Practice Essentials of Alcoholic Hepatitis

Practice Essentials
Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated

with long-term heavy intake of ethanol.
Signs and symptoms
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Patients who are severely affected present with subacute onset of fever,
hepatomegaly, leukocytosis, marked impairment of liver function (eg, jaundice,
coagulopathy), and manifestations of portal hypertension (eg, ascites, hepatic
encephalopathy, variceal hemorrhage). However, milder forms of alcoholic hepatitis
often do not cause any symptoms.
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See Clinical Presentation for more detail.
Diagnosis
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The diagnosis of alcoholic hepatitis is straightforward and requires no further
diagnostic studies in patients presenting with a history of alcohol abuse, typical
symptoms and physical findings, evidence of liver functional impairment, and
compatible liver enzyme levels. In milder cases of alcoholic hepatitis, a mild elevation
of the aspartate aminotransferase (AST) level may be the only diagnostic clue.
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See Workup for more detail.
Management
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In most patients with alcoholic hepatitis, the illness is mild. The short-term prognosis
is good, and no specific treatment is required. Hospitalization is not always
necessary. Alcohol use must be stopped, and care should be taken to ensure good
nutrition; providing supplemental vitamins and minerals, including folate and
thiamine, is reasonable.
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In contrast, patients with severe acute alcoholic hepatitis are at a high risk of early
death, at a rate of 50% or greater within 30 days. Patients with severe alcoholic
hepatitis may benefit over the short term from specific therapies directed toward
reducing liver injury, enhancing hepatic regeneration, and suppressing inflammation.
For the long term, the goals include improvement in liver function, prevention of
progression to cirrhosis, and reduction of mortality. Only prolonged alcohol
abstinence is of demonstrated benefit in all these areas.
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See Treatment and Medication for more detail.
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Background
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Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated
with long-term heavy intake of ethanol. reference_ids_tool_tip reference_ids [1] The pathogenesis is
not completely understood. reference_ids_tool_tip reference_ids [2]
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Patients who are severely affected present with subacute onset of fever,
hepatomegaly, leukocytosis, marked impairment of liver function (eg, jaundice,
coagulopathy), and manifestations of portal hypertension (eg, ascites, hepatic
encephalopathy, variceal hemorrhage). However, milder forms of alcoholic hepatitis
often do not cause any symptoms.
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Upon microscopic examination, shown below, the liver exhibits characteristic
centrilobular ballooning necrosis of hepatocytes, neutrophilic infiltration,
megamitochondria, and Mallory hyaline inclusions. Steatosis (fatty liver) and cirrhosis
frequently accompany alcoholic hepatitis.
VideoWidgets::figure
capt_n_gallery_link_url::incaption: Liver biopsy sample shows typical findings of
perivenular polymorphonuclear infiltrate and ballooning degeneration of hepatocytes
(hematoxylin and eosin [H&E] stain). Courtesy of H. Robert Lippman, MD.
Liver biopsy sample shows typical findings of perivenular polymorphonuclear
infiltrate and ballooning degeneration of hepatocytes (hematoxylin and eosin [H&E]
stain). Courtesy of H. Robert Lippman, MD.
View Media Gallery
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Disease that is sufficiently severe to cause an acute development of encephalopathy
is associated with substantial early mortality, which may be ameliorated by treatment
with glucocorticoids.
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Alcoholic hepatitis usually persists and progresses to cirrhosis if heavy alcohol use
continues. If alcohol use ceases, alcoholic hepatitis resolves slowly over weeks to
months, sometimes without permanent sequelae but often with residual cirrhosis.
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The American Association for the Study of Liver Diseases (AASLD) and the
American College of Gastroenterology issued guidelines in 2010 for the diagnosis,
therapy, and preventive care of alcoholic liver disease (ALD). reference_ids_tool_tip reference_ids [3]
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See also Alcoholic Fatty Liver, Alcohol and Substance Abuse Evaluation, Alcohol
Toxicity, Delirium Tremens,Autoimmune Hepatitis, Hepatitis B, Hepatitis C, and
Hepatitis in Pregnancy.
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Etiology and Pathophysiology
Although the association of alcohol and liver disease has been known since antiquity,
the precise mechanism of alcoholic liver disease remains in dispute. reference_ids_tool_tip
reference_ids [1]
Genetic, environmental, nutritional, metabolic, and immunologic factors, as
well as cytokines and viral disease have been invoked.
Ethanol metabolism
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Most tissues of the body, including the skeletal muscles, contain the necessary
enzymes for the oxidative or nonoxidative metabolism of ethanol. However, the major
site of ethanol metabolism is the liver. Within the liver, 3 enzyme systemsthe
cytosolic alcohol dehydrogenase (ADH) system, microsomal ethanol-oxidizing
system (MEOS), and peroxisomal catalase systemcan oxidize ethanol.
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Cytosolic ADH uses nicotinamide adenine dinucleotide (NAD) as an oxidizing agent.
ADH exists in numerous isoenzyme forms in the human liver and is encoded by 3
separate genes, designated as ADH1, ADH2, and ADH3. Variations in ADH isoforms
may account for significant differences in ethanol elimination rates.
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The microsomal ethanol-oxidizing system (MEOS) uses nicotinamide adenine
dinucleotide phosphate (NADPH) and molecular oxygen. The central enzyme of
MEOS is cytochrome P-450 2E1 (CYP2E1). This enzyme, in addition to catalyzing
ethanol oxidation, is also responsible for the biotransformation of other drugs, such
as acetaminophen, haloalkanes, and nitrosamines. Ethanol upregulates CYP2E1,
and the proportion of alcohol metabolized via this pathway increases with the
severity and duration of alcohol use.
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Peroxisomal catalase uses hydrogen peroxide as an oxidizing agent.
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The product of all 3 reactions is acetaldehyde, which is then further metabolized to
acetate by acetaldehyde dehydrogenase (ALDH). Acetaldehyde is a reactive
metabolite that can produce injury in a variety of ways.
Genetic factors
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Although the evidence to prove a genetic predilection to alcoholism is adequate, the
role of genetic factors in determining susceptibility to alcoholic liver injury is much
less clear. Most people who are alcoholics do not develop severe or progressive liver
injury. Attempts to link persons who are susceptible with specific human leukocyte
antigen (HLA) groups have yielded inconsistent results, as have studies of genetic
polymorphisms of collagen, ADH, ALDH, and CYP2E1.
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Similar conclusions were reached in a meta-analysis of 50 studies pertaining to the
association of alcoholic liver disease and genetic polymorphism. reference_ids_tool_tip
reference_ids [4]
Nonetheless, the fact remains that only a small fraction of even heavy
alcoholics develop severe liver disease (ie, cirrhosis). Thus, future case-control
studies investigating the genetic basis of alcohol-induced liver disease are urgently
needed.
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The genetic factor that most clearly affects susceptibility is male or female sex. For a
given level of ethanol intake, women are more susceptible than men to developing
alcoholic liver disease (see Epidemiology).
Malnutrition
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Most patients with alcoholic hepatitis exhibit evidence of protein-energy malnutrition
(PEM). In the past, nutritional deficiencies were assumed to play a major role in the
development of liver injury. This assumption was supported by several animal
models in which susceptibility to alcohol-induced cirrhosis could be produced by
diets deficient in choline and methionine. This view changed in the early 1970s after
key studies by Lieber and DeCarli performed in baboons demonstrated that alcohol
ingestion could lead to steatohepatitis and cirrhosis in the presence of a nutritionally
complete diet. reference_ids_tool_tip reference_ids [5] However, subsequent studies have suggested
that enteral or parenteral nutritional supplementation in patients with alcoholic
hepatitis may improve survival.
Toxic effects on cell membranes

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Ethanol and its metabolite, acetaldehyde, have been shown to damage liver cell
membranes. Ethanol can alter the fluidity of cell membranes, thereby altering the
activity of membrane-bound enzymes and transport proteins. Ethanol damage to
mitochondrial membranes may be responsible for the giant mitochondria
(megamitochondria) observed in patients with alcoholic hepatitis. Acetaldehyde-
modified proteins and lipids on the cell surface may behave as neoantigens and
trigger immunologic injury.
Hypermetabolic state of the hepatocyte

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Hepatic injury in alcoholic hepatitis is most prominent in the perivenular area (zone
3) of the hepatic lobule. This zone is known to be sensitive to hypoxic damage.
Ethanol induces a hypermetabolic state in the hepatocytes, partially because ethanol
metabolism via MEOS does not result in energy capture via formation of ATP. Rather,
this pathway leads to the loss of energy in the form of heat. In some studies,
antithyroid drugs, such as propylthiouracil (PTU), that reduce the basal metabolic
rate of the liver have shown to be beneficial in the treatment of alcoholic hepatitis.
Generation of free radicals and oxidative injury

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Free radicals, superoxides and hydroperoxides, are generated as byproducts of
ethanol metabolism via the microsomal and peroxisomal pathways. In addition,
acetaldehyde reacts with glutathione and depletes this key element of the
hepatocytic defense against free radicals. Other antioxidant defenses, including
selenium, zinc, and vitamin E, are often reduced in individuals with alcoholism.
Peroxidation of membrane lipids accompanies alcoholic liver injury and may be
involved in cell death and inflammation.
Steatosis
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Oxidation of ethanol requires conversion of nicotinamide adenine dinucleotide (NAD)
to the reduced form NADH. Because NAD is required for the oxidation of fat, its
depletion inhibits fatty acid oxidation, thus causing accumulation of fat within the
hepatocytes (steatosis). Some of the excess NADH may be reoxidized in the
conversion of pyruvate to lactate. Accumulation of fat in hepatocytes may occur
within days of alcohol ingestion; with abstinence from alcohol, the normal redox state
is restored, the lipid is mobilized, and steatosis resolves.
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Although steatosis has generally been considered a benign and reversible condition,
rupture of lipid-laden hepatocytes may lead to focal inflammation, granuloma
formation, and fibrosis, and it may contribute to progressive liver injury. Nonoxidative
metabolism of ethanol may lead to the formation of fatty acid ethyl esters, which may
also be implicated in the pathogenesis of alcohol-induced liver damage. reference_ids_tool_tip
reference_ids [6]
Formation of acetaldehyde adducts

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Acetaldehyde may be the principal mediator of alcoholic liver injury. The deleterious
effects of acetaldehyde include impairment of the mitochondrial beta-oxidation of
fatty acids, formation of oxygen-derived free radicals, and depletion of mitochondrial
glutathione. In addition, acetaldehyde may bind covalently with several hepatic
macromolecules, such as amines and thiols, in cell membranes, enzymes, and
microtubules to form acetaldehyde adducts. This binding may trigger an immune
response through the formation of neoantigens, impair the function of intracellular
transport through precipitation of intermediate filaments and other cytoskeletal
elements, and stimulate hepatic stellate cells to produce collagen.
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The levels of acetaldehyde in the liver represent a balance between its rate of
formation (determined by the alcohol load and activities of the 3 alcohol-
dehydrogenating enzymes) and its rate of degradation by ALDH. ALDH is
downregulated by long-term ethanol abuse, with resultant acetaldehyde
accumulation.
Role of the immune system

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Active alcoholic hepatitis often persists for months after cessation of drinking. In fact,
its severity may worsen during the first few weeks of abstinence. This observation
suggests that an immunologic mechanism may be responsible for perpetuation of the
injury. The levels of serum immunoglobulins, especially the immunoglobulin A (IgA)
class, are increased in persons with alcoholic hepatitis. Antibodies directed against
acetaldehyde-modified cytoskeletal proteins can be demonstrated in some
individuals. Autoantibodies, including antinuclear and antisingle-stranded or anti
double-stranded DNA antibodies, have also been detected in some patients with
alcoholic liver disease.
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B and T lymphocytes are noted in the portal and periportal areas, and natural killer
lymphocytes are noted around hyalin-containing hepatocytes. Patients have
decreased peripheral lymphocyte counts with an associated increase in the ratio of
helper cells to suppressor cells, signifying that lymphocytes are involved in a cell-
mediated inflammatory process. Lymphocyte activation upon exposure to liver
extracts has been demonstrated in patients with alcoholic hepatitis.
Immunosuppressive therapy with glucocorticoids appears to improve survival and
accelerate recovery in patients with severe alcoholic hepatitis.
Cytokines
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Tumor necrosis factor-alpha (TNF-alpha) can induce programmed cellular death
(apoptosis) in liver cells. Several studies have demonstrated extremely high levels of
TNF and several TNF-inducible cytokines, such as interleukin (IL)1, IL-6, and IL-8, in
the sera of patients with alcoholic hepatitis. Inflammatory cytokines (TNF, IL-1, IL-8)
and hepatic acute-phase cytokines (IL-6) have been postulated to play a significant
role in modulating certain metabolic complications in alcoholic hepatitis, and they are
probably instrumental in the liver injury of alcoholic hepatitis and cirrhosis, as shown
in the images below.
capt_n_gallery_link_url::incaption: Ethanol (ETOH) and cytokine production. CYP =

cytochrome P; IL = interleukin; NF-B = nuclear factor-kappa B; ROS = reactive
oxygen species; TNF = tumor necrosis factor.
Ethanol (ETOH) and cytokine production. CYP = cytochrome P; IL = interleukin; NF-
B = nuclear factor-kappa B; ROS = reactive oxygen species; TNF = tumor necrosis
factor.
View Media Gallery
capt_n_gallery_link_url::incaption: Mechanisms of cytokine injury. IL = interleukin;
NO = nitric oxide; O2- = superoxide anion; OH- = hydroxyl radical; PMN =
polymorphonuclear lymphocyte; TNF = tumor necrosis factor.
Mechanisms of cytokine injury. IL = interleukin; NO = nitric oxide; O2- = superoxide
anion; OH- = hydroxyl radical; PMN = polymorphonuclear lymphocyte; TNF = tumor
necrosis factor.
View Media Gallery
Role of concomitant viral disease

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Alcohol consumption may exacerbate injury caused by other pathogenic factors,
including hepatitis viruses. Approximately 20% of patients presenting with alcoholic
hepatitis have concomitant hepatitis C virus infection. reference_ids_tool_tip reference_ids [7]
Extensive epidemiologic studies suggest that the risk of cirrhosis in patients with
chronic hepatitis C infection is greatly exacerbated by heavy alcohol ingestion.
Possible mechanisms include the impairment of immune-mediated viral killing or
enhanced virus gene expression due to the interaction of alcohol and hepatitis C
virus.
Acetaminophen-alcohol interactions
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Long-term alcohol abuse has been established as potentiating acetaminophen
toxicity via induction of CYP2E1 and depletion of glutathione. Alcoholic patients may
develop severe, even fatal, toxic liver injury after ingestion of standard therapeutic
doses of acetaminophen. reference_ids_tool_tip reference_ids [8]
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Epidemiology
Alcohol abuse is the most common cause of serious liver disease in Western
societies. In the United States alone, alcoholic liver disease affects more than 2
million people (ie, approximately 1% of the population). The true prevalence of
alcoholic hepatitis, especially of its milder forms, is unknown, because patients may
be asymptomatic and may never seek medical attention.
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Globally, the prevalence of alcoholic hepatitis appears to differ widely among
different countries. In the Western hemisphere, when liver biopsies were performed
in people who drank moderate to heavy amounts of alcohol and were asymptomatic,
the prevalence of alcoholic hepatitis was found to be approximately 25-30%.
Racial and age differences in incidence

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Although no genetic predilection is noted for any particular race, alcoholism and
alcoholic liver disease are more common in minority groups, particularly among
Native Americans. Likewise, since the 1960s, death rates of alcoholic hepatitis and
cirrhosis have consistently been far greater for the nonwhite population than the
white population. The nonwhite male rate of alcoholic hepatitis is 1.7 times the white
male rate, 1.9 times the nonwhite female rate, and almost 4 times the white female
rate.
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Alcoholic hepatitis can develop at any age. However, its prevalence parallels the
prevalence of ethanol abuse in the population, with a peak incidence in individuals
aged 20-60 years.
Sexual differences in incidence

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Women are more susceptible than men to the adverse effects of alcohol. Women
develop alcoholic hepatitis after a shorter period and smaller amounts of alcohol
abuse than men, and alcoholic hepatitis progresses more rapidly in women than in
men.
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The estimated minimum daily ethanol intake required for the development of cirrhosis
is 40 g for men and 20 g for women older than 15-20 years. Furthermore, for patients
who continue to drink after a diagnosis of alcoholic liver disease, the 5-year survival
rate is approximately 30% for women compared with 70% for men.
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To date, no single factor can account for this increased female susceptibility to
alcoholic liver damage. Lower gastric mucosal alcohol dehydrogenase (ADH) content
in women has been suggested to possibly lead to less first-pass clearance of alcohol
in the stomach. A higher prevalence of autoantibodies has been found in the sera of
alcoholic females compared with alcoholic males, but their clinical significance is
questionable. Perhaps hormonal influences on the metabolism of alcohol or the
higher prevalence of immunologic abnormalities is responsible for the differences
described in the prevalence of alcoholic liver damage between men and women.
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Prognosis
The long-term prognosis of individuals with alcoholic hepatitis depends heavily on
whether patients have established cirrhosis and whether they continue to drink. With
abstinence, patients with this disease exhibit progressive improvement in liver
function over months to years, and the histologic features of active alcoholic hepatitis
resolve. If alcohol abuse continues, alcoholic hepatitis invariably persists and
progresses to cirrhosis over months to years. In one study, the estimated 5-year
survival after hospitalization for severe alcoholic hepatitis was 31.8%. Abstinence
was the only independent predictor of long-term survival. reference_ids_tool_tip reference_ids [9]
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Mild alcoholic hepatitis is a benign disorder with negligible short-term mortality.
However, when alcoholic hepatitis is of sufficient severity to cause hepatic
encephalopathy, jaundice, or coagulopathy, mortality can be substantial.
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The overall 30-day mortality rate in patients hospitalized with alcoholic hepatitis is
approximately 15%; however, in patients with severe liver disease, the rate
approaches or exceeds 50%. In those lacking encephalopathy, jaundice, or
coagulopathy, the 30-day mortality rate is less than 5%. Overall, the 1-year mortality
rate after hospitalization for alcoholic hepatitis is approximately 40%.
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In one study, the overall mortality among patients with severe alcoholic hepatitis was
66%. Age, white blood cell (WBC) count, prothrombin time (PT), and female sex
were all independent risk factors for the dismal outcome. reference_ids_tool_tip reference_ids [10]
Prognostic scoring systems

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During the past several decades, various formulas and algorithms have been
proposed for predicting the outcome of severe alcoholic hepatitis. The single most
reliable indicator of severity is the presence of hepatic encephalopathy.
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The American Association for the Study of Liver Diseases (AASLD) guideline
recommends using prognostic scoring systems such as the Maddrey discriminant
function (MDF) to stratify illness severity and the risk of poor outcome, both initially
and over the course of the illness. reference_ids_tool_tip reference_ids [3]
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The discriminant function (DF) of Maddrey and coworkers is based on PT and
bilirubin levels, and it is calculated as follows: DF = (4.6 PT prolongation) + total
serum bilirubin in mg/dL.
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Values greater than 32 indicate severe disease and predict a 30-day mortality rate of
approximately 50%, assuming only supportive treatment is given. However,
subsequent studies have found the DF to be an inexact predictor of mortality in
patients with alcoholic hepatitis, especially in those who receive glucocorticoids.
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Other formulas have been proposed for the assessment of prognosis of alcoholic
hepatitis, but none has become popular among clinicians. The Combined Clinical
and Laboratory Index of the University of Toronto permits a linear estimate of acute
mortality in persons with alcoholic hepatitis. Its major disadvantages are the large
number (14) of variables that must be scored and the complexity of the calculation
itself.
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In contrast to the Combined Clinical and Laboratory Index, a much simpler formula
for assessing mortality was proposed in a large series of 142 patients with
histologically proven alcoholic hepatitis based on PT, serum bilirubin level, and serum
albumin level. reference_ids_tool_tip reference_ids [11] According to this study, the mortality rate in
patients with a serum bilirubin level greater than 2 mg/dL, a serum albumin level less
than 2.5 g/dL, and a PT greater than 5 seconds was 75%. Conversely, patients who
did not meet all 3 criteria had a much lower mortality rate (approximately 25%).
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Model for end-stage liver disease (MELD) score
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Several retrospective studies have shown that the MELD score is useful in predicting
30- and 90-day mortality in patients with alcoholic hepatitis (see the MELD Score
calculator). Moreover, the MELD score seems to contain some practical and
statistical advantages over Maddrey's DF in predicting mortality among these
patients. In a cohort of 73 patients with alcoholic hepatitis at the Mayo Clinic, the
MELD score was the only independent predictor of mortality. reference_ids_tool_tip reference_ids [12]
Likewise, in another much larger retrospective study of 202 patients with alcoholic
hepatitis, the MELD score was found superior to not only Maddrey's DF but also to
the classical Child-Turcotte-Pugh (CTP) score. reference_ids_tool_tip reference_ids [13]
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Glasgow alcoholic hepatitis score (GAHS)
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The GAHS is one of the most recently described predictors of outcome in patients
with alcoholic hepatitis. This scoring system uses 5 different variables, including age,
bilirubin level, blood urea nitrogen (BUN) level, PT, and WBC count. The overall
accuracy of GAHS, which was validated in 195 patients with alcoholic hepatitis, was
81%, when predicting 28-day outcome. reference_ids_tool_tip reference_ids [14] In contrast, the
modified DF had an overall accuracy of only 50%. reference_ids_tool_tip reference_ids [14]
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Asymmetric dimethylarginine (ADMA) score
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The ADMA score is the most recently proposed predictor of adverse clinical outcome
in patients with severe alcoholic hepatitis. In a small prospective study of 27 patients
with alcoholic hepatitis, the ADMA score was a better predictor of outcome than the
CTP score, the DF, or the MELD score. reference_ids_tool_tip reference_ids [15]
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Other factors that correlate with poor prognosis include older age, impaired renal
function, encephalopathy, and a rise in the WBC count in the first 2 weeks of
hospitalization.
Complications
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Most complications of alcoholic hepatitis are identical to those of cirrhosis.
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Variceal hemorrhage
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Acute variceal bleeding constitutes one of the most devastating emergencies, not
only in gastroenterology but also in medicine at large. Resuscitation of the patient
and protection of the airway are the 2 most important steps in the treatment of acute
variceal bleeding. Cessation of the acute bleeding is usually achieved in more than
90% of patients with the combination of interventional endoscopy (sclerotherapy or
banding ligation) and the intravenous infusion of pharmaceutical agents that lower
the pressure within the portal system (somatostatin or one of its long-acting
analogues [eg, octreotide]). Alternatively and for patients who continue to bleed in
spite of interventional endoscopy and drug therapy, more invasive options, such as
balloon tamponade, a transjugular intrahepatic portosystemic shunt, and an
emergency portal-caval shunt, may be used.
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Hepatic encephalopathy
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The development of encephalopathy in patients with alcoholic hepatitis is invariably
associated with a grave prognosis. Treatment consists of close monitoring of the
patient and the administration of lactulose or nonabsorbable antibiotics. Low energy
or low protein intake is not indicated, except transiently in severe cases. The use of
benzodiazepine receptor antagonists (ie, flumazenil [Romazicon]) is still
experimental. Rarely, rapidly progressive worsening of encephalopathy leading to
deep coma may be associated with cerebral edema, as observed in fulminant
hepatic failure. In selected instances, aggressive treatment with intracranial pressure
monitoring and liver-assist devices may be considered.
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Coagulopathy and thrombocytopenia
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Profound hypoprothrombinemia may ensue during the course of severe alcoholic
hepatitis, especially in patients with variceal bleeding. Administer fresh frozen
plasma (FFP) to temporarily restore the depleted hepatic prothrombin stores. The
value of parenteral administration of vitamin K is dubious, because the hepatocytes
are incapable of synthesizing new prothrombin. Platelet transfusions are not usually
necessary to correct thrombocytopenia, unless the patient is actively bleeding or
undergoes an invasive procedure.
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Ascites
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Acute onset of ascites may develop in patients with alcoholic hepatitis, even in the
absence of overtly decompensated liver disease and portal hypertension. The
ascites is typically transudative, with a very low albumin concentration (< 1 g/dL). In
patients who are hemodynamically stable with normal renal function, bed rest and
salt restriction may be sufficient to mobilize fluid. The addition of diuretics (typically
spironolactone and furosemide) permits clearing of fluid in most patients. In some
individuals who do not respond to these measures, periodic large-volume
paracentesis with intravenous albumin supplementation may be required. With
continued abstinence, the salt-retaining tendency may improve; in many instances,
the diuretics can be withdrawn safely after a period of months without any
reaccumulation of ascites.
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Spontaneous bacterial peritonitis
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Spontaneous bacterial peritonitis may develop in patients with alcoholic hepatitis and
ascites, especially in those with concomitant gastrointestinal bleeding. Following a
confirmatory diagnostic paracentesis, broad-spectrum antibiotic therapy with a
second- or third-generation cephalosporin is the treatment of choice.
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Iron overload
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Several histopathologic studies have shown that as many as 50% of patients with
alcoholic liver disease have increased hepatic iron content compared with healthy
controls. This excess deposition of iron may play a significant role in the progression
of the alcoholic liver damage. Portosystemic shunts, especially the side-to-side
variety, enormously increase the deposition of iron in the liver. Occasionally, this
excessive iron deposition leads to a clinical and pathologic entity that is analogous to
primary hemochromatosis. Attempts to treat alcoholic liver disease with phlebotomy
to reduce iron overload have been hampered by the development of anemia, and no
clear benefit has been observed.
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Patient Education
Given the addictive nature of alcohol in most patients who use it heavily, counseling
complete abstinence is prudent. Refer patients to a program of rehabilitation and
support, and strongly encourage them to attend. Also, fully inform patients regarding
the serious potential health consequences of continued ethanol use.
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For patient education see Infections Center, Digestive Disorders Center, Mental
Health Center, as well as Alcoholism, Hepatitis B, Hepatitis C, and Cirrhosis.
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In August 2012, the Centers for Disease Control and Prevention (CDC) expanded
their existing, risk-based testing guidelines to recommend a 1-time blood test for
hepatitis C virus (HCV) infection in baby boomersthe generation born between
1945 and 1965, who account for approximately three fourths of all chronic HCV
infections in the United Stateswithout prior ascertainment of HCV risk (see
Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among
Persons Born During 19451965). reference_ids_tool_tip reference_ids [16] One-time HCV testing in
this population could identify nearly 808,600 additional people with chronic infection.
All individuals identified with HCV should be screened and/or managed for alcohol
abuse, followed by referral to preventative and/or treatment services, as appropriate.
Approach Considerations
thiamine, is reasonable. Patients who are coagulopathic should receive vitamin K
parenterally. Anticipate symptoms of alcohol withdrawal, and manage them
appropriately.
death, at a rate of 50% or greater within 30 days. In multiple studies, the strongest
factor predictive of short-term mortality was hepatic encephalopathy. In some
studies, a combination of hyperbilirubinemia and coagulopathy has also been found
to independently predict a high short-term mortality rate. Individuals with these
findings or with other complications, such as azotemia or gastrointestinal bleeding,
should be hospitalized. Usually, observing the patient in an intensive care unit (ICU)
until liver function is stable and the patient is clinically improving is prudent.
Patients with severe alcoholic hepatitis may benefit over the short term from specific
therapies directed toward reducing liver injury, enhancing hepatic regeneration, and
suppressing inflammation. Glucocorticosteroids are widely used for this purpose,
although their benefits have not been proven unequivocally. Various other treatments
remain experimental. For the long term, goals include improvement of liver function,
prevention of progression to cirrhosis, and reduction of mortality. Only prolonged
alcohol abstinence is of demonstrated benefit in all these areas.
Among future therapeutic directions, gene therapy is perhaps the most appealing
modality. Various genes involved in hepatic fibrogenesis, inflammatory response, and
oxidative stress are overexpressed in alcoholic hepatitis. Moreover, some candidate
genes correlate well with the histologic findings and disease severity, thus
suggesting that they may be potential targets for such therapy. [21]
Surgical considerations
Patients with acute alcoholic hepatitis are at a high risk of developing hepatic failure
following general anesthesia and major surgery. Because postoperative mortality
rates are high, surgery should be avoided in the setting of acute alcoholic hepatitis
unless it is absolutely necessary. If patients remain abstinent, alcoholic hepatitis
usually resolves over time, permitting surgery to be undertaken with a substantially
reduced risk.
Transfer
Patients with alcoholic hepatitis of mild to moderate severity can be treated in a
primary care setting. In general, for patients with severe alcoholic hepatitis or
cirrhosis, observation by a gastroenterologist or a hepatologist is desirable,
particularly if the illness is of sufficient severity or complexity to require intensive
care.
If patients become comatose or have complications that may require surgical
intervention, the treating physician should consider emergent transfer to a tertiary
care center with experience in the treatment of liver failure. In selected cases, the
use of novel liver-assist devices (artificial livers) may provide transient improvement
in the manifestations of liver failure.
Cessation of Alcohol Intake
Cessation of alcohol use is the mainstay of treatment of alcoholic hepatitis. The 2010
American Association for the Study of Liver Diseases (AASLD) alcoholic liver
disease (ALD) guideline states that complete abstinence should be enjoined on all
alcoholic hepatitis patients. [3]
In general, alcoholic hepatitis resolves or improves greatly following 6-12 months of
alcohol abstinence, and continued improvement may be observed for several years.
Mild alcoholic hepatitis often resolves completely, but, following severe alcoholic
hepatitis, residual cirrhosis can usually be demonstrated. If alcohol abuse persists,
alcoholic hepatitis invariably persists and progresses to cirrhosis, and the prognosis
is dramatically worse.
Some experts have questioned whether complete abstinence is necessary or
whether reduced amounts of alcohol would be sufficient for recovery in most
patients. Given the addictive nature of alcohol in most patients who use it heavily,
counseling complete abstinence is prudent. Patients should be referred to a program
of rehabilitation and support, and they should be strongly encouraged to attend. Also,
patients should be fully informed regarding the serious potential health
consequences of continued ethanol use.
Diet and Nutritional Support
For patients with milder alcoholic hepatitis, a general diet containing 100 g/d of
protein is appropriate. Provide supplemental multivitamins and minerals, including
folate and thiamine. Salt restriction may be required in patients with ascites.
Additional treatment includes nutritional support. The 2010 American Association for
the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline
recommends testing all patients with alcoholic hepatitis for protein-energy
malnutrition (PEM) and for vitamin and mineral deficiencies. [3]
Protein-energy malnutrition is almost universal in patients hospitalized for alcoholic
hepatitis. In a large Veterans Administration Cooperative Study of Alcoholic Hepatitis,
the severity of protein-energy malnutrition correlated with the severity of alcoholic
hepatitis and the predicted mortality rate. [22] In patients with alcoholic hepatitis and
severe protein-energy malnutrition, the mortality rate was 50%, compared with a
mortality rate of less than 10% in patients with mild protein-energy malnutrition. [22]
Oral intake vs parenteral/enteral hyperalimentation
Some studies have suggested that improved energy and protein intake may improve
the survival rate in patients with severe alcoholic hepatitis. However, complications
associated with parenteral hyperalimentation (eg, sepsis, hemothorax) or enteral
hyperalimentation (eg, aspiration pneumonia) may outweigh the benefits of these
approaches. Thus, if patients are able to take food orally, this is the route of choice,
and formal nutritional support can be reserved for those instances in which patients
are unable to ingest enough by mouth to meet their needs. Energy (caloric) intake
should be carefully measured to ensure adequate consumption. The use of
nutritional supplements and appetite stimulants may be appropriate.
The 2010 AASLD ALD guideline states that patients with advanced disease should
receive aggressive enteral nutritional therapy. [3] Patients with mild to moderate
alcoholic hepatitis (Maddrey discriminant function [MDF] score < 32, no liver
encephalopathy) that improves during the first week of hospitalization (ie, lower
serum bilirubin level or decreased MDF) and who are treated with nutritional therapy
and abstinence will probably neither need nor benefit from other interventions, but
these individuals should be monitored closely. [3]
Protein restriction vs normal protein intake
Except in patients with severe encephalopathy, protein restriction is unnecessary
and should be avoided because a protein-deficient diet impairs liver regeneration
and worsens liver function. Even in the presence of hepatic encephalopathy, patients
are usually able to ingest a minimum of 60-100 g/d of dietary protein if other
measures to control encephalopathy have been aggressively pursued. In rare
instances, restricting dietary proteins may be necessary. In these cases, alternatives
include provision of high-quality protein via the parenteral route or provision of oral
amino acid supplements that are selectively enriched with branched-chain amino
acids.
Pharmacotherapy
Use of medications in alcoholic hepatitis has been considered controversial. Many
treatments discussed in the Medication section are still investigational. [23] However,
according to the 2010 American Association for the Study of Liver Diseases (AASLD)
alcoholic liver disease (ALD) guideline [3] : (1) Naltrexone or acamprosate may be
used, in addition to counseling, to assist patients who have achieved abstinence to
avoid relapsing; and (2) in patients with severe disease (Maddrey discriminant
function [MDF] score 32), unless steroids are contraindicated, prednisolone should
be considered. Pentoxifylline may be considered, especially if prednisolone cannot
be used.
Prednisolone and pentoxifylline are recommended for the treatment of severe
alcoholic hepatitis, [1] but uncertainty about their benefit persists.
Results of the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH)
trial involving 1,103 subjects showed that treatment with the steroid prednisolone
reduced 28-day mortality in patients with severe alcoholic hepatitis, whereas
treatment with the oral phosphodiesterase inhibitor pentoxifylline did
not. [24, 25] However, the benefit of prednisolone did not extend beyond 28 days. There
was no difference in the mortality rates between the two treatments at 1 year.
Mortality at 28 days was 13.5% with prednisolone and pentoxifylline combined,
14.3% with prednisolone and placebo, 19.4% with pentoxifylline and placebo, and
16.7% with double placebo. For all patients treated with prednisolone, the mortality
rate was 13.9%; for those treated only with pentoxifylline or placebo, the rate was
18.0%. Mortality rates were similar in patients who received pentoxifylline
treatment (16.4%) and those who did not (15.5%). [24, 25]
Significant predictors of 28-day mortality included prednisone use, prothrombin time
ratio, bilirubin level, age, white blood cell count, urea level, creatinine level, and
hepatic encephalopathy. [24, 25] Neither treatment was significantly associated with a
survival benefit beyond 28 days. Infections were significantly more frequent in the
prednisolone group than in the no-prednisolone group. Patients who did not reduce
or increased their alcohol use had a 3-fold increased risk of death compared with
those who abstained. [24, 25]
Tort claims regarding steroid-induced aseptic necrosis of the hip are very common.
Physicians treating patients with alcoholic hepatitis for longer than the recommended
period should discuss the issue with the patient and the patient's family, and obtain
consent. Patients with mild forms of alcoholic hepatitis should not be treated with
steroids.
Liver Transplantation
Orthotopic liver transplantation is widely used in patients with end-stage liver
disease. [26, 1] Most patients with active alcoholic hepatitis are excluded from
transplantation because of ongoing alcohol abuse. In most liver transplantation
programs in the United States, patients must abstain from alcohol for at least 6
months before they can be considered for transplantation, and a thorough
psychosocial evaluation must demonstrate that patients have a low likelihood of
reverting to alcohol abuse.
Patients with alcoholic hepatitis may be informed that their liver injury can be
expected to subside, and liver function will improve following at least 6 months of
abstinence. If they still develop cirrhosis and its complications, they can be
considered for transplantation if they remain committed to sustained abstinence. The
prospect of liver transplantation can be a powerful motivational tool for encouraging
abstinence.
Challenges to liver transplantation policies
Current policies pertaining to liver transplantation in patients with end-stage alcoholic
liver disease (ie, cirrhosis), especially those with severe alcoholic hepatitis, have
been challenged. [27, 28]
First, the societal aspects of the issue (ie, the public perception and reservation
regarding the use of donated livers for self-inflicted disease) should not be any
different than those of intravenous (IV) drug addicts with the hepatitis C virus or even
the fast-food generation of obese persons with nonalcoholic steatohepatitis (NASH).
Second, the current fixed interval of ethanol abstinence, often at the behest of third-
party payers, as a prerequisite for transplantation remains controversial as a
predictor of future alcoholic relapse (ie, recidivism). [29, 30]
Finally, other investigators have proposed the conduct of pilot studies, on only a
small cohort of patients, to determine whether liver transplantation improves the
survival of patients with severe alcoholic hepatitis. [31]
2010 AASLD ALD recommendation
The recommendation of the 2010 American Association for the Study of Liver
Diseases (AASLD) alcoholic liver disease (ALD) guideline report is that patients with
end-stage alcoholic liver disease be evaluated for liver transplantation in the same
way as other possible candidates, after medical and psychosocial factors have been
carefully evaluated. [3] A formal assessment of the probability of long-term abstinence
should be included in the evaluation. [3]
Consultations
Largely, mild and moderate alcoholic hepatitis can be managed on a hospital
medical floor, requiring only a brief hospital stay. In fact, patients with the mildest
forms of the disease may never seek medical attention, or they can be treated safely
in outpatient settings. By contrast, severe acute alcoholic hepatitis requires intensive
medical care and often a multidisciplinary approach.
Nutrition services and gastroenterology/hepatology
Adequate nutritional support is of paramount importance for the survival and
recovery of patients with alcoholic hepatitis. The complexity of the disease and the
wide variation in nutritional regimens and modalities mandate consultation with a
nutritionist. Customarily, the gastroenterology service of the hospital should be able
to handle this issue and should be instrumental in treatment.
In patients with alcoholic hepatitis who have developed cirrhosis, especially those
with coexistent chronic viral hepatitis B or C, consider periodic surveillance for
hepatocellular carcinoma. A common algorithm includes determination of serum
alpha-fetoprotein (AFP) levels at 6-month intervals along with annual diagnostic
ultrasonography. The finding of a liver nodule or an elevated AFP level should lead to
referral to a liver specialist and additional diagnostic studies.
In general, for patients with severe alcoholic hepatitis or cirrhosis, observation by a
gastroenterologist or a hepatologist is desirable, particularly if the illness is of
sufficient severity or complexity to require intensive care.
Nephrology
The onset of acute renal failure may indicate the development of hepatorenal
syndrome or, alternatively, an episode of acute tubular necrosis resulting either from
the use of nephrotoxic drugs or from acute intravascular volume changes. In these
instances, obtaining consultation with a nephrologist is advisable.
Neurology
If a patient with alcoholic hepatitis exhibits mental status changes, focal neurologic
findings, or seizures, consider consultation with a neurologist.
Infectious disease
The fever and leukocytosis that accompany alcoholic hepatitis often raise concerns
regarding possible sepsis or other infectious processes. Routine evaluation with
urinalysis, chest radiography, and cultures of blood and urine is appropriate, and
findings from these tests are usually negative. If concerns persist, consultation with
an infectious disease specialist is appropriate.
Long-Term Monitoring
In the absence of complications, patients generally can be discharged from acute
medical inpatient care facilities once alcohol withdrawal symptoms have cleared;
liver function has begun to improve; and the complications of liver failure, such as
encephalopathy, have resolved with appropriate treatment.
In patients who have a potential for rehabilitation, transferring them to an inpatient
substance abuse treatment program rather than discharging them from the hospital
may be appropriate.
Patients recently discharged from the hospital following an acute bout of alcoholic
hepatitis should generally be observed within 2 weeks of their discharge.
Subsequent periodic follow-up visits, at intervals ranging from weeks to several
months, are appropriate to monitor patients' responses to treatment, including
obtaining electrolyte levels and liver test results, and to encourage sobriety.
hepatocellular carcinoma. A common algorithm includes determination of the serum
alpha-fetoprotein (AFP) level at 6-month intervals along with annual diagnostic
Immunizing patients with alcoholic liver disease against common infectious
pathogens, including hepatitis A virus, hepatitis B virus, pneumococci, and influenza
A virus, is prudent.
History and Physical Examination

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Heavy alcohol use is a prerequisite for the development of alcoholic hepatitis. The
history is usually apparent; however, in some patients, alcohol use may be covert.
para, childcount:0
Clues to the presence of alcoholism include a history of multiple motor vehicle
accidents, convictions for driving while intoxicated, and poor interpersonal
relationships. Alcoholism exhibits a genetic predisposition, and a history of
alcoholism in a close relative may also indicate that a patient is at risk.
Presentation
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Patients with clinically symptomatic alcoholic hepatitis typically present with
nonspecific symptoms of nausea, malaise, and low-grade fever. The clinical
presentation may be precipitated by complications of impaired liver function or portal
hypertension, such as upper gastrointestinal hemorrhage from esophageal varices,
confusion and lethargy from hepatic encephalopathy, or increased abdominal girth
from ascites.
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A person who uses alcohol heavily may come to medical attention because of an
intercurrent medical illness that produces altered mental status or persistent
vomiting, which, in turn, triggers alcohol withdrawal symptoms. In such instances, the
clinician must be alert to the presence of a precipitating illness (eg, subdural
hematoma, acute pancreatitis, gastrointestinal hemorrhage) and to the likelihood of
alcohol withdrawal symptoms (eg, seizures, delirium tremens) in addition to the
problems associated with alcoholic hepatitis.
2010 AASLD screening and diagnostic recommendations for ALD
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The 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic
liver disease (ALD) practice guideline includes the following recommendations for
screening and diagnosis reference_ids_tool_tip reference_ids [3] :
itemizedlist
listitem
para, childcount:0After discussion of alcohol use with the patient, if abuse or excess
use is suspected, screen the patient for alcohol abuse using a structured
questionnaire such as the Alcohol Use Disorders Identification Test (AUDIT)
listitem
para, childcount:0If the patient's history or a screening test is positive for alcohol
abuse, use laboratory testing to verify the diagnosis of ALD and rule out other
considerations
listitem
para, childcount:0If ALD is present, examine the patient for evidence of other
alcohol-related organ damage
Physical examination
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Patients with alcoholic hepatitis are commonly febrile with tachycardia. Mild
tachypnea with primary respiratory alkalosis may be observed. The liver is usually
enlarged, often with mild hepatic tenderness. Hepatomegaly results from both
steatosis and swelling of the injured hepatocytes.
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Manifestations of hepatic failure or portal hypertension may include scleral icterus
with darkening of the urine, splenomegaly, asterixis (a flapping tremor characteristic
of metabolic encephalopathies), peripheral edema, and bulging flanks with shifting
abdominal dullness (indicating the presence of ascites).
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Spider angiomata, proximal muscle wasting, altered hair distribution, and
gynecomastia may be observed, although these findings most commonly reflect
coexistent cirrhosis.
Diagnostic Considerations
Common considerations in alcoholic patients with jaundice include chronic

pancreatitis with biliary strictures and pancreaticobiliary neoplasms.
A disorder histologically resembling alcoholic hepatitis can occur in patients who do

not use alcohol. This syndrome, termed nonalcoholic steatohepatitis (NASH), is
being recognized with increasing frequency. It occurs most frequently in the setting
of obesity, hyperlipidemia, or type 2 diabetes mellitus. NASH is also observed in the
setting of chronic parenteral hyperalimentation and in individuals who undergo
jejunoileal bypass surgery for treatment of obesity. In most cases, NASH is indolent;
however, in some individuals, it may progress insidiously to cirrhosis. NASH is
currently believed to be responsible for a large fraction of cases of what was
previously termed cryptogenic cirrhosis. In most patients with NASH, the ratio of
aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is less than 1,
unless cirrhosis is present.
Changes in the mental status of patients with alcoholic hepatitis do not always imply
the presence of hepatic encephalopathy. Other conditions (eg, subdural hematomas)
should be excluded by obtaining a computed tomography (CT) scan of the brain.
Differential Diagnoses
Chronic Pancreatitis
Hepatitis B
Hepatitis C
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The diagnosis of alcoholic hepatitis is straightforward
and requires no further diagnostic studies in patients
presenting with a history of alcohol abuse, typical
symptoms and physical findings, evidence of liver
functional impairment, and compatible liver enzyme
levels. In milder cases of alcoholic hepatitis, a mild
elevation of the aspartate aminotransferase (AST) level
may be the only diagnostic clue.
para, childcount:1
Studies have indicated that serum C-reactive protein
(CRP) is an accurate marker of alcoholic hepatitis (ie,
sensitivity, 41%; specificity, 99%; positive predictive
value [PPV], 98%; negative predictive value [NPV],
88%). reference_ids_tool_tip reference_ids [17]
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An electrolyte panel may demonstrate electrolyte
disorders from the effects of vomiting, portal
hypertension with decreased circulating volume,
alcoholic ketoacidosis, or respiratory alkalosis. In
addition, hypophosphatemia and hypomagnesemia are
common consequences of coexistent malnutrition.
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In August 2012, the Centers for Disease Control and
Prevention (CDC) expanded their existing, risk-based
testing guidelines to recommend a 1-time blood test for
hepatitis C virus (HCV) infection in baby boomersthe
generation born between 1945 and 1965, who account
for approximately three fourths of all chronic HCV
infections in the United Stateswithout prior
ascertainment of HCV risk (see Recommendations for
the Identification of Chronic Hepatitis C Virus Infection
Among Persons Born During 19451965). reference_ids_tool_tip
reference_ids [16]
One-time HCV testing in this population could
identify nearly 808,600 additional people with chronic
infection. All individuals identified with HCV should be
screened and/or managed for alcohol abuse, followed by
referral to preventative and/or treatment services, as
appropriate.
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Imaging studies are rarely required for the diagnosis of
alcoholic hepatitis, but they can be useful in excluding
other causes of liver disease. Ultrasonography is
generally the preferred modality due to its low cost,
noninvasiveness, and wide availability. Similar and
complementary information can be obtained by
computed tomography (CT) scanning or magnetic
resonance imaging (MRI) of the abdomen; however,
these 2 imaging studies are more expensive than
ultrasonography and are usually required only in atypical
cases. CT scanning and MRI are more sensitive and
accurate than ultrasonography if liver cancer is
suspected.
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CBC Count
A complete blood cell (CBC) count commonly reveals
some degree of neutrophilic leukocytosis with bandemia.
Usually, this is moderate; however, rarely, it is severe
enough to provide a leukemoid picture.
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Alcohol is a direct marrow suppressant, and moderate
anemia may be observed. In addition, alcohol use
characteristically produces a moderate increase in mean
corpuscular volume.
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Thrombocytosis may be observed as part of the
inflammatory response; conversely, myelosuppression or
portal hypertension with splenic sequestration of
platelets may produce thrombocytopenia.
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Screening Blood Tests
Screening blood tests to exclude other conditions
(appropriate in any patient with alcoholic hepatitis) may
include the following:
itemizedlist
listitem
para, childcount:0Hepatitis B surface antigen (HBsAg)
detects hepatitis B
listitem
para, childcount:0Antihepatitis C virus by enzyme-
linked immunosorbent assay (ELISA) detects hepatitis C
listitem
para, childcount:0Ferritin and transferrin saturation
detect hemochromatosis
listitem
para, childcount:0Marked elevation of aminotransferase
levels should raise concern for viral hepatitis or drug
hepatotoxicity; in particular, people who are alcoholics
may develop severe liver necrosis from standard
therapeutic doses of acetaminophen
listitem
para, childcount:0Rapid deterioration of liver function
(see Liver Tests) should raise the possibility of
hepatocellular carcinoma (HCC), which can be tested for
by determination of alpha-fetoprotein (AFP) levels as
well as findings on an imaging study of the liver
listitem
para, childcount:0Jaundice with fever can be caused by
gallstones producing cholangitis and is suggested by a
disproportionate elevation of the alkaline phosphatase
(ALP) level
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Liver Tests
Liver enzyme levels exhibit a characteristic pattern. In
most patients, the aspartate aminotransferase (AST)
level is moderately elevated, whereas the alanine
aminotransferase (ALT) level is in the reference range or
only mildly elevated. This is the opposite of what is
observed in most other liver diseases.
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An AST/ALT ratio greater than 1 is almost universal in
persons with alcoholic hepatitis. Even in severe disease,
the elevations of aminotransferase levels are modest,
and an AST level greater than 500 U/L should raise
suspicion of an alternative diagnosis. An AST/ALT ratio
greater than 1 may accompany cirrhosis of any cause
and, therefore, is less diagnostically specific in the
setting of cirrhosis.
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Alkaline phosphatase (ALP) level elevations are typically
mild in persons with alcoholic hepatitis. Levels greater
than 500 U/L occur in a small percentage of patients, but
abnormalities of this magnitude suggest a coexisting
infiltrative or biliary obstructive process.
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The gamma-glutamyl transpeptidase (GGTP) level is
elevated markedly by alcohol use. Although a normal
value helps to exclude alcohol as a cause of liver
disease, an elevated level is of no value in distinguishing
between simple alcoholism and alcoholic hepatitis.
Liver function tests

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Common liver function tests include albumin level,
bilirubin level, and prothrombin time (PT).
Hypoalbuminemia occurs because of decreased hepatic
synthetic function and coexisting protein-energy
malnutrition (PEM). Hyperbilirubinemia is typically a
mixture of unconjugated and conjugated bilirubin, with
the latter predominating. Bilirubinuria is normally present
in patients who are icteric. Coagulopathy predominantly
affects the extrinsic pathway of coagulation (measured
by PT). It is usually unresponsive to vitamin K.
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The severity of hyperbilirubinemia and coagulopathy
reflects the severity of alcoholic hepatitis and is of
prognostic value.
Serum biomarkers
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Ash test
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The diagnostic value of serum biomarkers, such as the
Ash test (ie, the 6 components of the FibroTest-ActiTest
plus AST), was tested and validated in 275 patients with
alcoholic hepatitis. reference_ids_tool_tip reference_ids [18] Both the sensitivity
and the specificity of the Ash test in predicting alcoholic
steatohepatitis were impressive (0.80 and 0.84,
respectively). reference_ids_tool_tip reference_ids [18]
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Carbohydrate-deficient transferrin (CDT)
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Carbohydrate-deficient transferrin is perhaps the most
reliable marker of chronic alcoholism, irrespective of the
presence of liver disease. reference_ids_tool_tip reference_ids [19]
Carbohydrate-deficient transferrin has been proposed as
a reliable biomarker in the differentiation of nonalcoholic
steatohepatitis (NASH) from alcoholic hepatitis.
reference_ids_tool_tip reference_ids [20]
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Ultrasonography
In general, real-time ultrasonography is the preferred
imaging study in evaluating patients with suspected
alcoholic hepatitis, because it is inexpensive,
noninvasive, and widely available. This modality
provides a good evaluation of the liver and other viscera,
and it permits guided liver biopsy.
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On ultrasonograms, the liver in patients with alcoholic
hepatitis appears enlarged and diffusely hyperechoic.
Features suggestive of coexistent portal hypertension
and/or cirrhosis include the presence of varices,
splenomegaly, and ascites.
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Ultrasonography is also helpful in excluding gallstones,
bile duct obstruction, and hepatic or biliary neoplasms.
Jaundice with fever can be caused by gallstones
producing cholangitis; ultrasonographic examination of
the abdomen is usually sufficient to exclude this
possibility. However, if stones are found or fever persists,
cholangiography may be necessary.
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Rapid deterioration of liver function should raise the
possibility of hepatocellular carcinoma, which can be
tested for by performing imaging studies (eg,
ultrasonography, computed tomography [CT] scanning,
magnetic resonance imaging [MRI]) of the liver.
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Liver Biopsy
Liver biopsy is not always required in the evaluation of
alcoholic hepatitis, but it may be useful in establishing
the diagnosis, in determining the presence or absence
of cirrhosis, and in excluding other causes of liver
disease.
para, childcount:1
The 2010 American Association for the Study of Liver
Diseases (AASLD) alcoholic liver disease (ALD) practice
guideline recommends considering liver biopsy for
patients whose diagnosis is reasonably uncertain and
for patients likely to undergo medical treatment for
severe alcoholic hepatitis. The risk of performing the
biopsy should be weighed against the risk associated
with the probable course of therapy, or the possible risk
of an investigational treatment. reference_ids_tool_tip reference_ids [3]
Percutaneous liver biopsy

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Percutaneous biopsy can be performed at the bedside
by an experienced practitioner, usually a
gastroenterologist or a hepatologist. Real-time
ultrasonographic guidance may be desirable to optimize
the biopsy site selection and to reduce the risk of
complications.
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Usually, a biopsy should be avoided in the presence of
severe thrombocytopenia or coagulopathy because of
the risk of serious (possibly fatal) hemorrhage.
Transjugular liver biopsy

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If biopsy information is considered essential and the risk
of percutaneous biopsy appears excessive, an
alternative approach is to perform a biopsy
angiographically via a catheter passed into the hepatic
vein under fluoroscopic guidance. In principle, the risk of
hemorrhage should be reduced, because the puncture
site is contained within the venous system.
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At the time of transjugular liver biopsy, the angiographer
can determine the transhepatic venous pressure
gradient. In alcoholic hepatitis and cirrhosis, the
pressure measurement obtained with a catheter wedged
retrograde in a branch of the hepatic vein accurately
reflects the portal venous pressure.
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Histologic Features
In alcoholic hepatitis, liver injury is characteristically
most prominent in the centrilobular (perivenular) areas
(zone 3 of Rappaport). Hepatocytes exhibit ballooning
with necrosis. Focal accumulation of polymorphonuclear
leukocytes, as shown in the image below, is noted in the
areas of injury. Lymphocytes may also be present,
especially in the portal tracts.
capt_n_gallery_link_url::incaption: Liver biopsy sample shows
typical findings of perivenular polymorphonuclear infiltrate and
ballooning degeneration of hepatocytes (hematoxylin and eosin
[H&E] stain). Courtesy of H. Robert Lippman, MD.
Liver biopsy sample shows typical findings of perivenular
polymorphonuclear infiltrate and ballooning degeneration of hepatocytes
(hematoxylin and eosin [H&E] stain). Courtesy of H. Robert Lippman,
MD.
View Media Gallery
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Ropy eosinophilic hyaline inclusions termed Mallory
bodies may be observed in the perinuclear cytoplasm.
With electron microscopy, Mallory bodies may be
observed to be composed of fibril clumps that
histochemically are identifiable as intermediate
filaments. Mallory bodies are characteristic of alcoholic
hepatitis, but are not always present, and occasionally,
they can be observed in a variety of other disorders.
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Macrovesicular steatosis, perivenular fibrosis, and frank
cirrhosis commonly coexist with alcoholic hepatitis.
thiamine, is reasonable. Patients who are coagulopathic should receive vitamin K
parenterally. Anticipate symptoms of alcohol withdrawal, and manage them
appropriately.
death, at a rate of 50% or greater within 30 days. In multiple studies, the strongest
factor predictive of short-term mortality was hepatic encephalopathy. In some
studies, a combination of hyperbilirubinemia and coagulopathy has also been found
to independently predict a high short-term mortality rate. Individuals with these
findings or with other complications, such as azotemia or gastrointestinal bleeding,
should be hospitalized. Usually, observing the patient in an intensive care unit (ICU)
until liver function is stable and the patient is clinically improving is prudent.
Patients with severe alcoholic hepatitis may benefit over the short term from specific
therapies directed toward reducing liver injury, enhancing hepatic regeneration, and
suppressing inflammation. Glucocorticosteroids are widely used for this purpose,
although their benefits have not been proven unequivocally. Various other treatments
remain experimental. For the long term, goals include improvement of liver function,
prevention of progression to cirrhosis, and reduction of mortality. Only prolonged
alcohol abstinence is of demonstrated benefit in all these areas.
Among future therapeutic directions, gene therapy is perhaps the most appealing
modality. Various genes involved in hepatic fibrogenesis, inflammatory response, and
oxidative stress are overexpressed in alcoholic hepatitis. Moreover, some candidate
genes correlate well with the histologic findings and disease severity, thus
suggesting that they may be potential targets for such therapy. [21]
Surgical considerations
Patients with acute alcoholic hepatitis are at a high risk of developing hepatic failure
following general anesthesia and major surgery. Because postoperative mortality
rates are high, surgery should be avoided in the setting of acute alcoholic hepatitis
unless it is absolutely necessary. If patients remain abstinent, alcoholic hepatitis
usually resolves over time, permitting surgery to be undertaken with a substantially
reduced risk.
Transfer
Patients with alcoholic hepatitis of mild to moderate severity can be treated in a

primary care setting. In general, for patients with severe alcoholic hepatitis or
cirrhosis, observation by a gastroenterologist or a hepatologist is desirable,
particularly if the illness is of sufficient severity or complexity to require intensive
care.
If patients become comatose or have complications that may require surgical

intervention, the treating physician should consider emergent transfer to a tertiary
care center with experience in the treatment of liver failure. In selected cases, the
use of novel liver-assist devices (artificial livers) may provide transient improvement
in the manifestations of liver failure.
Cessation of Alcohol Intake
Cessation of alcohol use is the mainstay of treatment of alcoholic hepatitis. The 2010
American Association for the Study of Liver Diseases (AASLD) alcoholic liver
disease (ALD) guideline states that complete abstinence should be enjoined on all
alcoholic hepatitis patients. [3]
In general, alcoholic hepatitis resolves or improves greatly following 6-12 months of

alcohol abstinence, and continued improvement may be observed for several years.
Mild alcoholic hepatitis often resolves completely, but, following severe alcoholic
hepatitis, residual cirrhosis can usually be demonstrated. If alcohol abuse persists,
alcoholic hepatitis invariably persists and progresses to cirrhosis, and the prognosis
is dramatically worse.
Some experts have questioned whether complete abstinence is necessary or

whether reduced amounts of alcohol would be sufficient for recovery in most
patients. Given the addictive nature of alcohol in most patients who use it heavily,
counseling complete abstinence is prudent. Patients should be referred to a program
of rehabilitation and support, and they should be strongly encouraged to attend. Also,
patients should be fully informed regarding the serious potential health
consequences of continued ethanol use.
Diet and Nutritional Support
For patients with milder alcoholic hepatitis, a general diet containing 100 g/d of
protein is appropriate. Provide supplemental multivitamins and minerals, including
folate and thiamine. Salt restriction may be required in patients with ascites.
Additional treatment includes nutritional support. The 2010 American Association for
the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline
recommends testing all patients with alcoholic hepatitis for protein-energy
malnutrition (PEM) and for vitamin and mineral deficiencies. [3]
Protein-energy malnutrition is almost universal in patients hospitalized for alcoholic

hepatitis. In a large Veterans Administration Cooperative Study of Alcoholic Hepatitis,
the severity of protein-energy malnutrition correlated with the severity of alcoholic
hepatitis and the predicted mortality rate. [22] In patients with alcoholic hepatitis and
severe protein-energy malnutrition, the mortality rate was 50%, compared with a
mortality rate of less than 10% in patients with mild protein-energy malnutrition. [22]
Oral intake vs parenteral/enteral hyperalimentation
Some studies have suggested that improved energy and protein intake may improve
the survival rate in patients with severe alcoholic hepatitis. However, complications
associated with parenteral hyperalimentation (eg, sepsis, hemothorax) or enteral
hyperalimentation (eg, aspiration pneumonia) may outweigh the benefits of these
approaches. Thus, if patients are able to take food orally, this is the route of choice,
and formal nutritional support can be reserved for those instances in which patients
are unable to ingest enough by mouth to meet their needs. Energy (caloric) intake
should be carefully measured to ensure adequate consumption. The use of
nutritional supplements and appetite stimulants may be appropriate.
The 2010 AASLD ALD guideline states that patients with advanced disease should
receive aggressive enteral nutritional therapy. [3] Patients with mild to moderate
alcoholic hepatitis (Maddrey discriminant function [MDF] score < 32, no liver
encephalopathy) that improves during the first week of hospitalization (ie, lower
serum bilirubin level or decreased MDF) and who are treated with nutritional therapy
and abstinence will probably neither need nor benefit from other interventions, but
these individuals should be monitored closely. [3]
Protein restriction vs normal protein intake
Except in patients with severe encephalopathy, protein restriction is unnecessary

and should be avoided because a protein-deficient diet impairs liver regeneration
and worsens liver function. Even in the presence of hepatic encephalopathy, patients
are usually able to ingest a minimum of 60-100 g/d of dietary protein if other
measures to control encephalopathy have been aggressively pursued. In rare
instances, restricting dietary proteins may be necessary. In these cases, alternatives
include provision of high-quality protein via the parenteral route or provision of oral
amino acid supplements that are selectively enriched with branched-chain amino
acids.
Pharmacotherapy

treatments discussed in the Medication section are still investigational. [23] However,
according to the 2010 American Association for the Study of Liver Diseases (AASLD)
alcoholic liver disease (ALD) guideline [3] : (1) Naltrexone or acamprosate may be
used, in addition to counseling, to assist patients who have achieved abstinence to
avoid relapsing; and (2) in patients with severe disease (Maddrey discriminant
function [MDF] score 32), unless steroids are contraindicated, prednisolone should
be considered. Pentoxifylline may be considered, especially if prednisolone cannot
be used.
Prednisolone and pentoxifylline are recommended for the treatment of severe

alcoholic hepatitis, [1] but uncertainty about their benefit persists.
Results of the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH)
trial involving 1,103 subjects showed that treatment with the steroid prednisolone
reduced 28-day mortality in patients with severe alcoholic hepatitis, whereas
treatment with the oral phosphodiesterase inhibitor pentoxifylline did
not. [24, 25] However, the benefit of prednisolone did not extend beyond 28 days. There
was no difference in the mortality rates between the two treatments at 1 year.
Mortality at 28 days was 13.5% with prednisolone and pentoxifylline combined,
14.3% with prednisolone and placebo, 19.4% with pentoxifylline and placebo, and
16.7% with double placebo. For all patients treated with prednisolone, the mortality
rate was 13.9%; for those treated only with pentoxifylline or placebo, the rate was
18.0%. Mortality rates were similar in patients who received pentoxifylline
treatment (16.4%) and those who did not (15.5%). [24, 25]
Significant predictors of 28-day mortality included prednisone use, prothrombin time

ratio, bilirubin level, age, white blood cell count, urea level, creatinine level, and
hepatic encephalopathy. [24, 25] Neither treatment was significantly associated with a
survival benefit beyond 28 days. Infections were significantly more frequent in the
prednisolone group than in the no-prednisolone group. Patients who did not reduce
or increased their alcohol use had a 3-fold increased risk of death compared with
those who abstained. [24, 25]
Tort claims regarding steroid-induced aseptic necrosis of the hip are very common.
Physicians treating patients with alcoholic hepatitis for longer than the recommended
period should discuss the issue with the patient and the patient's family, and obtain
consent. Patients with mild forms of alcoholic hepatitis should not be treated with
steroids.
Liver Transplantation
Orthotopic liver transplantation is widely used in patients with end-stage liver

disease. [26, 1] Most patients with active alcoholic hepatitis are excluded from
transplantation because of ongoing alcohol abuse. In most liver transplantation
programs in the United States, patients must abstain from alcohol for at least 6
months before they can be considered for transplantation, and a thorough
psychosocial evaluation must demonstrate that patients have a low likelihood of
reverting to alcohol abuse.
Patients with alcoholic hepatitis may be informed that their liver injury can be
expected to subside, and liver function will improve following at least 6 months of
abstinence. If they still develop cirrhosis and its complications, they can be
considered for transplantation if they remain committed to sustained abstinence. The
prospect of liver transplantation can be a powerful motivational tool for encouraging
abstinence.
Challenges to liver transplantation policies
Current policies pertaining to liver transplantation in patients with end-stage alcoholic

liver disease (ie, cirrhosis), especially those with severe alcoholic hepatitis, have
been challenged. [27, 28]
First, the societal aspects of the issue (ie, the public perception and reservation
regarding the use of donated livers for self-inflicted disease) should not be any
different than those of intravenous (IV) drug addicts with the hepatitis C virus or even
the fast-food generation of obese persons with nonalcoholic steatohepatitis (NASH).
Second, the current fixed interval of ethanol abstinence, often at the behest of third-
party payers, as a prerequisite for transplantation remains controversial as a
predictor of future alcoholic relapse (ie, recidivism). [29, 30]
Finally, other investigators have proposed the conduct of pilot studies, on only a
small cohort of patients, to determine whether liver transplantation improves the
survival of patients with severe alcoholic hepatitis. [31]
2010 AASLD ALD recommendation
The recommendation of the 2010 American Association for the Study of Liver
Diseases (AASLD) alcoholic liver disease (ALD) guideline report is that patients with
end-stage alcoholic liver disease be evaluated for liver transplantation in the same
way as other possible candidates, after medical and psychosocial factors have been
carefully evaluated. [3] A formal assessment of the probability of long-term abstinence
should be included in the evaluation. [3]
Consultations
Largely, mild and moderate alcoholic hepatitis can be managed on a hospital

medical floor, requiring only a brief hospital stay. In fact, patients with the mildest
forms of the disease may never seek medical attention, or they can be treated safely
in outpatient settings. By contrast, severe acute alcoholic hepatitis requires intensive
medical care and often a multidisciplinary approach.
Nutrition services and gastroenterology/hepatology
Adequate nutritional support is of paramount importance for the survival and

recovery of patients with alcoholic hepatitis. The complexity of the disease and the
wide variation in nutritional regimens and modalities mandate consultation with a
nutritionist. Customarily, the gastroenterology service of the hospital should be able
to handle this issue and should be instrumental in treatment.
hepatocellular carcinoma. A common algorithm includes determination of serum
alpha-fetoprotein (AFP) levels at 6-month intervals along with annual diagnostic
In general, for patients with severe alcoholic hepatitis or cirrhosis, observation by a

gastroenterologist or a hepatologist is desirable, particularly if the illness is of
sufficient severity or complexity to require intensive care.
Nephrology
The onset of acute renal failure may indicate the development of hepatorenal
syndrome or, alternatively, an episode of acute tubular necrosis resulting either from
the use of nephrotoxic drugs or from acute intravascular volume changes. In these
instances, obtaining consultation with a nephrologist is advisable.
Neurology
If a patient with alcoholic hepatitis exhibits mental status changes, focal neurologic
findings, or seizures, consider consultation with a neurologist.
Infectious disease
The fever and leukocytosis that accompany alcoholic hepatitis often raise concerns
regarding possible sepsis or other infectious processes. Routine evaluation with
urinalysis, chest radiography, and cultures of blood and urine is appropriate, and
findings from these tests are usually negative. If concerns persist, consultation with
an infectious disease specialist is appropriate.
Long-Term Monitoring
In the absence of complications, patients generally can be discharged from acute

medical inpatient care facilities once alcohol withdrawal symptoms have cleared;
liver function has begun to improve; and the complications of liver failure, such as
encephalopathy, have resolved with appropriate treatment.
In patients who have a potential for rehabilitation, transferring them to an inpatient

substance abuse treatment program rather than discharging them from the hospital
may be appropriate.
Patients recently discharged from the hospital following an acute bout of alcoholic
hepatitis should generally be observed within 2 weeks of their discharge.
Subsequent periodic follow-up visits, at intervals ranging from weeks to several
months, are appropriate to monitor patients' responses to treatment, including
obtaining electrolyte levels and liver test results, and to encourage sobriety.
hepatocellular carcinoma. A common algorithm includes determination of the serum
alpha-fetoprotein (AFP) level at 6-month intervals along with annual diagnostic
Immunizing patients with alcoholic liver disease against common infectious

pathogens, including hepatitis A virus, hepatitis B virus, pneumococci, and influenza
A virus, is prudent.
Medication Summary
intro: para, childcount:1
treatments discussed in this section remain investigational. reference_ids_tool_tip reference_ids [23]
para, childcount:1
The 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic
liver disease (ALD) guideline does indicate that the following drugs may be
considered reference_ids_tool_tip reference_ids [3] :
itemizedlist
listitem
para, childcount:0Naltrexone or acamprosate may be used, in addition to counseling,
to assist patients who have achieved abstinence to avoid relapsing.
listitem
para, childcount:1Prednisolone should be considered, unless steroids are
contraindicated, in patients with severe disease (Maddrey discriminant function
[MDF] score 32); pentoxifylline may also be considered, especially if prednisolone
cannot be used. In a clinical trial, the use of prednisolone and pentoxifylline in
combination did not result in improved 6-month survival over use of prednisolone
alone in patients with severe alcoholic hepatitis. reference_ids_tool_tip reference_ids [32]
para, childcount:0
Note that tort claims regarding steroid-induced aseptic necrosis of the hip are very
common. When patients with alcoholic hepatitis are treated with these agents for
longer than the recommended period, physicians should discuss the issue with the
patient and the patient's family, and obtain consent. Patients with mild forms of
alcoholic hepatitis should not be treated with steroids.
para, childcount:1
The conclusion of the 2010 AASLD ALD guideline report was that the use of
complementary and alternative medications for alcoholic hepatitis has not
demonstrated convincing benefits, and should be considered investigational only.
Monoclonal antibodies
Infliximab (Remicade) is a monoclonal antibody against tumor necrosis factoralpha
(TNF-alpha) that has been used successfully in immunologically mediated
inflammatory diseases, such as Crohn disease and rheumatoid arthritis. In 2 small
pilot studies of subjects with alcoholic hepatitis, infliximab improved the MDF scores,
serum bilirubin and C-reactive protein (CRP) levels, and, more importantly, patient
survival. reference_ids_tool_tip reference_ids [33, 34]
In contrast, a subsequent randomized, double-blinded, controlled trial of 36 subjects
with severe alcoholic hepatitis failed to confirm the findings of the pilot studies.
In fact, the trial was discontinued because of the high rate of
infections and because of mortality in the infliximab group. This study was criticized
for the concomitant use of corticosteroids, the high dose of infliximab (10 mg/kg vs 5
mg/kg), and the selection of infliximab instead of an anti-TNF agent with a limited
duration and action (ie, etanercept).
Better-designed controlled clinical trials are probably necessary to resolve the

controversy and avoid a possible type I error. Currently, corticosteroids are the only
recommended pharmaceutical therapy for severe alcoholic hepatitis (ie, MDF score >
32).
Hemorheologic agents
Pentoxifylline (Trental) is a hemorheologic agent that lowers blood viscosity that has
been shown to decrease portal hypertension in experimental animals with cirrhosis
as well as has been found to have inhibitory effects on TNF. Following 2 encouraging
pilot studies in a small number of subjects, a large, randomized, double-blinded,
placebo-controlled trial in 101 subjects with acute alcoholic hepatitis showed
significant improvement in short-term survival. reference_ids_tool_tip reference_ids [36] The benefit of
pentoxifylline appears to be related to a significant decrease in the risk of developing
hepatorenal syndrome.
Anabolic steroids
Anabolic steroids (eg, oxandrolone) have been used to treat alcoholic hepatitis
because of their ability to stimulate protein synthesis and cell repair. These agents
may also enhance nutrition through increased appetite.
para, childcount:2
In a large study of 273 subjects with severe alcoholic hepatitis, although treatment
with both oxandrolone and nutritional supplementation showed no benefit on survival
when the results of all subjects were analyzed, when subjects were stratified
according to their nutritional status upon admission to the hospital, a significant
improvement in short-term and long-term survival was noted in those with moderate
malnutrition. reference_ids_tool_tip reference_ids [37] The survival rate in subjects who were severely
malnourished did not improve. reference_ids_tool_tip reference_ids [37]
para, childcount:1
The above landmark study was confirmed in a meta-analysis of 5 randomized control
trials that included 499 patients with alcoholic hepatitis who were treated with
anabolic-androgenic steroids: anabolic steroids had no significant effect on mortality,
liver-related mortality, liver complications, or liver histology. reference_ids_tool_tip reference_ids [38]
para, childcount:1
Thiocarbamide compounds
para, childcount:2
The 2010 AASLD ALD guideline states that propylthiouracil (PTU) should not be
used. reference_ids_tool_tip reference_ids [3] Investigators reported the combined results of 6
randomized clinical trials, which included 710 patients, in a meta-analytical study in
which PTU had no beneficial effect on all-cause mortality, liver-related mortality, liver
complications, or liver histology. reference_ids_tool_tip reference_ids [39]
para, childcount:1
Hepatotropic hormones
para, childcount:0
Insulin and glucagon are hepatotropic hormones that may play an important role in
promoting liver cell regeneration in response to injury. In 2 clinical trials, the
administration of insulin and glucagon along with glucose (to prevent hypoglycemia)
led to a modest improvement of liver function in patients with alcoholic hepatitis;
however, insulin-induced severe hypoglycemia resulted in several deaths.
para, childcount:0
Other promoters of hepatic regeneration include prostaglandins and malotilate, which
appeared to improve survival in a multicenter European trial. Peptide growth factors,
such as hepatocyte growth factor, are candidates for future study.
para, childcount:1
Alkaloid agents
para, childcount:1
The 2010 AASLD ALD guideline states that colchicine should not be used.
This agent interferes with the transcellular movement and
transport of collagen from the cytoplasm to the extracellular space, thus inhibiting
fibrogenesis. In the 2 randomized double-blinded trials in the literature, colchicine
was ineffective in treating patients with severe alcoholic hepatitis. By contrast, of 7
studies on the use of colchicine in patients with cirrhosis (mostly alcoholic), 4 studies
demonstrated improvement and 3 studies demonstrated a tendency toward
improvement.
para, childcount:1
Chelating agents
para, childcount:0
Penicillamine inhibits collagen synthesis in vitro by decreasing cross-linking and has
been used successfully for other liver diseases (eg, Wilson disease) for its copper-
chelating properties. However, no controlled trial with this agent has been performed
in alcoholic hepatitis.
para, childcount:1
Sulfhydryl agents
para, childcount:1
Sulfhydryl agents can act as free-radical scavengers and promote formation of
reduced glutathione, an important element of hepatic antioxidant defense. The 2010
AASLD ALD guideline recommends only investigational use of S-adenosyl-l-
methionine (SAM). reference_ids_tool_tip reference_ids [3] This agent protects against alcoholic liver
injury in animal models. A randomized, double-blinded, placebo-controlled trial in
patients with alcoholic hepatitis resulted in improved survival of patients who
received SAM compared with controls.
para, childcount:1
Antidotes
para, childcount:0
N-acetyl-L-cysteine (NAC) is widely used as an antidote for acetaminophen
hepatotoxicity. Data from limited case-controlled studies suggest a beneficial effect of
NAC in alcoholic liver disease. The beneficial effect is particularly apparent in
patients who are alcoholics and who also consume therapeutic doses of
acetaminophen; however, preliminary evidence from prospective randomized trials
did not show benefit.
para, childcount:1
Antioxidants
para, childcount:0
Vitamin E, a potent antioxidant substance, has been found to be hepatoprotective in
both experimental animals and humans. However, a double-blinded trial among
patients with alcoholic liver disease failed to improve liver chemistry, the
hospitalization rate, and the cumulative mortality rate when the patients were
administered 500 mg of vitamin E daily compared with the placebo-treated control
group.
para, childcount:0
Cyanidanol-3 (catechin) is a naturally occurring flavonoid with antioxidant properties.
As a hepatoprotective agent, it has been studied extensively in experimental toxic
liver injury. Cyanidanol gained popularity in Europe in the mid 1980s and was used
for a wide variety of liver diseases. Unfortunately, prospective randomized trials in
subjects with alcoholic hepatitis failed to show any benefit. Moreover, the
administration of cyanidanol is associated with adverse effects, such as allergic
hyperthermia and autoimmune hemolytic anemia.
para, childcount:1
Several other antioxidant agents have been used in the treatment of alcoholic
hepatitis, albeit with little success. In a randomized clinical trial, corticosteroids were
far superior to a "cocktail" of antioxidants in improving the usually measured clinical
parameters and liver histology. reference_ids_tool_tip reference_ids [40]
para, childcount:1
Nutritional supplements
para, childcount:0
Polyunsaturated lecithin (PPC, phosphatidyl choline) has been studied because of
the empiric observation that choline deficiency in rats (which impairs endogenous
lecithin synthesis) increases sensitivity to alcoholic liver injury. The precise
mechanism is unknown. Beneficial effects have also been demonstrated in
preventing alcoholic liver injury in baboons.
para, childcount:2
PPC failed to demonstrate any hepatoprotective effects in alcohol-induced liver injury
in a multicenter Veterans Affairs cooperative study among 789 subjects. reference_ids_tool_tip
reference_ids [41]
In fact, approximately 20% of these subjects showed progressive liver
fibrosis with continued moderated amounts of alcohol ingestion. reference_ids_tool_tip reference_ids
[41]
Thus, PPC does not appear to have a viable role in acute alcoholic hepatitis.
para, childcount:1
Calcium channel blockers
para, childcount:0
Several preliminary reports on alcoholic hepatitis have indicated a beneficial effect of
calcium channel blockers (eg, diltiazem, verapamil); however, the only randomized
double-blinded trial of amlodipine failed to demonstrate any improvement in patients
with alcoholic hepatitis.
para, childcount:1
Bile acids
para, childcount:0
Hepatoprotective bile acids include ursodeoxycholic acid (Ursodiol), a tertiary bile
acid that has been used extensively either as monotherapy or as an adjuvant therapy
in various cholestatic liver diseases, such as primary biliary cholangitis and primary
sclerosing cholangitis. Preliminary data from a small clinical trial in patients with
alcoholic hepatitis showed a significant improvement in liver chemistry test results.
para, childcount:1
Herbal agents
para, childcount:1
Herbal agents have also been tried in alcoholic hepatitis. Silymarin is the active
ingredient in milk thistle; it is a member of the flavonoids and has shown remarkable
hepatoprotective effects in experimental toxic liver injury. The precise mechanism of
its hepatoprotective mediation is not known, but it is probably related to its
antioxidant properties. In humans with mild alcoholic hepatitis, silymarin improves
liver chemistry test results. In a single controlled trial among 170 subjects with
alcoholic liver disease, silymarin reduced the liver-related deaths. However, in a
meta-analysis of 13 clinical trials (about half of them double-blind), it was concluded
that milk thistle did not significantly influence the clinical course of patients with
alcoholic hepatitis. reference_ids_tool_tip reference_ids [42]
Corticosteroids
Class Summary
Strong evidence of immunologic and inflammatory liver injury in alcoholic hepatitis
provides the rationale for the use of glucocorticosteroids. Over the past 30 years,
more than 50 clinical trials have been published evaluating the use of
glucocorticosteroids in treating alcoholic hepatitis. In most studies, treatment
consists of the equivalent of 30-40 mg/d of prednisolone for 30 days, followed by a
rapid taper and withdrawal over the subsequent 2-4 weeks.
Study results have not been uniform. Larger studies demonstrate a significant benefit
in severe alcoholic hepatitis, including reduction in mortality. Two meta-analyses of
12 randomized, prospective, placebo-controlled trials support the conclusion that
glucocorticosteroid treatment reduces early mortality in patients with severe acute
alcoholic hepatitis.
All studies conclude that in mild alcoholic hepatitis, no benefit can be demonstrated
with glucocorticosteroid treatment; therefore, this treatment is only appropriate in
individuals with severe alcoholic hepatitis characterized by encephalopathy,
hyperbilirubinemia, and/or coagulopathy.
Glucocorticosteroids may suppress inflammatory and immune-mediated hepatic
destruction, but their marked anti-anabolic effect suppresses regeneration and may
slow healing. They may increase the complications and mortality associated with
gastrointestinal bleeding, pancreatitis, or sepsis, and they should be withheld or used
judiciously if any of these are present.
When Louvet et al investigated whether the presence of infection in patients with
severe alcoholic hepatitis contraindicates corticosteroid treatment, the investigators
determined that infection was not independently associated with patient survival and
although infection screening is warranted in patients with severe alcoholic hepatitis, it
should not contraindicate steroid use. [43] Prednisolone was administered to 246
patients suffering from severe alcoholic hepatitis, including to 63 patients in whom
infectionspecifically, spontaneous bacterial peritonitis or bacteremia (n =28),
pulmonary infection (n =8), urinary tract infection (n =20), or other infection (n = 7)
was present at hospital admission.
Patients suffering from infection before corticosteroid administration had a 2-month
survival rate (70.9%) that was similar to that of the study's other patients (71.6%).
Louvet et al also observed that postadmission infection developed more frequently in
patients who were nonresponders to corticosteroid therapy (42.5%) than it did in
responders (11.1%). [43] In addition, in a multivariate analysis, only the Lille model
yielded an independent prediction of infection upon steroid use. [44, 45]
Methylprednisolone (Solu-Medrol, Medrol, Depo-Medrol)
View full drug information
Methylprednisolone decreases inflammation by suppressing the migration of
polymorphonuclear leukocytes and reversing increased capillary permeability. This
agent may be preferable to other glucocorticoids (eg, prednisone), because hepatic
metabolism is not required.
Prednisolone (Orapred ODT, Prelone, Pred Forte, Omnipred)
View full drug information
Prednisolone decreases autoimmune reactions, possibly by suppressing key
components of the immune system. This agent does not need to undergo hepatic
metabolism.
1. Casanova J, Bataller R. Alcoholic hepatitis: Prognosis and

treatment. Gastroenterol Hepatol. 2014 Apr. 37(4):262-8. [Medline].
2. Mueller S, Millonig G, Seitz HK. Alcoholic liver disease and hepatitis C: a

frequently underestimated combination. World J Gastroenterol. 2009 Jul 28.
15(28):3462-71. [Medline]. [Full Text].
3. [Guideline] O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver

disease. Hepatology. 2010 Jan. 51(1):307-28. [Medline]. [Full Text].
4. Zintzaras E, Stefanidis I, Santos M, Vidal F. Do alcohol-metabolizing enzyme

gene polymorphisms increase the risk of alcoholism and alcoholic liver
disease?. Hepatology. 2006 Feb. 43(2):352-61. [Medline].
5. Lieber CS, DeCarli LM. An experimental model of alcohol feeding and liver
injury in the baboon. J Med Primatol. 1974. 3(3):153-63. [Medline].
6. Testino G, Sumberaz A, Ancarani AO, et al. Influence of body mass index,

cholesterol, triglycerides and steatosis on pegylated interferon alfa-2a and
ribavirin treatment for recurrent hepatitis C in patients transplanted for HCV
and alcoholic cirrhosis. Hepatogastroenterology. 2009 Mar-Apr. 56(90):501-
3. [Medline].
7. Shoreibah M, Anand BS, Singal AK. Alcoholic hepatitis and concomitant

hepatitis C virus infection. World J Gastroenterol. 2014 Sep 14. 20(34):11929-
34. [Medline]. [Full Text].
8. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity

with regular intake of alcohol: analysis of instances of therapeutic
misadventure. Hepatology. 1995 Sep. 22(3):767-73. [Medline].
9. Potts JR, Goubet S, Heneghan MA, Verma S. Determinants of long-term

outcome in severe alcoholic hepatitis. Aliment Pharmacol Ther. 2013 Sep.
38(6):584-95. [Medline].
10. Horie Y, Ishii H, Hibi T. Severe alcoholic hepatitis in Japan: prognosis and
therapy. Alcohol Clin Exp Res. 2005 Dec. 29(12 Suppl):251S-8S. [Medline].
11. Mihas AA, Doos WG, Spenney JG. Alcoholic hepatitis--a clinical and
pathological study of 142 cases. J Chronic Dis. 1978. 31(6-7):461-
72. [Medline].
12. Dunn W, Jamil LH, Brown LS, et al. MELD accurately predicts mortality in
patients with alcoholic hepatitis. Hepatology. 2005 Feb. 41(2):353-
8. [Medline].
13. Srikureja W, Kyulo NL, Runyon BA, Hu KQ. MELD score is a better prognostic
model than Child-Turcotte-Pugh score or discriminant function score in
patients with alcoholic hepatitis. J Hepatol. 2005 May. 42:700-6. [Medline].
14. Forrest EH, Evans CD, Stewart S, et al. Analysis of factors predictive of
mortality in alcoholic hepatitis and derivation and validation of the Glascow
alcoholic hepatitis score. Gut. 2005 Aug. 54:14-5. [Medline].
15. Mookerjee RP, Malaki M, Davies NA, et al. Increasing dimethylarginine levels
are associated with adverse clinical outcome in severe alcoholic
hepatitis. Hepatology. 2007 Jan. 45:62-71. [Medline].
16. Centers for Disease Control and Prevention. Recommendations for the
identification of chronic hepatitis C virus infection among persons born during
1945-1965. MMWR Recomm Rep. 2012 Aug 17. 61:1-32. [Medline]. [Full
Text].
17. Vanbiervliet G, Le Breton F, Rosenthal-Allieri MA, et al. Serum C-reactive
protein: a non-invasive marker of alcoholic hepatitis. Scand J Gastroenterol.
2006 Dec. 41(12):1473-9. [Medline].
18. Thabut D, Naveau S, Charlotte F, et al. The diagnostic value of biomarkers

(AshTest) for the prediction of alcoholic steato-hepatitis in patients with
chronic alcoholic liver disease. J Hepatol. 2006 Jun. 44:1175-85. [Medline].
19. Mihas AA, Tavassoli M. Laboratory markers of ethanol intake and abuse: a
critical appraisal. Am J Med Sci. 1992 Jun. 303(6):415-28. [Medline].
20. Ohtsuka T, Tsutsumi M, Fukumura A, Tsuchishima M, Takase S. Use of serum

carbohydrate-deficient transferrin values to exclude alcoholic hepatitis from
non-alcoholic steatohepatitis: a pilot study. Alcohol Clin Exp Res. Dec 2005.
29(12 suppl):236S-9S. [Medline].
21. Colmenero J, Bataller R, Sancho-Bru P, et al. Hepatic expression of candidate

genes in patients with alcoholic hepatitis: correlation with disease
severity. Gastroenterology. 2007 Feb. 132:687-97. [Medline].
22. Mendenhall C, Roselle GA, Gartside P, Moritz T. Relationship of protein

calorie malnutrition to alcoholic liver disease: a reexamination of data from
two Veterans Administration Cooperative Studies. Alcohol Clin Exp Res. 1995
Jun. 19(3):635-41. [Medline].
23. Lucey MR. Management of alcoholic liver disease. Clin Liver Dis. 2009 May.
13(2):267-75. [Medline].
24. Osterwell N. STOPAH: Only steroid reduces alcoholic hepatitis death risk.
Medscape Medical News from WebMD. Available
at http://www.medscape.com/viewarticle/834928. November 14, 2014;
Accessed: November 20, 2014.
25. Thursz M, Forrest E, Roderick P, et al. The clinical effectiveness and cost-
effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a
22 factorial randomised controlled trial. Health Technol Assess. 2015 Dec.
19(102):1-104. [Medline].
26. Immordino G, Gelli M, Ferrante R, et al. Alcohol abstinence and orthotopic

liver transplantation in alcoholic liver cirrhosis. Transplant Proc. 2009 May.
41(4):1253-5. [Medline].
27. Pfitzmann R, Schwenzer J, Rayes N, Seehofer D, Neuhaus R, Nussler NC.

Long-term survival and predictors of relapse after orthotopic liver
transplantation for alcoholic liver disease. Liver Transpl. 2007 Feb. 13(2):197-
205. [Medline].
28. Lucey MR, Schaubel DE, Guidinger MK, Tome S, Merion RM. Effect of
alcoholic liver disease and hepatitis C infection on waiting list and
posttransplant mortality and transplant survival benefit. Hepatology. 2009 Aug.
50(2):400-6. [Medline].
29. Webb K, Shepherd L, Day E, Masterton G, Neuberger J. Transplantation for

alcoholic liver disease: report of a consensus meeting. Liver Transpl. 2006
Feb. 12(2):301-5. [Medline].
30. Lucey MR. Liver transplantation for alcoholic liver disease: past, present, and
future. Liver Transpl. 2007 Feb. 13(2):190-2. [Medline].
31. McCormick PA, Burroughs AK. Relation between liver pathology and
prognosis in patients with portal hypertension. World J Surg. 1994 Mar-Apr.
18(2):171-5. [Medline].
32. Mathurin P, Louvet A, Duhamel A, et al. Prednisolone with vs without

pentoxifylline and survival of patients with severe alcoholic hepatitis: a
randomized clinical trial. JAMA. 2013 Sep 11. 310(10):1033-41. [Medline].
33. Spahr L, Rubbia-Brandt L, Frossard JL, et al. Combination of steroids with

infliximab or placebo in severe alcoholic hepatitis: a randomized controlled
pilot study. J Hepatol. 2002 Oct. 37(4):448-55. [Medline].
34. Tilg H, Jalan R, Kaser A, Davies NA, Offner FA, Hodges SJ, et al. Anti-tumor
necrosis factor-alpha monoclonal antibody therapy in severe alcoholic
hepatitis. J Hepatol. 2003 Apr. 38(4):419-25. [Medline].
35. Naveau S, Chollet-Martin S, Dharancy S, et al. A double-blind randomized

controlled trial of infliximab associated with prednisolone in acute alcoholic
hepatitis. Hepatology. 2004 May. 39(5):1390-7. [Medline].
36. Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline

improves short-term survival in severe acute alcoholic hepatitis: a double-
blind, placebo-controlled trial. Gastroenterology. 2000 Dec. 119(6):1637-
48. [Medline].
37. Mendenhall CL, Moritz TE, Roselle GA, et al. A study of oral nutritional
support with oxandrolone in malnourished patients with alcoholic hepatitis:
results of a Department of Veterans Affairs cooperative study. Hepatology.
1993 Apr. 17(4):564-76. [Medline].
38. Rambaldi A, Gluud C. Anabolic-androgenic steroids for alcoholic liver

disease. Cochrane Database Syst Rev. 2006. (4):CD003045. [Medline].
39. Rambaldi A, Gluud C. Propylthiouracil for alcoholic liver disease. Cochrane

Database Syst Rev. 2005. (4):CD002800. [Medline].
40. Phillips M, Curtis H, Portmann B, Donaldson N, Bomford A, O'Grady J.

Antioxidants versus corticosteroids in the treatment of severe alcoholic
hepatitis- A randomized clinical trial. J Hepatol. Apr 2006. 44:784-
90. [Medline].
41. Lieber CS, Weiss DG, Groszmann R, Paronetto F, Schenker S. II. Veterans
Affairs Cooperative Study of polyenylphosphatidylcholine in alcoholic liver
disease. Alcohol Clin Exp Res. 2003 Nov. 27(11):1765-72. [Medline].
42. Rambaldi A, Jacobs BP, Iaquinto G, Gluud C. Milk thistle for alcoholic and/or
hepatitis B or C liver diseases--a systematic cochrane hepato-biliary group
review with meta-analyses of randomized clinical trials. Am J Gastroenterol.
2005 Nov. 100(11):2583-91. [Medline].
43. Louvet A, Wartel F, Castel H, et al. Infection in patients with severe alcoholic
hepatitis treated with steroids: early response to therapy is the key
factor. Gastroenterology. 2009 Aug. 137(2):541-8. [Medline].
44. Garcia-Saenz-de-Sicilia M, Duvoor C, Altamirano J, et al. A day-4 Lille model

predicts response to corticosteroids and mortality in severe alcoholic
hepatitis. Am J Gastroenterol. 2016 Dec 6. [Medline].
45. Rahimi E, Pan JJ. Prognostic models for alcoholic hepatitis. Biomark Res.
2015 Jul 21. 3:20. [Medline].
46. Bucci L, Garuti F, Camelli V, et al, for the Italian Liver Cancer (ITA.LI.CA)
Group., Italian Liver Cancer ITA LI CA Group. Comparison between alcohol-
and hepatitis C virus-related hepatocellular carcinoma: clinical presentation,
treatment and outcome. Aliment Pharmacol Ther. 2016 Feb. 43(3):385-
99. [Medline].
47. Jaruvongvanich V, Upala S, Sanguankeo A. Association between systemic

inflammatory response syndrome and mortality in alcoholic hepatitis: A meta-
analysis. Hepatology. 2016 Aug. 64(2):696-7. [Medline].
48. Llopis M, Cassard AM, Wrzosek L, et al. Intestinal microbiota contributes to

individual susceptibility to alcoholic liver disease. Gut. 2016 May. 65(5):830-
9. [Medline].
49. Mitchell MC, Friedman LS, McClain CJ. Medical management of severe
alcoholic hepatitis: expert review from the Clinical Practice Updates
Committee of the AGA Institute. Clin Gastroenterol Hepatol. 2017 Jan.
15(1):5-12. [Medline].

Practice Essentials of Alcoholic Hepatitis

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Practice Essentials of Alcoholic Hepatitis

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Practice Essentials

Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated

Toxic effects on cell membranes

Hypermetabolic state of the hepatocyte

Generation of free radicals and oxidative injury

Formation of acetaldehyde adducts

Role of the immune system

capt_n_gallery_link_url::incaption: Ethanol (ETOH) and cytokine production. CYP =

Role of concomitant viral disease

Racial and age differences in incidence

Sexual differences in incidence

Prognostic scoring systems

History and Physical Examination

Common considerations in alcoholic patients with jaundice include chronic

A disorder histologically resembling alcoholic hepatitis can occur in patients who do

Liver function tests

Percutaneous liver biopsy

Transjugular liver biopsy

Patients with alcoholic hepatitis of mild to moderate severity can be treated in a

If patients become comatose or have complications that may require surgical

Cessation of Alcohol Intake

In general, alcoholic hepatitis resolves or improves greatly following 6-12 months of

Some experts have questioned whether complete abstinence is necessary or

Diet and Nutritional Support

Protein-energy malnutrition is almost universal in patients hospitalized for alcoholic

Oral intake vs parenteral/enteral hyperalimentation

Protein restriction vs normal protein intake

Except in patients with severe encephalopathy, protein restriction is unnecessary

Use of medications in alcoholic hepatitis has been considered controversial. Many

Prednisolone and pentoxifylline are recommended for the treatment of severe

Significant predictors of 28-day mortality included prednisone use, prothrombin time

Orthotopic liver transplantation is widely used in patients with end-stage liver

Challenges to liver transplantation policies

Current policies pertaining to liver transplantation in patients with end-stage alcoholic

2010 AASLD ALD recommendation

Largely, mild and moderate alcoholic hepatitis can be managed on a hospital

Nutrition services and gastroenterology/hepatology

Adequate nutritional support is of paramount importance for the survival and

In general, for patients with severe alcoholic hepatitis or cirrhosis, observation by a

In the absence of complications, patients generally can be discharged from acute

In patients who have a potential for rehabilitation, transferring them to an inpatient

Immunizing patients with alcoholic liver disease against common infectious

Better-designed controlled clinical trials are probably necessary to resolve the

1. Casanova J, Bataller R. Alcoholic hepatitis: Prognosis and

2. Mueller S, Millonig G, Seitz HK. Alcoholic liver disease and hepatitis C: a

3. [Guideline] O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver

4. Zintzaras E, Stefanidis I, Santos M, Vidal F. Do alcohol-metabolizing enzyme

6. Testino G, Sumberaz A, Ancarani AO, et al. Influence of body mass index,

7. Shoreibah M, Anand BS, Singal AK. Alcoholic hepatitis and concomitant

8. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity

9. Potts JR, Goubet S, Heneghan MA, Verma S. Determinants of long-term

18. Thabut D, Naveau S, Charlotte F, et al. The diagnostic value of biomarkers

20. Ohtsuka T, Tsutsumi M, Fukumura A, Tsuchishima M, Takase S. Use of serum

21. Colmenero J, Bataller R, Sancho-Bru P, et al. Hepatic expression of candidate

22. Mendenhall C, Roselle GA, Gartside P, Moritz T. Relationship of protein

26. Immordino G, Gelli M, Ferrante R, et al. Alcohol abstinence and orthotopic

27. Pfitzmann R, Schwenzer J, Rayes N, Seehofer D, Neuhaus R, Nussler NC.

29. Webb K, Shepherd L, Day E, Masterton G, Neuberger J. Transplantation for

32. Mathurin P, Louvet A, Duhamel A, et al. Prednisolone with vs without

33. Spahr L, Rubbia-Brandt L, Frossard JL, et al. Combination of steroids with

35. Naveau S, Chollet-Martin S, Dharancy S, et al. A double-blind randomized

36. Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline