dietary intake may be limited by anorexia
and nausea with the result that a high percentage
of total daily energy may be consumed as alcohol
(Morgan, 1981). These patients are, in consequence, frequently malnourished and this has a
detrimental effect on survival (Mendenhall et al.,
1993). There is, therefore, a clear rationale for
the provision of nutritional supplementation in
this population.
A number of controlled studies have been
undertaken, which show that, in general, nutritional supplementation may improve nutritional
status and liver function in patients with alcoholic
hepatitis, but that it does not, in itself, improve
survival (Nasrallah and Galambos. 1980; Calvey
et al., 1985; Diehl et al., 1985; Mendenhall et al.,
1985; Naveau et al., 1986; Achord, 1987; Soberon
et al., 1987; Simon and Galambos, 1988; Bonkovsky et al., 1991a,b; Mezey etal., 1991; Kearns
etal., 1992).
A small number of studies have been undertaken in which nutritional supplements have been
provided for patients with alcoholic hepatitis via
oral or enteral routes (Calvey et al., 1985; Mendenhall et al., 1985; Soberon et al., 1987; Kearns et
al., 1992). Mendenhall et al. (1985), for example,
assessed the effects of oral nutritional support on
outcome in 57 patients with moderate to severe
alcoholic hepatitis. Thirty-four patients were
given a standard hospital diet and were allowed
to eat ad libitum. The remaining 23 patients were
given the same diet together with a dietary supplement high in calories, protein and branchedchain amino acids; both groups were monitored
over 30 days. At the end of the trial period
improvements were observed in six of the nine
variables used to assess nutritional status in the
patients receiving the oral supplement, whereas
these variables were either unchanged or else had
deteriorated in the patients given the hospital diet
alone; mortality rates were similar in the control
(21%) and supplemented (17%) groups. These
two dietary regimens were obviously not comparable as they were neither isocaloric nor isonitrogenous. Thus, it is not possible to draw any
conclusions from this study on the benefits of
nutritional supplementation over provision of a
diet adequate in calories and protein consumed
ad libitum.
Calvey et al. (1985) undertook a more detailed
study in 64 patients with severe alcoholic hepatitis,
all of whom were provided with a basic daily diet
containing 1800-2400 kcal, 40-80 g of protein and
22 mmol of sodium. Twenty-one patients received
an additional 65 g of conventional protein and
2000 non-protein calories daily, while a further 21
patients received 45 g of conventional protein,
25 g of branched-chain amino acids and 2000 nonprotein calories daily. These supplements were
given orally, enterally or, if necessary, intravenously, for ~3 weeks.
No differences were observed in mortality rates
between the control (32%) and supplemented
(38%) groups. Overall, the mortality rate was
significantly higher in the patients who failed to
achieve positive nitrogen balance independently
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Such individuals are, however, encountered
infrequently; in the study by Carithers el al.
(1989), only 66 patients fulfilling these criteria
were recruited from four centres in 5 years, while
in the study by Ramond et al. (1992), only 61 such
patients were recruited from two centres in 3
years. Once identified, these individuals should
be given 40 mg of prednisolone daily for 4 weeks,
followed by 20 mg daily for 1 week and then
10 mg daily for a final week. The complications of
treatment are surprisingly few, but patients should
be carefully monitored.
The treatment regimen may need to be modified
in patients with evidence of past or present infection with hepatitis B or C. Corticosteroids may
reactivate or increase viral replication and this
may have clinical consequences (Wands et al.,
1975; Lok et al., 1991; Magrin et al., 1994);
equally, withdrawal of corticosteroid treatment
may be associated with the development of an
acute hepatitis or even hepatic failure (Rakela et
al., 1983; Thung etal., 1985). If these patients are
to be treated at all, then the prednisolone dosage
should probably be reduced and its withdrawal
prolonged beyond 2 weeks.
TREATMENT OF ALCOHOLIC HEPATITIS
workers were able to show that it is possible to
feed these patients enterally and that enteral feeds
are well-tolerated. Similar conclusions were
drawn by other workers (Soberon et al., 1987).
A total of seven controlled studies of the effects
of parenteral nutritional supplements in patients
with alcoholic hepatitis have been undertaken to
date (Table 4) (Nasrallah and Galambos, 1980;
Diehl et al., 1985; Naveau et al., 1986; Achord,
1987; Simon and Galambos, 1988; Bonkovsky et
al., 1991a,b; Mezey et al., 1991). Overall, the
number of treated patients is small. The majority
of patients appear to have had mild to moderate
alcoholic hepatitis as evidenced by the mortality
rates in the control populations which ranged from
zero to 22%. Histological confirmation of the
diagnosis was obtained from zero to 100% of
patients in the various studies; between zero and
100% of the individuals biopsied had established
cirrhosis. Inclusion and exclusion criteria varied
between studies. All subjects were given a wellbalanced, hospital diet which provided at least
30 kcal/kg and 1 g of protein/kg daily and received
oral supplements of multivitamins, folic acid and
minerals. The experimental groups received, in
addition, a parenteral infusion of standard amino
Table 4. Effect of parenteral nutritional supplementation in patients with alcoholic hepatitis included in randomized,
controlled, clinical trials
Control group
Trial
1 I Idl
First author Year
Patients Deaths Patients;
n
n
n(%)
Deaths
n (%)
18
10
4(22)
0 (0)
17
5
0 (0)t
0 (0)
Standard diet + i.v. 90 g a.a. +
2800 kcal as glucose & lipid
Standard diet + i.v. 43g a.a. +
200 g glucose
Standard diet + i.v. 70 g a.a. +
100 g glucose/50 j; lipid
20
1 (5)
20
1 (5)
14
3(21)
14
1 (7)
18
3(17)
16
4 (25)
Standard diet + i.v. 70 g a a. +
lOOg glucose
Standard diet + i.v. 52 g a a. +
130 g glucose
12
0 (0)
9
0 (0)
26
5(19)
28
6 (21)
duration
(days)
Control regimen
(daily)
Experimental regimen
(daily)
Standard diet + i.v. 70g a.a.*
Standard diet + i v 52g a.a. +
130 g glucose
Nasrallah
Diehl
1980
1985
25
30
Naveau
1986
28
Standard diet
Standard diet +
i.v. 130g
glucose
Standard diet
Achord
1987
21
Standard diet
Simon
1988
28
Bonkovsky
1991
21
Standard diet +
132 g protein
& 3200 kcal
orally
Standard diet
Mezey
1991
30
Standard diet +
i.v. 130g
glucose
Treatment group
'a.a. = amino acids.
tTrial in which the experimental regimen conferred benefit.
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of the dietary regimen used (58 vs 3%)
(P < 0.001). This confirms the observation made
by Fiaccadori et al. (1984) that survival is significantly decreased in patients with chronic liver
disease who are unable to maintain nitrogen equilibrium.
Kearnsera/. (1992) randomized 31 patients with
alcoholic hepatitis to receive, for 28 days, either
a standard hospital diet or the same diet supplemented with a casein-based, enteral feed. During
the trial period, patients in the supplemented
group showed a more rapid clearing of their
encephalopathy, a significant fall in their mean
serum bilirubin concentration and a significant
increase in their mean antipyrine clearance. The
mortality rates in the supplemented (13%) and
non-supplemented (27%) groups were, however,
not significantly different. This study has been
criticized because the energy intake in the nonsupplemented group met only 80% of predicted
requirements, whereas the intake in the supplemented group exceeded predicted requirements by 70%. Likewise the daily protein intakes
in the non-supplemented and supplemented
groups were widely disparate (50 vs 103 g). Thus,
conclusions are difficult to draw. However, these
123
124
M. Y. MORGAN
vein. Standard feeds and parenteral solutions
should suffice. There is no evidence, at present,
that provision of nutrients in excess of requirements confers any additional benefit.
Anabolic steroids
Anabolic steroids might benefit patients with
alcohol-related liver disease because of their
effects on nucleic acid and protein synthesis
(Bengmark and Olsson, 1964). To date, three
randomized, controlled studies have been undertaken on the effects of anabolic steroids in patients
with alcoholic hepatitis (Mendenhall et al., 1984;
Bonkovsky et al., 1991a,b; Mendenhall et al.,
1993).
In the first study, Mendenhall et al. (1984)
randomized 173 men with moderate to severe
alcoholic hepatitis to treatment with either oxandrolone, 80 mg daily, for 30 days, or a placebo
preparation. The 30-day mortality rate was 13%
in the moderately ill patients and 29% in the
severely ill patients; treatment with oxandrolone
did not affect the short-term outcome. In the
individuals with moderately severe alcoholic
hepatitis, who survived the first 30 days, a significant reduction was observed in the 6-month mortality rate in relation to treatment (3.5% vs 20%;
P < 0.02). No such beneficial effect was observed
in individuals with severe alcoholic hepatitis and
overall survival rates at 30 months were similar in
the oxandrolone and placebo-treated groups.
Bonkovsky et al. (1991a,b) randomized 39
patients with moderate to severe alcoholic hepatitis to 21 days' treatment with either oxandrolone
80 mg daily, oxandrolone plus intravenous amino
acid supplementation, intravenous amino acid
supplementation alone, or to so-called 'standard
therapy'. No significant differences in outcome
were observed between the four groups, although
improvement in laboratory variables was most
marked in individuals who received both oxandrolone and nutritional supplementation.
More recently, Mendenhall et al. (1993)
randomized 273 men with moderate to severe
alcoholic hepatitis to treatment with either oxandrolone, 80 mg daily, for 30 days, and then
40 mg daily for 60 days, or to a placebo preparation. The oxandrolone-treated patients received,
in addition, a branched-chain amino acidenriched, oral supplement which provided 60 g of
protein and 1600 kcal daily, for 30 days, and then
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acids with or without glucose and lipid. In two of
the studies the control group received an intravenous infusion of glucose in addition to the standard diet, while in a third study individuals in the
control group received an enteral supplement in
addition to their standard diet. Treatment was
continued for between 21 and 30 days. A wide
range of variables were used to assess both liver
function and nutritional status and these varied
considerably between studies. In all seven studies,
however, the end-point was death.
The results of these studies are extremely difficult to interpret because it is often unclear what
comparisons workers were trying to make. In
several, the comparison made was ostensibly of
the effects on outcome of a nutritionally adequate
diet against a regimen providing excess protein
and calories. However, in the majority of these
studies voluntary food intake was appreciably less
than the amount offered and less than the amount
required to sustain adequate nutritional status. In
consequence, the comparisons made were effectively between regimens which were either
nutritionally adequate or nutritionally inadequate.
Because of the difficulties inherent in interpretation of these data, conclusions cannot be
drawn. However, a number of observations can
be made; first, voluntary food intake is likely
to be poor in patients with moderate to severe
alcoholic hepatitis, with the result that they may
not be able to attain optimal nutrient intake
unaided; second, provision of adequate energy
and protein intakes will result in improvement
in nutritional status and liver function even in
patients who are severely ill, but has little effect
on short-term mortality; third, no appreciable
adverse events are associated with the provision
of high-calorie, high-protein nutritional supplements; these regimens are well-tolerated by
even the most severely ill patients without exacerbation of fluid retention, azotaemia or hepatic
encephalopathy.
Thus, it would seem essential to ensure that all
patients with alcoholic hepatitis are adequately
nourished. They should receive a minimum of
30 kcal/kg and 1 g of protein/kg daily and this
should be given, whenever possible, by the oral
or enteral route; if difficulties are encountered in
meeting requirements, then a proportion should
be given parenterally, preferably via a peripheral
125
TREATMENT OF ALCOHOLIC HEPATITIS
Table 5. Mortality rates in patients with alcoholic hepatitis in relation to their degree of malnutrition, their daily calorie
intake and treatment with oxandrolone (modified from Mendenhall el al.. 1993)
Moderate malnutrition
Oxandrolone
Yes
No
Severe malnutrition
>2500 kcal/day
<2500 kcal/day
>25OO kcal/day
<2500 kcal/day
4%
28%
30%
33%
21%
13%
59%
45%
androlone is a relatively inexpensive drug and its
use in the studies to date has been associated
with few side-effects. It probably deserves further
study.
Insulin and glucagon
A number of factors are known to control hepatic regeneration in animals, of which the best
studied are insulin and glucagon (Baker, 1985). It
seems reasonable to assume that the mechanisms
controlling hepatic regeneration in humans are
similarly regulated; the use of hepatotrophic factors in the treatment of alcoholic hepatitis is based
on this assumption. To date, six randomized, controlled trials of insulin and glucagon in the treatment of alcoholic hepatitis have been undertaken
(Baker et al., 1981; Mirouze et al., 1981; Radvan
et al., 1982; Feher et al., 1987; Bird et al., 1991;
Trinchet et al., 1992) (Table 6).
The results of the first trial, that by Baker et al.
(1981), were encouraging, if inconclusive. Thus,
although mean serum bilirubin concentrations and
prothrombin times improved to a significantly
greater degree in the patients receiving insulin
and glucagon, the 21-day mortality rates in the
control (24%) and treated patients (12%) were
not significantly different (Table 6).
Similarly encouraging but more conclusive
results were reported by Feher et al. (1987). In
their study, the mean serum bilirubin concentration, serum aspartate transaminase and y-glutamyl transpeptidase activities and prothrombin
time improved significantly in the treatment
group, whilst only the mean serum bilirubin concentration showed improvement in the control
group, and then to a lesser degree. In addition,
the 21-day mortality rate in the treated patients
(15%) was significantly less than in the control
subjects (42%) {P < 0.02) (Table 6).
No significant benefits of treatment were, however, reported in the remaining four studies
(Mirouze etal., 1981; Radvan etal., 1982; Bird et
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45 g of protein and 1200 kcal daily for the remaining 60 days.
Overall, the 6-month cumulative mortality rate
was 35% in patients receiving oxandrolone and
nutritional supplementation and 39% in the control subjects. No selective beneficial effect was
observed in relation to disease severity as in the
original study carried out by this group
(Mendenhall et al., 1984). However, a selective
beneficial effect of treatment was observed in
relation to the degree of malnutrition. Thus, in
patients with moderate malnutrition, the 6-month
mortality rate was significantly lower in patients
receiving the active treatment regimen than the
control regimen. No such effect was observed in
the patients with severe malnutrition.
In order to reconcile the results of their two
trials and to try to separate the beneficial effects
of nutritional supplementation from those of
oxandrolone, the above group, combined their
two study populations and re-analysed their data
(Mendenhall et al., 1993). They showed that
patients with alcoholic hepatitis who were moderately malnourished benefitted from treatment
with oxandrolone, provided that their oral intake,
whether supplemented or not, exceeded
2500 kcal/day (Table 5). In these individuals, the
6-month mortality rate was 4% compared to mortality rates of between 28% and 33% in their
counterparts whose dietary intake was inadequate
or who were not receiving the anabolic steroid
(Table 5). In patients with alcoholic hepatitis and
severe malnutrition, oxandrolone had no effect
on outcome but mortality was significantly lower
in those individuals consuming in excess of
2500 kcal/day (19% vs 51%; P< 0.001) (Table
5).
These workers finally concluded that patients
with alcoholic hepatitis need vigorous nutritional
support, and if they are moderately malnourished
they should also be given oxandrolone, although
they did not suggest a treatment regimen. Ox-
126
M. Y. MORGAN
Table 6. Effect of treatment with insulin and glucagon in patients with alcoholic hepatitis included in randomized.
controlled, clinical trials
Control group
First
author
Year
Trial
duration
(weeks)
Baker
Mirouze
Radvan
Feher
Bird
Trinchet
1981
1981
1982
1987
1991
1992
3
2
2
3
3
3
Treatment group
Glucagon
(mg/24h)
Patients
n
Deaths
24
36
48
30
30
30
2.4
4.0
4.8
3.0
3.0
3.0
25
12
15
33
43
35
6(24)
7(58)
7(47)
14 (42)
14 (33)
5(14)
25
14
16
33
43
37
3(12)
6(43)
4(25)
5(15)'
15 (35)
10 (27)
163
53 (33)
168
43 (26)
n (%)
Patients
n
Deaths
n (%)
Insulin
(U/24h)
"Trial in which treatment conferred significant benefit.
Colchicine
Colchicine inhibits granulocyte migration into
areas of inflammation and interferes with the
degradation of polymorphonuclear leucocytes
(Malawista, 1975). It also inhibits microtubule
assembly (Olmstead and Borisy, 1973) and the
transcellular movement of collagen (Ehrlich and
Bornstein, 1972), and increases collagenase
activity (Harris and Krane, 1971). Thus, on theoretical grounds, it might attenuate the inflammatory response associated with alcohol-related
hepatocyte injury, and might diminish collagen
deposition and enhance its dissolution.
Two randomized, controlled studies of colchicine in the treatment of alcoholic hepatitis have
been undertaken, neither of which reported
benefit (Trinchet et al., 19896; Akriviadis et al.,
1990). Thus, Akriviadis et al. (1990) treated 72'
patients with severe alcoholic hepatitis with either
colchicine, 1 mg daily, or a placebo preparation,
for 30 days, and recorded death rates of 17%
in the control and 19% in the colchicine-treated
group. Similarly, Trinchet et al. (1989b) treated
67 patients with histologically-proven alcoholic
hepatitis, 50% of whom had cirrhosis, with either
1 mg of colchicine daily, or a placebo preparation,
for 6 months; liver biopsies were repeated at 3
and 6 months. Overall, no significant differences
were observed in clinical, laboratory or histological variables between the two groups, over
the time-course of the study, although there was
some evidence of preferential histological
improvement in the colchicine-treated patients at
3 months. Almost 60% of patients were lost to
follow-up during this trial, so that conclusions are
difficult to draw.
Thus, there is no evidence, at present, that
patients with alcoholic hepatitis benefit from treatment with colchicine, at least in the short-term.
Propylthiouracil
Both alcohol and hypoxia produce liver injury
which is predominantly centrizonal in distribution. Oxygen consumption rates are increased
in animals with alcohol-induced liver injury and,
if the liver oxygen supply is reduced, centrizonal
necrosis will develop (Israel et al., 1973, 1975a).
These changes can be suppressed by thyroidectomy and abolished by use of propylthiouracil
(Bernstein et al., 1975; Israel et al., 1975b). Ithas,
therefore, been suggested that chronic alcohol
abuse might produce a hypermetabolic state
within the liver, in man, resulting in an increased
demand for oxygen, and ultimately to centrizonal
hypoxia. As such, treatment with propylthiouracil
might attenuate or even abolish these changes.
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al., 1991; Trinchet et al., 1992) (Table 6).
Hypoglycaemia was observed, as a complication, in all of these studies and resulted in the
death of at least one treated patient (Baker et al.,
1981). In addition, a number of difficulties arose
in maintaining intravenous access for prolonged
periods of time. Given the potential complications
and complexity of this form of treatment, and the
limited evidence of its efficacy, its use is not to
be recommended. A better understanding of the
mechanisms controlling hepatic regeneration, in
man, might result in the development of more
useful treatment regimens.
TREATMENT OF ALCOHOLIC HEPATITIS
reductions in the degree of hepatocellular necrosis
and in the active deposition of collagen in liver
biopsies obtained from both groups of patients,
but the improvements appeared greater in the
patients receiving the penicillamine. However,
the number of paired pre- and post-treatment
biopsies was too small for adequate statistical
analysis of these histological changes in relation
to treatment. Further short- and long-term studies
of penicillamine in the treatment of alcoholic
hepatitis are needed.
Hepatoprotective agents
A number of so-called 'hepatoprotective
agents' are available and are used extensively,
particularly in Continental Europe, for the treatment of alcoholic liver disease (Morgan, 1985)
However, the evidence that their use confers any
significant benefit is poor.
(+)-Cyanidanol-3 (Catechin) is the best known
and most extensively investigated hepatoprotective agent (Morgan, 1985). It is a naturally
occurring bioflavonoid which has antioxidant and
membrane-stabilizing properties and an ability to
scavenge free radicals. It has been shown to normalize the NADH/NAD + ratio, to increase ATP
concentrations, and to stabilize lysosomal membranes in the livers of rats with alcohol-related
liver injury. Two short-term, double-blind, randomized, controlled trials of (+)-cyanidanol-3 in
patients with alcoholic hepatitis have been undertaken, to date (Henning, 1981; Sanchez-Tapias et
al., 1981); no significant effects of treatment were
observed after 2 weeks or 3 months of therapy.
Thioctic acid (a-lipoic acid) is a naturally
D-Penicillamine
occurring compound which is a cofactor in the
Penicillamine inhibits the cross-linkage of newly pyruvate dehydrogenase and a--ketoglutarate
formed collagen thus rendering it more sus- dehydrogenase enzyme complexes forming part
ceptible to the actions of collagenase (Nimni and of the citric acid cycle; it also stimulates prostaBavetta, 1965). It might, therefore, reduce or glandin synthesis via its action on prostaglandin
impede hepatic fibrogenesis and prevent pro- cyclooxygenase (Morgan, 1985). Apart from some
gression of alcoholic hepatitis. Resnick et al. evidence to suggest that it may be of value in
(1974) randomized 40 patients with moderately treating liver failure following Amanita phalloides
severe alcoholic hepatitis to treatment with either poisoning, reports of its beneficial effects in liver
D-penicillamine, 1 g daily, or a placebo pre- disease are largely anecdotal. Marshall et al.
paration, for 8 weeks. Similar improvements were (1982) undertook a double-blind, randomized,
observed in mean serum bilirubin concentrations controlled trial of thioctic acid, over 6 months, in
and aspartate aminotransferase activities in both patients with pre-cirrhotic, alcohol-related liver
groups during the trial and the mortality rates of disease, including several with histologically pro19% in the control and 16% in the penicillamine- ven alcoholic hepatitis. No beneficial effects of
treated patients were comparable. There were treatment were observed additional to those
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To date, four randomized, controlled trials of
propylthiouracil in the treatment of alcoholic
hepatitis have been undertaken (Orrego et al.,
1979; Halle et al.. 1981; Serrano-Cancino et al.,
1981; Peirrugues et al., 1989).
In the first study, Orrego et al. (1979) randomized 133 patients with alcohol-related liver
disease, 38 (29%) of whom had alcoholic
hepatitis, to treatment with either 300 mg of propylthiouracil daily, or a placebo preparation, for
6 weeks. The patients with alcoholic hepatitis who
received the active drug were said to show more
rapid improvement in a number of clinical and
laboratory variables than those who received the
placebo preparation. However, few data were
provided to support this assertion.
In the remaining three studies, treatment with
propylthiouracil was reported to be of little benefit
(Halle et al., 1981; Serrano-Cancino et al., 1981;
Peirrugues et al., 1989). Halle et al. (1981), for
example, randomized 67 patients with severe
alcoholic hepatitis to treatment with either 225 mg
of propylthiouracil daily, or a placebo preparation, for 6 weeks, and were unable to show any
beneficial effects of treatment on either morbidity
or mortality. Approximately 20% of patients in
both control and treatment groups died, while
13% of the treated patients became hypothyroid.
Thus, there is no evidence, at present, that
patients with alcoholic hepatitis benefit from treatment with propylthiouracil. It should also be
remembered that propylthiouracil itself can
induce fatal hepatic necrosis (Limaye and
Ruffolo, 1987).
127
128
M. Y. MORGAN
Hepatic transplantation
Orthotopic liver transplantation is associated
with a 5-year survival of approximately 70%; it
therefore provides an excellent therapeutic option
for many patients with end-stage chronic liver
disease (Neuberger, 1989; Starzl etal., 1989; Bird
et al., 1990; Lucey, 1993). The suitability of
patients with alcoholic liver disease as candidates
for liver transplantation has been debated since
the advent of hepatic transplantation programmes
and clear guidelines are still lacking (Bird et al.,
1990; Krom, 1994; Sherman and Williams, 1995).
A number of objections have been raised to the
consideration of such patients as transplant
recipients; first, they may have other alcoholrelated medical problems, such as cardiomyopathy, pancreatitis, neuropathy and malnutrition,
which might impede their management and
worsen their overall prognosis; second, they may
have a variety of emotional, financial and social
problems and may lack the support necessary to
withstand the rigors of the transplant procedure
and the months thereafter; many of these individuals depend on social support which could
result in financial burdens additional to the costs
of the transplant procedure per se; third, they
might resume alcohol misuse/abuse following
transplantation and this might lead to non-compliance with treatment regimens and damage to
the allograph; finally, inclusion of such patients
in transplant programmes might adversely affect
donor recruitment and might result in the deferment of treatment for patients with non-alcoholic
liver disease.
Nevertheless, a number of centres now offer a
transplant service to such patients. Little information is available from these centres on how
many patients with end-stage alcoholic liver
disease have been excluded from their transplant
programmes because of the presence of other
alcohol-related disorders. Patients are rigorously
evaluated before being accepted by transplant
services, and it is to be assumed that other organ
damage is diligently sought, and, if identified and
found to be clinically significant, would be a
contraindication, relative or definite, to candidacy.
Where transplantation has been undertaken in
patients with alcoholic liver disease, outcomes are
good, both in terms of survival and quality of life,
and do not differ substantially from those reported
in patients with non-alcoholic liver disease (Bird
et al., 1990; Kumar et al., 1990; Knechtle et al.,
1992; Lucey et al., 1993) (Fig. 3). Importantly, it
increases 2-year survival in the patients with the
most severely decompensated disease (Poynard et
al., 1994).
It was initially suggested that only individuals
who had successfully abstained from alcohol for 6
months or more should be considered as transplant candidates in order to lessen the risk of
recidivism post-transplantation. Starzl et al.
(1988), however, refuted this suggestion and
showed, in an early series, that 1-year recidivism
rates were low even in individuals drinking up to
the time of transplantation. Campbell etal. (1993)
warned, however, that early recidivism rates
should be treated with caution, because in their
series the early recidivism rate of 11.5% rose to
32% by 3 years post-transplant. In many of the
reported series recidivism rates were consistently
higher in individuals who were drinking up to the
time of transplantation compared with those who
were abstinent beforehand (Bird et al., 1990;
Kumar et al., 1990). Indeed, Osorio et al. (1994)
have shown that the single most important predictor of abstinence post-transplantation is
abstinence before the transplant procedure. However, this view has recently been challenged by
Howard et al. (1994), following their controlled
assessment of 20 individuals who had been transplanted for alcoholic liver disease some 1-6 years
previously. All had remained abstinent from alcohol in the 7-10 months following surgery when
medical supervision was at its closest, but there-
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reflecting abstinence from alcohol.
Silymarin is the active principle of the fruit
Silybium marianum and consists of a complex of
three isomeric compounds of the phenyl-chromanone group (Morgan, 1985). Experimental and
clinical studies suggest that it may have a favourable effect on the course of various hepatic disorders. Trinchet et al. (1989a) undertook a shortterm, double-blind, randomized, controlled trial
of silymarin in patients with biopsy-proven
alcoholic hepatitis. No significant benefits of treatment were observed additional to those reflecting
abstinence from alcohol.
Thus, there is no evidence, at present, that
these so-called 'hepatoprotective agents' benefit
patients with alcoholic hepatitis.
TREATMENT OF ALCOHOLIC HEPATITIS
129
100
80
>
3
U)
<D
O)
TO
60
C
40
a>
a>
a.
20
24
36
48
60
Fig. 3 Actuarial patient survival after liver transplantation for alcoholic ( • ; n = 41) and non-alcoholic ( • ; n = 93) liver
disease in adult recipients (Knechtle ei al.. 1992)
after 80% had returned to drinking. Although the
mean alcohol intake was relatively modest at 25 g
daily, 40% were drinking above 'low-risk' levels,
defined as 112 g/week for women and 168 g/week
for men, 50% were binge-drinking intermittently,
and 15% were drinking heavily and regularly.
There was no relationship between alcohol consumption post-transplantation and the duration of
abstinence before the procedure.
The return to drinking post-transplantation is
obviously not without consequence. Campbell et
al. (1993) showed that 18% of their transplant
recipients were abusing alcohol sufficiently
severely to require admission to hospital. Perhaps
more disturbing is the observation that severe
alcoholic liver injury develops rapidly in the
grafted liver in individuals who return to drinking
(Baddour et al., 1992). Thus, in a group of 23 liver
graft recipients who continued to abuse alcohol
post-transplantation, histological evidence of
alcoholic hepatitis was observed in all 23 within
77-579 days of transplantation, whereas cirrhosis
was observed in four (Baddour et al., 1992). Howard el al. (1994) reported on liver biopsies undertaken a mean of 36 months post-transplantation
in eight patients, two of whom had returned to
regular heavy drinking; cirrhosis was evident in
the biopsies from both of these patients.
The majority of patients with alcoholic liver
disease who are transplanted have end-stage
cirrhosis. There are very few reports of transplantation being undertaken for alcoholic hepatitis per se. Bonet et al. (1993) have recently documented their experience of transplanting cirrhotic
individuals with and without superadded alcoholic
hepatitis. The 1-year survival rates in the patients
with cirrhosis alone (81%) and in those with cirrhosis and alcoholic hepatitis (89%) were comparable. However, the 1-year post-transplant
sobriety rate was 89% in the patients with cirrhosis
alone, but only 51% in the patients with superadded alcoholic hepatitis. No details were given
of the patients' drinking behaviour pre-transplantation, but it is reasonable to assume that the
patients with alcoholic hepatitis were more likely
to have been actively abusing alcohol.
The results of this study have given rise to the
suggestions that the use of transplantation as a
treatment option for patients with alcoholic hepatitis has no place outside the setting of a welldesigned controlled trial (Miller et al., 1994) or
that it should be abandoned altogether (Sorrell et
al., 1994). Therefore, at present, no conclusions
can be drawn about the place of hepatic transplantation as a treatment for acute alcoholic hepatitis.
POTENTIAL NEW THERAPEUTIC
APPROACHES
A number of potential new therapeutic ap-
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12
Months
130
M. Y. MORGAN
the peripheral route.
The outcome in patients with mild to moderate
alcoholic hepatitis is determined, to a large extent,
by their ability to maintain abstinence from
alcohol. They should be carefully monitored over
time.
Patients with severe alcoholic hepatitis are less
easily managed as the majority will already have
cirrhosis. Many present with severe hepatocellular
failure with jaundice, ascites and hepatic
encephalopathy and/or with the complications of
portal hypertension such as hypersplenism and
bleeding oesophageal varices. Deterioration in
their clinical status and laboratory variables is
commonly seen following admission; the development of renal failure usually heralds a fatal
outcome.
These patients should be managed in a specialist
liver unit with the facilities to treat the complications of their liver disease; they should
receive intensive nutritional support. A small subgroup of carefully selected patients may benefit,
at least in the short-term, from treatment with
corticosteroids. No firm recommendation can be
made about the value of other treatment modalities at present. The place of hepatic transplantation for these extremely sick patients is still
the subject of debate.
The mortality rate in this population is high,
exceeding 60% in some series. The outcome in
the survivors is, as in the patients with less severe
disease, determined largely by their ability to
remain abstinent from alcohol. They need careful
long-term monitoring.
A RATIONAL APPROACH TO
TREATMENT
REFERENCES
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alcoholic hepatitis will improve significantly following abstinence from alcohol and the provision
of a diet sufficient to meet their nutritional needs.
In general, therefore, they should ingest a minimum of 30 kcal and 1 g of protein per kg body
weight daily. Dietary intake should be carefully
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is not achieved within 48 h, then nasogastric or
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