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Several breath tests have been proposed to diagnose and determine disease sever-
ity of liver disease from alcohol, including the
13
C labeled breath tests, aminopyrine
breath test, galactose breath test, methacetin breath test, and keto-isocaproic acid
breath test, studies based on the quantication of volatile organic compounds. If
conrmed, these tests can help the clinician identify patients in whom therapeutic
and preventive measures may be started to prevent disease progression [139].
Histology
Steatosis is the earliest nding in alcohol mediated liver injury [140]. Fat appears
within hepatocytes giving the appearance of droplets that coalesce in the cytoplasm
pusing the nucleus to the periphery. Fat tends to predominate in the pericentral, zone
3, of the liver lobule, continuing towards zones 2 and 1. In association with absti-
nence, fat can disappear from hepatocytes over several weeks, with some remnants
in periportal macrophages. Fat lled hepatocytes can rupture stimulating an inam-
matory response comprised of lymphocytes, macrophages, and eosinophils in the
form of lipogranuloma, which disappear without brosis [140]. Alcoholic foamy
degeneration is a complication of ALD characterized by microvesicular steatosis
where fat appears in the cytoplasm as small droplets, and where the nucleus remains
in the center of the hepatocyte; megamitochondria and bile pigment can be present,
the latter in the perivenular hepatocytes and canaliculi. This type of liver injury, in
which inammation tends to be absent, is considered to be a degenerative process
that can be complicated by jaundice and hepatomegaly, with a mixed liver prole
and a prolonged picture of cholestasis. Hepatic decompensation was reported in less
than 10% of the 20 patients in the original series, and resolved in association with
abstinence from alcohol [141, 142]. Regarding cholestasis, loss of type 3 inositol
1,4,5-trisphosphate receptor (ITPR3) from biliary epithelial cells has been described
in liver diseases characterized by bile duct injury, including primary biliary cholan-
gitis and primary sclerosing cholangitis [143]. As the absence of ITPR3in biliary
epithelial cells is associated with decreased bicarbonate secretion, it has been sug-
gested that loss of ITPR3in this type of cell may be a common factor to conditions
associated with cholestasis [144]. Biliary epithelial cells express Toll-like receptor
4 (TLR4), the LPS (i.e., endotoxin) receptor, the stimulation of which activates
nuclear factor-κB (NF-κB), which subsequently downregulates ITPR3. Liver sam-
ples from seven patients out of 28 with alcoholic hepatitis and cholestasis, assessed
by serum activity of alkaline phosphatase, had decreased expression of ITPR3,
documented by immunohistochemistry [145]; thus, as endotoxemia is characteristic
of excessive alcohol use, and is considered to contribute to ALD [109, 114], these
ndings provide a mechanism underlying cholestasis in alcoholic hepatitis, and
lend support to the idea that endotoxin contributes to the pathogenesis of ALD.
Perivenular brosis consists of a rim of brous tissue covering at least two thirds
of the perimeter of the terminal venule; in association with alcohol induced steato-
sis, it prognosticates the progression of liver disease in the absence of abstinence
[140, 146].
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Alcoholic hepatitis is a clinicopathological syndrome that can only be unequivo-
cally diagnosed by liver histology. Histologically it is characterized by steatosis,
acidophilic necrosis of hepatocytes, i.e., apoptotic bodies, and an inammatory
inltrate characterized by neutrophils. Mallory bodies, eosinophilic, irregularly
shaped structures that have the appearance of a twisted rope (Cesar del Rosario,
M.D., personal communication) and are located in the cytoplasm of the hepatocyte
can be identied. Megamitochondria, appearing like needle-like cytoplasmic pro-
jections, can also be appreciated. The severity of the disease is associated with the
degree of hepatocellular necrosis, with ballooned hepatocytes (Fig.8.3) and Mallory
bodies, around which the inammatory inltrate tends to be localized. Other fea-
tures include bile stasis, bile ductular proliferation, and various degrees of brosis
around hepatocytes and venules [140].
A role of interleukin 8 in the pathogenesis of alcoholic hepatitis was suggested
from a study that reported marked expression of the cytokine in correlation with the
neutrophil inammatory inltrate, a marker of severity, and in serum, signicantly
higher levels in patients who died from complications of the disease [147]. These
ndings were extended in a morphometric study in which neutrophils and T lym-
phocytes CD3+ inltration, degree of apoptosis, expression of CXC and CC chemo-
kines, protein levels of IL-8 and Gro-alpha, and serum concentrations of IL-8 and
Gro-alpha were evaluated. The expression of CCL2 and CXCL10, IL-8, Gro-alpha,
CXCL5, CXCL6 was enhanced in samples from patients with alcoholic hepatitis
compared to that of samples in the control group, the latter four correlating with
neutrophil inltration, and with worse prognosis, with IL-8 protein levels identied
as an independent predictor of 90day mortality after the clinical presentation [148].
Some of the ndings from a study that included 36 consecutive patients admitted to
a hospital in Spain with a diagnosis of alcoholic hepatitis, supported by the clinical
presentation and liver histology, concluded that transforming growth factor-beta1
(TGF-β1), a cytokine that plays a fundamental role in the development of hepatic
brosis, was enhanced in the liver of patients with alcoholic hepatitis as well as
other factors that mediate degradation of collagen in the liver, tissue inhibitor metal-
loproteinases (TIMP-1), matrix metalloproteinase-2 (MMP-2), and urokinase-type
Fig. 8.3 Ballooned
hepatocytes in a patient
with alcohol induced liver
disease (arrow)
(Hematoxylin and eosin
stain, 40X)
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plasminogen activator (ut-PA), chemokine (C-X-C motif) ligand 1 (i.e., GrO-a),
dual oxidase 1(DUOX-1), and monocyte chemoattractant protein 1(MCP-1), medi-
ators of inammation. In addition, important components of the phagocytic NADPH
oxidase, which mediates neutrophil derived oxidant stress, was increased. The
increase in TNF-alpha was mild, although, together with IL-6 correlated with infec-
tion. The results of this study identied potential treatment pathways and seemed to
support documented histological ndings of patients with alcoholic hepatitis, i.e.
mediators of collagen deposition, collagen degradation, and the inammatory con-
sequences of the neutrophil invasion of the liver in alcoholic hepatitis [149].
Plasma levels of CCL2 were signicantly higher in patients with alcoholic hepa-
titis than those without and correlated with disease severity, IL-8 expression, and
degree of neutrophil inltrate, with a predominance of the −2518 A> G CCL2
polymorphism in patients with severe disease [150].
Patients with alcoholic hepatitis have been documented to have a dysregulated
immune state as suggested by increased plasma concentrations of proinammatory
cytokines, including IL-8, a potent neutrophil chemotactic factor [148], but lower
levels of the anti-inammatory macrophage-derived chemokine (MDC), compared
to the control groups, including a group of heavy alcohol drinkers without liver
disease, the latter ndings being consistent with a prior report [149]. In addition,
CD4 T cells reacted poorly upon stimulation based on the low production of IFN-γ.
Monocytes had a low expression of cluster of differentiation 38 (CD 38), a reec-
tion of reduced leukocyte activation, in patients with alcoholic hepatitis, a nding
that correlated with increased mortality, and which seems a paradox, as it is the
migration of neutrophils to the liver that is believed to contribute to the pathogenesis
of alcoholic hepatitis. Abstinence from alcohol was associated with the resolution
of immunological dysregulation, emphasizing the importance of abstinence at any
stage of ALD.CD38 and IL-8 were highlighted in this study as potentially relevant
in the pathogenesis of alcoholic hepatitis thus identifying potential pathways
towards drug development [151].
The lesion of sclerosing hyaline necrosis can be appreciated in cases of severe
liver injury in alcoholic hepatitis, with hepatocellular necrosis around the terminal
venules, occluded by brous tissue, which can be associated with portal hyperten-
sion, in the absence of cirrhosis, as it has been clinically described [152] (Fig.8.4),
and in patients with cirrhosis and superimposed alcoholic hepatitis with marked
liver cell necrosis and neutrophilic inltrate [153]. The lesion of sclerosing hyaline
necrosis can progress, and brosis extends pericellularly; the bad prognostic fea-
tures include brous septa, and general hepatocellular necrosis, occlusion of hepatic
venules, which results from perivenular brosis, leading to luminal obstruction of
venules [140]. In addition, lymphocytic phlebitis, characterized by an inammatory
inltrate of the central and sublobular veins, and in as much as 52% of cases of
alcoholic hepatitis in one series [154], veno-occlusive lesions, the degree of which
correlate with the magnitude of portal hypertension [140, 154].
Alcoholic cirrhosis is the transformation of the liver architecture by regenerating
nodules surrounded by brous septa (Fig.8.5). The nodules tend to be small, i.e.,
micronodular, measuring 3mm in diameter, although macronodules can also form,
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Fig. 8.4 Liver histology of
a patient with sclerosing
hyaline necrosis in a
patient with alcoholic
hepatitis. Strands of
collagen (blue) extend
from the central vein
surrounding swollen
hepatocytes, and sinusoids
lled with collagen.
(Masson stain, 500X)
(published with permission
[152])
Fig. 8.5 Cirrhosis in a
patient with liver disease
from alcohol use disorder;
there is a nodule
surrounded by collagen
(Trichrome stain, high
power)
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reportedly in association with alcohol abstinence. Features of inammation charac-
terized by neutrophils and plasma cells can be appreciated in the brous septa, usu-
ally when alcohol consumption has continued. Ductal metaplasia is noted in the
periportal area. Alpha1 1-antitrypsin globules can be observed in the periphery of
the nodules, suggesting impaired protein secretion by the hepatocytes [155], as well
as Periodic Acid-Schiff (PAS)-positive granules identifying protein bound copper in
the hepatocytes [140]. Hepatic oncocytes, characterized by a granular cytoplasm,
can also be appreciated in the nodules' periphery [140, 156]. Portal brosis is not
common in pure ALD; however, activated macrophages found in these areas have
suggested that they may be the source of substances that mediate alcohol induced
liver injury [140].
Iron metabolism in the context of excessive alcohol use and ALD has been dis-
cussed above. Siderosis is a feature in the liver histology of ALD, with iron detected
in hepatocytes and Kupffer cells, modestly [140]. Intense iron staining in the liver
of patients with ALD prompts the investigation of genetic forms of iron overload.
Characteristically, there is IgA deposition along the sinusoids in the liver of
patients with ALD, a ndings that has suggested a pathological role for the immu-
noglobulin [157]. In this regard, however, it was documented that B cells, isolated
from human liver tissue, included IgA producing cells that reacted with commensal
bacterial products, ndings interpreted to suggest that the IgA originating from the
liver could be involved in the clearance of intestinal antigens that get to the liver
through the portal vein, and thus, protect the liver from injury due to gut-derived
antigens in ALD [158].
Treatment
The management of patients with AUD with or without liver disease is founded on
abstinence; when AUD is associated with liver disease, in addition to abstinence, the
treatment is aimed to stop the progression of the liver disease, and in cases of alco-
holic hepatitis, to stop the acute inammatory cascade that can result in liver failure
and death.
Patients with AUD require collaborative management between substance abuse
experts, internists, gastroenterologists, and hepatologists if they have liver disease,
and support groups, including faith based organizations.
The Food and Drug Administration has approved several medications to manage
AUD, including disulram, acamprosate, and naltrexone.
Disulram inhibits the enzyme mitochondrial aldehyde dehydrogenase; in the
presence of alcohol, even small amounts of disulram produces unpleasant effects
that include ushing, throbbing headache, nausea, vomiting, sweating, and thirst as
well as respiratory and cardiovascular complications [159]. A meta-analysis of the
results of clinical studies on disulram documented that in open label trials, the
drug was more effective than the controls in maintaining abstinence; however, no
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efcacy was demonstrated in “blind trials.” More side effects were reported in the
disulram trials than in the control groups, with no difference in the number of
deaths between them [160].
Naltrexone is an opioid antagonist that decreases the pleasant sensations associ-
ated with alcohol intake, and it has been reported to decrease craving [161, 162].
Acamprosate is a drug most effective in combination with psychosocial support
in the treatment of AUD.The mechanisms of action of this drug in the treatment of
AUD may include functional antagonism of the ionotropic glutamate N-methyl-d-
aspartate (NMDA) receptor, but, as the binding between the drug and the receptor is
weak, it is suggested that instead, the drug may modulate NMDA receptors via
regulatory polyamine sites, or that it may act on metabotropic glutamate recep-
tors [163].
Other drugs approved by the FDA for other indications have also been used to
treat AUD, including uoxetine, duloxetine, tiagabine, levitiracetam, gabapentin,
pregabalin, sertraline, citalopram, ritanserin, aripiprazole, ondansetron, quetiapine,
and topiramate [164].
Baclofen is a selective GABA-B receptor agonist used to treat AUD; the mecha-
nism by which this drug helps in the management of alcoholism is unknown.
Baclofen was documented to reduce the craving for alcohol and promote abstinence
and prevent relapses after a period of sobriety in patients with and without liver
disease [165], including cirrhosis [166]. However, the Cochrane Collaboration,
which analyzed the clinical trials of baclofen for AUD, interpreted that the results of
the studies, in general, were encouraging but that the evidence remained “uncertain”
in support of the use of baclofen for the treatment of AUD [167].
In a randomized clinical trial, baclofen, at a dose of 10mg orally three times a
day, was associated with abstinence in 30 of 42 patients (71%) with a cumulative
mean duration of 62.8days versus placebo, associated with abstinence in 12 of 42
(29%) with a mean duration of 30.8days in the absence of liver related side effects.
The dropout rate was 14% for the drug, versus 31% for the placebo, reported as
insignicant [165]. A study examined the effect of baclofen in 100 patients recruited
over 3years, 65 of whom had cirrhosis; after 1year, 44 of the 86 patients being fol-
lowed were abstinent, and the rest still drank up to 30g per day on baclofen. The
drug was associated with improved liver function and reduction of serum GGTP
activity, a marker of excessive alcohol use [168]. In the author’s experience, baclofen
has been associated with abstinence of alcohol in patients with and without liver
disease and not associated with complications.
A meta-analysis of results from 24 randomized controlled trials that included
2861 patients with AUD compared the effect of naltrexone to that of the placebo on
the frequency of relapse, as a primary outcome, and time to rst drink, drinking
days, the number of standard drinks for a dened period, and craving over time.
Naltrexone was associated with a signicant decrease in the frequency of relapses
but not on return to drinking, suggesting that it was an option for the treatment of
AUD at short term. Of note, it was also reported that patients on naltrexone reported
nausea, dizziness, and fatigue more frequently than those of placebo, effects that
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may be related to the opioid antagonism effect of the drug. The reader is referred to
the FDA website for information regarding hepatotoxicity. A recent online update
reported naltrexone to be associated with increased activity of ALT and AST in 13%
and 10%, respectively, and of GGTP in 1%–10% [169, 170]; however, naltrexone
had not been associated with hepatotoxicity [161, 171]. Based on these reports [161,
171] and the author’s experience with the use of naltrexone in patients with pruritus
from cholestasis [172], naltrexone was successfully used to treat the patient whose
history is presented in this chapter without any complications.
Alcohol Withdrawal
Patients with alcohol abuse disorder with or with liver disease can develop alcohol
withdrawal and delirium tremens (DT), a dangerous condition associated with high
mortality, in association with the discontinuation of alcohol use, and not infre-
quently during hospitalization. The clinician must be able to identify signs of alco-
hol withdrawal or DT to treat and prevent complications.
Risk factors for severe withdrawal syndrome include chronic heavy drinking and
a history of generalized seizures and delirium tremens (DT) [173]. A history of DTs
and baseline systolic blood pressure of at least 140mmHg were associated with an
increase in the risk of a severe alcohol withdrawal syndrome in an analysis of 530
studies. One thousand fty-one of 1355 patients had documented DT, 53 had sei-
zures and 251 DT. The Alcohol Withdrawal Severity Scale (PAWSS) [174] was
most useful in the prediction of a severe alcohol withdrawal syndrome when patients
were documented to have at least four individual ndings with a likelihood ratio of
174 although, with a wide condence interval (95%, 43–696, and specicity of
0.93), and a LR of 0.07 (95% CI, 0.02–0.26; sensitivity, 0.99) when there were only
up to three ndings [175].
Patients at risk for alcohol withdrawal must be treated to prevent it. The treat-
ment of alcohol withdrawal concerns the provision of a quiet, controlled environ-
ment where the patient is attended by obtaining vital signs frequently, and providing
hydration, and sedation, as needed to avoid symptoms (i.e., not a standard dose
given without examining the patient). Patients with AUD can be malnourished and
have multivitamin deciencies, including pyridoxine and thiamine. Thiamine
administration should always precede the administration of glucose to prevent
Wernicke’s encephalopathy [176]. The foundation of the treatment is benzodiaze-
pines, including chlordiazepoxide, diazepam, lorazepam, and including oxazepam,
which does not require further breakdown by the liver and hence, a decreased risk
in metabolite accumulation. The treatment must be individualized; in this regard,
anticonvulsants have been reported in association with a decrease in the symptoms
of withdrawal. In addition, combination therapy with beta blockers, to reduce hype-
rautonomic states and craving, and alpha agonists, i.e., clonidine, to decrease the
severity of withdrawal have been recommended [177].
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Delirium Tremens
The management of patients with DT includes supportive care, in the medical inten-
sive care unit, when possible, in a quiet well lit room, with documented vital signs
every 15–30min with attention to keeping the patient oriented to self, time, and
place. The use of thiamine is emphasized; a dose of 500mg intravenously, once or
twice a day, has been recommended. Pharmacotherapy with benzodiazepines intra-
venously is recommended to achieve some sedation but maintaining an arousable
state until delirium resolves, which tends to occur in approximately 3days after
initiation of therapy. In patients with uncontrolled agitation and hallucination, anti-
psychotics, e.g., haloperidol, at low doses intravenously not to exceed 20mg over
30–60 min, are useful. For patients who do not respond to sedation, ventilation
support, management with propofol is recommended. The patient must be moni-
tored in a controlled environment as the mortality associated with DT is high, and
there are side effects of medications, such as respiratory depression and hypoten-
sion, which must be identied in a timely fashion. The reader is referred to a review
and its commentaries published in 2015 [178].
Treatment ofAlcoholic Hepatitis
Malnutrition is common in patients with liver disease, and it is particularly problem-
atic in patients with alcoholic hepatitis, in whom it can be associated with bad out-
comes [179]. It is recommended that patients ingest a caloric intake of 35kcal/kg
and a daily protein intake of 1.2–1.5g/kg. In patients unable to eat, feeding through
a feeding tube is an option; it is recommended that it be placed by an experienced
operator under direct endoscopic visualization. A study that examined the effect of
tube feeding on patients who had bled from varices did not document complications
related to prior variceal bleeding and its treatment with band ligation or sclerother-
apy [180].
The benecial effect of steroids on the treatment of severe AH has been docu-
mented at least in regard to short-term survival [181–186], although not without
controversy [187]. Pentoxifylline, which inhibits tumor necrosis factor-α activity,
considered to be involved in AH’s pathogenesis, has been studied in its treatment;
however, the level of evidence does not support its use in patients with severe AH
[187]. Other medications that have been studied for AH treatment, including inix-
imab, propylthiouracil, N-acetylcysteine, silymarin, colchicine, insulin, glucagon,
oxandrolone, testosterone, and polyunsaturated lecithin are not recommended and
will not be discussed here [188].
A landmark placebo controlled study of 4weeks duration examined the use of
prednisolone, 40 mg/day, in 37 patients with alcoholic hepatitis, documented by
liver histology. Patients exhibited a broad clinical spectrum from asymptomatic to
hepatic encephalopathy, including coma and hepatic synthetic dysfunction.
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Prednisolone was associated with an increase in caloric intake. Only one of the nine
patients with hepatic encephalopathy randomized to prednisolone died versus six
patients randomized to placebo. A rapid progression to cirrhosis was documented
on liver histology during the follow-up period of 4months, with ve of the nine
patients without cirrhosis at baseline exhibiting it on follow up, and with no docu-
mented benet of prednisolone to deter progression to cirrhosis, i.e., four of the nine
patients who had been randomized to placebo did not progress to cirrhosis [189].
The benecial effect of prednisolone on short-term survival was strong and set the
stage for clinical trials on the treatment of AH.In this regard, several controlled
clinical trials have documented a benecial effect of corticosteroids in alcoholic
hepatitis, mostly in severe cases [184–186]; however, other studies have not docu-
mented a therapeutic effect of this type of drug [190]. The Maddrey discriminant
function (DF) is a tool developed from a one month study that included 55 patients
with AH treated in a randomized, double blind placebo controlled study of 40mg
per day of prednisolone for a period of 28 to 32days, from which six of the 31
patients randomized to placebo died, versus one of the 24 randomized to the drug.
From the 18 patients with hepatic encephalopathy, six (33%) from the placebo
group died, versus one of the 13 from the prednisolone group; nevertheless, the dif-
ference was not signicant. However, from a stepwise discriminant analysis, it was
determined that hepatic encephalopathy, progressive renal insufciency, prolonged
prothrombin time, and serum bilirubin greater than 10mg/dl predicted a bad out-
come. The DF, calculated as 4.6×(prothrombin time in seconds)+serum bilirubin,
when greater than 32, predicted mortality, and treatment with prednisolone improved
survival during the duration of the study [183]. A follow-up study in which 66
patients with AH were enrolled within 7days of admission to the hospital docu-
mented that two of the 35 patients (6%) treated with steroids (i.e., methylpredniso-
lone) died versus 11 of the 31 (35%) patients treated with placebo, a signicantly
different advantage favoring the steroid. Hepatic encephalopathy was again identi-
ed as a factor that changed the natural history of AH in relationship with the use of
steroids, i.e., nine of the 19 (47%) patients with hepatic encephalopathy randomized
to placebo died, as compared to one of the 14 (7%) patients randomized to methyl-
prednisolone, a signicant difference. It was concluded from this study that methyl-
prednisolone therapy decreases mortality in patients with AH complicated by
hepatic encephalopathy or with a DF greater than 32 [184].
Many years after the important studies on steroids and alcoholic hepatitis, the
early change in serum bilirubin level was reported as an important prognostic factor
in severe alcoholic hepatitis treated with prednisolone. By the use of 6month sur-
vival data in patients with AH, it was documented that an early change in serum bili-
rubin at 7days, which happened in 73% of patients, was associated with continuous
improvement in liver function and survival of 82.8%± 3.3% as compared with
23%±5.8%, p<0.0001, an analysis that opened a new pathway in the management
of patients with AH: the use of the Lille score [191].
The Lille model was developed from a group of 320 patients with AH treated
with steroids, prospectively, and validated from 118 patients. This study determined
that a score of 0.45 at 7days post initiation of treatment with steroids in patients
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with AH identied those who would not benet from the treatment, i.e., non-
responders, which comprised 40% of the patients. Statistical analysis was docu-
mented to show that the Lille score had a signicantly higher area under the receiver
operating curve (AUROC), 0.89±0.02, higher than other predicting models, i.e.,
Child–Pugh and Maddrey scores, i.e. DF; in the validation study, the AUROC also
signicantly higher for the Lille score, 0.85±0.04, higher than other scores, includ-
ing the MELD and the Glasgow scores. A Lille score greater than 0.45 was associ-
ated with a signicant decrease in the 6months survival and predicted 75% of the
deaths [192].
In combination with methylprednisolone, 40mg per day, pentoxifylline, 400mg,
was not associated with a therapeutic advantage over prednisolone alone in a study
that included 270 patients, with age that ranged from 18 to 70years, and severe AH
documented by liver histology, jaundice, exhibited 6months prior to entry into the
study, and a Maddrey DF of at least 32 followed for 6 months. Mortality was
reported as not signicantly different between the two groups, 69.9% (95% CI,
62.1%–77.7%) as compared to 69.2% (95% CI; 61.4%–76.9%), corresponding to
40 vs. 42 deaths, respectively, and no signicant difference in the incidence of hepa-
torenal syndrome [193].
Conversion of prednisone to prednisolone is required for the effect of the latter;
thus, because liver function may be impaired in patients with AH, it is preferable to
use prednisolone for the treatment of AH.In addition, in a controlled study, predni-
sone’s use to treat patients with AH was not associated with improved survival
[194]. Patients are considered candidates for prednisolone therapy when the
Maddrey DF is equal or greater than 32; it is prescribed at a dose of 40mg per day
for 28days, at which time it can be tapered off and discontinued. Intravenous meth-
ylprednisolone at a dose of 32mg per day is given to patients who cannot take medi-
cations orally. The decision to continue treatment with steroids is based on the
response according to the Lille score, which supports their discontinuation if greater
than 0.45 on day seven. A Lille score of 0.45 on day four of steroid therapy is now
proposed as sufcient to discontinue treatment. Vigilance regarding the develop-
ment of infections to which patients with alcoholic hepatitis are highly susceptible,
prior, during, and in the immediate follow-up period post treatment is necessary.
Liver transplantation is an option for patients with severe AH in whom steroid treat-
ment is not associated with improvement [195]. A study that included 26 patients
with a rst episode of severe AH not responsive to steroid therapy reported that
cumulative survival at 6months in association with early liver transplantation was
77% versus the 23% for a historical control group. The benet was notable during
the rst month post transplantation, and it was sustained over 2years of follow up.
Three patients went back to drinking alcohol post transplant, one at 720days, one
at 740days, and one at 1140days [195]. Thus, early referral to a liver transplant
center is necessary.
Continuous follow up of patients with AH and any condition in the spectrum of
ALD is fundamental to facilitate referral to addiction experts and to attend compli-
cations of liver disease that may develop over time. Patients with cirrhosis must be
screened for the presence of esophageal varices to decide on prevention of index
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