Editorial

Steroids or cocktails for alcoholic hepatitis

Robert O’Shea, Arthur J. McCullough*

The Department of Gastroenterology and Hepatology, The Center of Metabolism and Nutrition, The Lerner College of Medicine at the Cleveland

Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA

0168-8278/$32.00 q 2006 European Association for the

doi:10.1016/j.jhep.2006.01.011

* Corresponding author. Tel.: C1 216 444 8501.

E-mail address: amcculough@metrohealth.org (A.J.

See Article, pages 784–790

Alcoholic hepatitis (AH) is a clinico-pathologic syn-

drome; the therapy of which remains a much discussed and

controversial area of clinical hepatology. Corticosteroids

(CS) have been used in the treatment of this disorder for five

decades and are, thus, the most extensively studied

treatment modality [1].

There have been 13 published trials in the English

literature which used CS for AH. Five of these studies

showed benefit, while the other eight found no benefit [1].

However, the results of one of these trials [2] and a meta-

analysis [3] suggested that steroids should be targeted to the

specific subset of AH patients with severe disease, which

was not done in all of the 13 studies.

The importance of this observation has been substan-

tiated by the fact that the two randomized placebo controlled

double-blind prospective studies [4,5] which included only

patients with severe AH, both showed a significant benefit

of CS in terms of 30 day hospital survival. In addition, a

subsequent study [6] demonstrated that 1 month of CS

improved survival up to 1 year. Based largely on these

treatment trials, published guidelines recommend the use of

CS for severe AH [7].

However, their efficacy remains debated and many

hepatologists are hesitant to use CS in patients with AH.

This hesitancy is due to a number of factors. First, the

personal experience of many clinicians is that patients with

severe AH still die despite the use of CS. This is in fact the

case for a number of reasons. Some patients with severe AH

are too sick to respond to CS. In a large VA cooperative

study [8], when patients were stratified by disease severity

(quantified by Maddrey Discriminant Function—MDF

score), patients with a score of O54 did not respond to

CS while those with %54 did. Another reason for

Study of the Liver. Pub

McCullough).

hesitancy is that approximately five patients with severe

AH need to be treated with CS to save one patient [9].

However, the survival curves from the combined data of the

last three randomized placebo controlled double-blind trials

of CS in severe AH demonstrated clearly that CS

significantly improved 30-day survival in these patients

[9]. The final reason for hesitancy is that histologically

confirmed AH may correlate poorly with the clinical

impression of AH [1,6] and as many as 28% of patients

with a clinical diagnosis of AH do not have histologic

features of AH on liver biopsy. Therefore, many clinicians

choose pentoxifylline, which is the only other treatment

with demonstrated clinical efficacy [10]. Since there are

virtually no significant side effects caused by pentoxifylline,

clinicians are not concerned using this therapy even if their

clinical diagnosis might be wrong.

The second factor often quoted for the justification not to

use CS is the fact that the largest trial was negative [8].

However, as mentioned above, when the patients in the trial

were stratified according to disease severity, CS were

effective in the patients with severe disease. The final factor

is the well-known side effects of CS and the co-morbidities

that occur in these diseases (such as GI bleeding, infection

and pancreatitis), which discourage CS use. Subsequently,

there is clearly a need for a treatment strategy in addition to

CS in severe AH.

In the current issue of the Journal, Phillips et al. [11]

compare a cocktail of eight different anti-oxidants with CS

in AH. The anti-oxidants included in the cocktail are

B-carotene, Vitamin C, Vitamin E, selenium, methionine,

allopurinol, desferrioxamine and n-acetylcysteine. The

rationale for this strategy is well justified [12,13]. However,

perhaps somewhat surprisingly and contrary to the authors’

hypothesis, survival in the anti-oxidant group was less than

in the CS group. Before the implications of this observation

are discussed, it is important to address the study design and

Journal of Hepatology 44 (2006) 633–636

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R. O’Shea, A.J. McCullough / Journal of Hepatology 44 2006 633–636634

outcome measures used in the study performed by Phillips

et al.

Regarding the study design, it is important to consider

disease severity for enrollment in a clinical trial of AH.

The mortality rate of hospitalized patients with AH varies

widely ranging from 0 to 100%. Based on clinical

experience and many clinical trials, it is clear that patients

with mild disease do not need to be treated with

extraordinary measures. It is also likely that patients with

severe disease in extremis may be too ill for any form of

drug treatment to be effective. Consequently, it is important

to identify those patients who might benefit from aggressive

intervention, as well as those patients for whom the

therapeutic benefit risk ratio is favorable. Although other

scoring systems are currently being evaluated [6,14–16], the

MDF (as calculated by Phillips et al.) is the most widely

used method for calculating disease severity and its

prognostic value has been prospectively confirmed in

clinical trials. However, none of these scoring systems

were used as inclusion criteria in the paper under discussion.

Although the patients clearly had severe AH as demon-

strated by a mean MDF of 61 in both the antioxidant and the

CS group, the range of MDF scores were wide; 7–163 and

15–200 in these two groups, respectively. These discrimi-

nant function scores at both extremes suggest that at least a

percentage (not given) of these patients had either mild

disease not needing treatment or disease in extremis and not

likely to respond for reasons stated above. Therefore, it

would have been of interest to see the results displayed

according to the MDF scoring of !32 (mild disease and not

needing treatment), 32–54, and O54. If this were done, the

investigators might have noticed a different therapeutic

response dependant on the discriminant function. More

information also would have been helpful regarding the

histologic comparison between the two groups and how

histologic severity was defined.

Another issue regarding the study design is the fact

that it is unclear what triggered cessation of treatment.

Some patients completed 28 days of treatment as stated

in the Methods section, while other patients had

premature termination of therapy based on a favorable

clinical response; the definition of which was not

provided and would have been helpful. This latter point

is important since the study using pentoxifylline

demonstrated similar improvement in the MDF in both

the treatment and placebo group over the entire course of

the 30-day study despite improved survival in the

treatment group [10].

Regarding outcome measures, survival is certainly the

most important clinical outcome measure as recognized by

Phillips et al. However, although the concentrations of three

of the antioxidants in the cocktail were measured in blood, it

would have been useful to measure the effect anti-oxidant

treatment on some measure of oxidative stress since

antioxidants were the new therapy in the study. This

limitation is not restricted to this current paper under

discussion, but it also pertains to many of the clinical trials

that have been performed in the area of clinical hepatology.

Nonetheless, these investigators are to be commended for

performing a hypothesis driven study evaluating an

important new therapeutic strategy in these patients.

We assume the reason that the current study employed

a cocktail consisting of eight different anti-oxidants is

that previous studies using a single anti-oxidant have

been uniformly disappointing for liver disease [17–19],

as well as for most other disease states [20] and healthy

controls [21]. Therefore, Phillips et al.’s rationale for

taking the cocktail approach is that the sum may be

greater than the parts, and that a combination of these

anti-oxidants may be more effective together than singly.

Each of the eight anti-oxidants used in the cocktail are

well recognized and have been studied for their anti-

oxidative effects. Therefore, we need to ask the question

why did not this approach work. Is it possible that the

sum was less than its parts? Is it possible that perhaps a

significant anti-oxidant effect was not achieved? Unfortu-

nately, these questions cannot be answered by the

present study. Vitamin A has the potential for hepato-

toxicity and Vitamin E and Vitamin C may both become

pro-oxidants [22,23]. While it is unlikely that any one of

the anti-oxidants used in the cocktail were harmful at the

doses employed, it might be possible that the cocktail

produced a pro-oxidant state and a positive effect of any

single agent might have been neutralized by the mix of

the anti-oxidants.

The lack of efficacy of this anti-oxidant cocktail also is

discouraging because there is an enormous body of evidence

implicating oxidative stress in the pathophysiology of AH

[11,12]. However, there are still a number of aspects of

oxidative stress that are poorly understood. Studying pro-

oxidants in vivo is difficult due to their inherent reactivity.

Consequently, they cannot be measured directly, but rather

the products of the reaction of these molecules with

endogenous and exogenous targets are measured. However,

there are relatively clear data supporting the involvement of

two pro-oxidant species in ALD. These species generally

fall under the categories of reactive oxygen species (ROS)

derived from superoxide anion (O2%K) and reactive nitrogen

species (RNS) derived from nitric oxide (NO). These

reactive species are produced in both parenchymal and non-

parenchymal cells within the liver and by different

organelles within these cells. In addition, different anti-

oxidants have different kinetics which are not usually

considered in therapeutic trials [13]. Therefore, the site and

source of ROS and RNS are unclear and there are many

enzymes in vivo capable of inducing these pro-oxidants

[12]. Much of the data regarding the efficacy of anti-

oxidants and alcohol are derived from animal studies in

which the alcohol and anti-oxidant are administered

concomitantly. This is in contrast to the pattern of alcohol

injury in a patient in whom anti-oxidants are employed after

R. O’Shea, A.J. McCullough / Journal of Hepatology 44 2006 633–636 635

many of the downstream events may have already been

impacted.

The best way to gauge anti-oxidants is to monitor

markers of oxidative stress. Remarkably, no trial has

attempted to measure and monitor markers of oxidation

in trials employing anti-oxidants in liver disease. This

flaw is particularly relevant since recent studies such as

that by Meagher et al. [21] revealed no suppression of

systemic indices of anti-oxidant stress despite massive

doses of Vitamin E in normal individuals. F2-isopros-

tanes derived from the free radical oxidation of

arachidonic acid are the most widely studied molecular

markers of oxidative stress [24]. However, there may be

better markers especially as they relate to Vitamin E

treatment. Vitamin E has little effect on oxidants derived

from nitric oxide [25] or on pathways catalyzed by

myeloperoxidase [26]. These latter two sources of

oxidant stress may be particularly important since alcohol

primed Kupffer cells and monocytes, increase phagocyte

and bacteriocidal activities as well as the production of

cytokines from these cells [27,28]. Since the inducible

form of NOS (iNOS) is one of the two major

documented sources of pro-oxidants in these cells and

myeloperoxidase might be another source [29], perox-

isomal proliferator–activator receptor gamma (PPAR-g)

agonists [30] and HMG-COa reductase antagonists [31]

may be better anti-oxidants than those used in current

clinical trials. Therefore, antioxidant studies need a

change of direction. Future studies of oxidant therapy

in alcoholic liver disease need to test the oxidation

hypothesis by monitoring anti-oxidant effects through the

measurement of specific oxidative products. The ideal

marker of oxidative stress in AH remains unclear but

would be one that has been linked to AH, that is

elevated in AH and that is modulated by a hypothesis

driven intervention.

In summary, the use of CS in severe AH has been stirred,

but not shaken, and along with pentoxifylline remain the

only agents that currently have evidence based data for their

use in severe AH.

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