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255© The Author(s), under exclusive license to Springer-Verlag London Ltd., part
of Springer Nature 2022
N. V. Bergasa (ed.), Clinical Cases in Hepatology,
https://doi.org/10.1007/978-1-4471-4715-2_8
Chapter 8
Alcohol Induced Liver Disease
NoraV.Bergasa
A 48-year-old man was evaluated in the hepatology clinic because of an abnormal
liver prole. He had alcohol use disorder and had drunk excessively for many years,
with four, 24 ounce beer cans per day for the last 20. He did not have a history of
alcohol withdrawal. He was pleasant and a good historian. He had attempted to stop
to drink alcohol by himself, with psychotherapy, by participation in peer chaired
meetings, but nothing had worked for him. He had diabetes mellitus type 2, asthma,
hypertension, and hyperlipidemia on treatment. Physical exam was notable for a
ushed appearance and marked hepatomegaly. The liver panel revealed transami-
nases (AST and ALT) and gamma glutamyl transpeptidase (GGTP) serum activities
of 267, 168, 1407 IU/ml, respectively, and normal bilirubin and serum albumin
concentrations. Liver disease workup was notable for serum ferritin of 2729ng/ml
and transferrin saturation of 82%, and heterozygote for the C282Y mutation. A liver
biopsy revealed steatosis, cirrhosis, and iron deposition on hepatocytes. After a rap-
port was established with the hepatologist, treatment of alcohol use disorder was
initiated with naltrexone, 9days after his last drink. On naltrexone, which he took
for several months, he stopped drinking alcohol. In consultation with hematology,
the patient underwent phlebotomy to a transferrin saturation of 28%. He has
remained abstinent from alcohol for 9years; no additional phlebotomies have been
necessary.
N. V. Bergasa (*)
Department of Medicine, H+H/Metropolitan, New York, NY, USA
New York Medical College, Valhalla, NY, USA
Hepatology, H+H/Woodhull, Brooklyn, NY, USA
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Etiology
Alcohol can cause liver disease [1]. The National Institute of Alcohol Abuse and
Alcoholism (NIAAA) denes binge drinking as a drinking pattern that brings blood
alcohol concentration (BAC) levels to 0.08g/dL, which typically occurs after four
drinks for women and ve drinks for men in about 2h, with one drink having 14g
of alcohol [2]. The Substance Abuse and Mental Health Services Administration
(SAMHSA) denes binge drinking as ve or more alcoholic drinks for males or
four or more alcoholic drinks for females on the same occasion (i.e., at the same
time or within a couple of hours of each other) on at least 1day in the past month
(the month prior to when the question is being asked) [3]. SAMHSA denes heavy
alcohol use as binge drinking on ve or more days in the past month. NIAAA
denes low risk drinking for women as no more than three drinks on any single day
and no more than seven drinks per week and for men as no more than four drinks on
any single day and no more than 14 drinks per week. NIAAA research has docu-
mented that only about two in 100 people who drink within these limits have alco-
hol use disorder (AUD) [3].
Genetics
Fifteen percent of subjects who drink alcohol excessively develop cirrhosis, which
suggests that unique features, including genetics, determine the susceptibility to this
complication. Evidence in support of this idea has been provided from twin studies
that have shown twin concordances for alcoholism and its complications by zygos-
ity among male veterans from data from 15,924 male twin pairs registered in the
National Academy of Sciences-National Research Council Twin Registry from
which a prevalence for liver cirrhosis was reported as 14.2%, with case-wise twin
concordance rates for cirrhosis of 14.6 and 5.4% in monozygotic and dizygotic
twins, respectively [4].
It is reported that at low doses, most of the ingested alcohol is oxidized in the
stomach, as rst pass, by the activity of alcohol dehydrogenase (ADH) found in the
mucosa, which has been suggested to provide a barrier against systemic toxicity of
ethanol [5, 6]. In women, the ingestion of equivalent amounts of alcohol resulted in
higher serum alcohol levels than in men. Also, women were reported to have reduced
activity of gastric ADH compared to men and it was almost absent in women who
drank alcohol excessively, which may have an impact on the higher vulnerability to
develop liver disease in women versus men [7].
In the liver, alcohol is metabolized mostly by the action of ADH to form acetal-
dehyde, which is highly toxic, and by aldehyde dehydrogenase (ALDH) to acetate,
subsequently broken down to water and carbon dioxide for elimination [8]. Single
nucleotide polymorphisms in the genes that code for alcohol metabolizing enzymes
change their function, affecting the production and elimination of ALDH. The
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single nucleotide polymorphism (SNP) rs1229984 or Arg48His in ADH1B was
reported in a wide range of East Asian subjects, 19% to 91% [9] but was uncommon
in other races [10]. The SNP rs671in ALDH is associated with loss of function and
decreased enzyme activity and accumulation of acetaldehyde; this SNP was docu-
mented in 30–50% of East Asians [8]. The ADH2-2 allele is reported in association
with a decrease in the risk of alcohol dependence but with an increase in the risk of
developing alcoholic liver disease (ALD) [11, 12].
In addition, alcohol is metabolized in the liver by the enzyme cytochrome
P450IIE1 (CYP2E1), which may increase in chronic alcohol intake [13]. The rapid-
ity with which alcohol is metabolized in the liver depends on catalytic enzymes’
availability, which appears to be determined genetically.
PNPLA3 has been consistently reported in association with non alcoholic fatty
liver disease (NAFLD) and brosis in that condition [14–16]. NAFLD and ALD
have common histological features, and, likely some of the mechanisms of fat-
induced liver injury and susceptibility to the conditions are the same. In this regard,
from a meta-analysis that included ten studies exploring a role of PNPLA3in ALD,
it was documented that the odds ratio (OR) for ALD was 2.09, 95% condence
interval (CI) of 1.79–2.44 for SNP rs738409 CG in heterozygotes and 3.37 (95% CI
2.49–4.58) for GG homozygotes [17], with an OR of 2.62 (95% CI 1.73–3.97) in
association with alcohol associated cirrhosis versus OR of 8.45 (95% CI 2.52–28.37)
for steatosis. PNPLA3 codes adiponutrin, related to adipose triglyceride lipase
(ATGL/PNPLA2), a triglyceride hydrolase in adipose tissue [18, 19]. Also, through
genome-wide association studies (GWAS), the SNP rs626283 was identied in
MBOAT7 (P=1.03×10(−9)) and rs58542926 (P=7.89×10
−10
) in TM6SF2 both
as genetic risks for the development of alcohol-related cirrhosis in subjects of
European descent [20]. In addition to what has been stated above in reference to
PNPLA3, the SNP identied in association with ALD (and NAFLD) contributes to
the concentration of retinyl palmitate in the liver, suggesting a role in the steatosis
aspect of fatty liver disease alcohol and non- alcohol related [21]. TM6SF2 regulates
liver fat metabolism with opposing effects on triglyceride secretion and droplet lipid
content in hepatocytes [22]. MBOAT7 specically transfers polyunsaturated fatty
acids, including arachidonoyl-CoA to lysophosphatidylinositol, other lysophospho-
lipids
,
and associated metabolites of arachidonic acid that are involved in inamma-
tion [23–25]. The mechanisms through which these SNPs mediate vulnerability to
NAFLD or ALD are unknown; however, a role in the processing of fat and inam-
mation is plausible.
From a GWAS in patients with alcoholic hepatitis, a orid manifestation of ALD,
it was reported in abstract form, the identication of an SNP in the Solute Carrier
Family 38, Member A4 (SLC38A4) gene with OR 1.32 at a notable signicance for
this type of study; SLC38A4 is expressed mostly in the liver and is involved in
amino acid transport [26].
In human beings, the expression of class mu glutathione-S-transferase in the
liver is associated with liver disease [27]. The null phenotype GSTM1(0) was more
common in alcoholic patients than in the controls and was associated with cirrho-
sis [27].
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The role of genes including those associated with oxidative stress, endotoxin
response, cytokine activity, activation of brosis mechanisms such as CD14,
glutathione- S-transferase, interleukin 10, interleukin 1B, manganese superoxide
dismutase, nuclear factor of kappa light polypeptide gene enhancer in B cells 1,
Toll-like receptor 4, transforming growth factor β1, and tumor necrosis factor α
have been reported to play a role in alcohol induced liver disease, but, robust and
consistent information in support of their role has not been published [28].
Certain animal strains exhibit preference for or disinterest in alcohol. It was
reported from a study of microarray analysis of brain gene expression from different
mice strains that 3800 unique genes signicantly and consistently changed between
the models that differ in alcohol preference. Several functional groups that included
mitogen-activated protein kinase signaling and transcription regulation pathways
were documented as signicantly overrepresented. Those pathways may play an
important role in establishing a high voluntary alcohol drinking level in some mouse
models. Further analysis was reported to identify an alcohol preference quantitative
trait locus the candidate genes for an alcohol preference quantitative locus Arhgef12,
Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d,
Scn4b, Tcf12, Vps11, and Zfp291and four ESTs were identied in chromosome 9
[29]. This type of analysis may provide some clues to understand the genetic predis-
position to liver disease from alcohol in human beings.
Increased GABAergic neurotransmission may contribute to the desirable mood
effects of alcohol [30]. There have been inconsistent reports on the association
between SNPs in the gene that codes gamma aminobutyric acid (GABA) and alco-
hol use disorders [31, 32] but not regarding risks for liver disease from alcohol yet.
Whether genetically modied or not, obesity and cigarette smoking have been
identied in association with a risk to develop cirrhosis in patients who excessively
drink alcohol. A large study from Scotland documented that obesity and excessive
alcohol intake increase the relative rate of death from liver disease [33]. There was
a signicant interaction between obesity and excessive alcohol intake that increased
the risk of death from liver disease. This study provided data from two prospective
cohort studies from Scotland that included 9559 men over the years of 1965 and
1968 and 1970 to 1973 before the deluge of literature on NAFLD. The study docu-
mented that high mass body index (BMI) and alcohol intake were signicantly asso-
ciated with mortality due to liver disease. Individuals who drank 15 or more drinks
per week regardless of the BMI and those who were obese and drank had a greater
relative risk for liver disease versus those who were not obese or underweight who
did not drink. The adjusted relative rate for mortality from liver disease in under-
weight and normal weight with 95% condence interval (CI) for men was 3.16
(1.28 to 7.8), 7.01 (3.02 to 16.3) for overweight, and 18.9 (6.84 to 52.4) for obese
men. The relative rate for obese men who consumed fewer than 15 drinks per week
was reported as 5.3 (1.36 to 20.7) with a relative excess risk from interactions
between BMI and alcohol consumption of 5.58 (1.09 to 10.1) [33]. A study from
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California in the United States that included data from 128,934 subjects who had
undergone health examinations between 1978 and 1985 documented that cigarette
smoking was independently related to alcoholic cirrhosis. In addition, and consis-
tent with recent writings [34], coffee was associated with a decrease in the risk of
alcoholic cirrhosis, with drinking at least four cups of coffee per day being associ-
ated with one fth of the risk for cirrhosis from alcohol of that of persons who did
not drink coffee [35], an idea conrmed from another study that concluded that
coffee but not other caffeine containing beverages might “inhibit” the development
of alcoholic (and nonalcoholic) liver cirrhosis [36]. The role of coffee in society is
important [37]. One wonders what the coffee drinking habits in women who drink
alcohol excessively are. The author did not nd a publication that specically
reported the relationship between coffee and ALD; however, from a relatively large
European study, it was documented that “regular coffee but not espresso” was an
independent factor protecting from liver brosis in severely obese women. The lack
of protection is devastating for espresso drinkers; thus, no alcohol remains one’s
only option.
Women are more susceptible to ALD than men. From a study in Denmark that
included 6152 people who drank alcohol, women and men had a 35 and 27 fold
increase in mortality from cirrhosis, respectively, compared to the general popula-
tion with ve drinks per day, i.e., threshold, but not more, being associated with
death from cirrhosis. This study added information supporting the idea of the alco-
hol threshold, at which there is liver injury, and beyond which there may not be
signicant differences in liver disease [38]. From a community hospital in NewYork
City, New York, in the United States, a retrospective study that included 2002 to
2011 data revealed that patients of Hispanic ethnicity exhibited increased morbid-
ity, as evidenced by admissions to the intensive care unit and mechanical ventilation
requirements. There was a signicant association between mortality and the
Hispanic women group versus non-Hispanic patients (p= 0.0007); however, the
90day mortality for Hispanic (n=6) vs. non-Hispanic women (n=1) was not sig-
nicantly different (p=0.20). This study, limited by its retrospective nature and the
relatively small number of patients (n=165), highlights the vulnerability of women,
and of women of certain Hispanic ethnicity not only to develop ALD but to be
gravely ill from it [39]. The perennial question of the susceptibility of women to
develop ALD remains; in this regard, differences in the pharmacokinetics of alcohol
between men and women, a role of estrogen and progesterone and their different
availability in pre- and post- menopausal states, and the relationship between hor-
monal concentrations and intestinal permeability, which would increase the expo-
sure of the liver and the whole system to bacterial products, including endotoxins,
metabolism, and the physical volume where alcohol is distributed, smaller in
women than in men that increases the concentration of alcohol to which the tissues
are exposed have been proposed, and some investigated without the provision of
unequivocal results [40–42].
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Epidemiology
In the United States, the prevalence of chronic liver disease from alcohol was
reported from data extracted from Medicare claims between 1999 and 2012 among
the fee-for-service participants, comprised of 106,458 subjects as the second most
common cause, 21% in the whole group, and also, the most common cause of liver
disease in Caucasians, 38.2% [43].
A study that reported data from the National Survey on Drug Data recorded
information on drinking patterns in relation to socioeconomic and demographic
characteristics and alcohol dependence, characterized by craving, increase toler-
ance to alcohol, withdrawal symptoms, and failed attempts to quit that can result in
drinking even increased amounts [of alcohol] [3]. In this study, excessive drinking
was dened as binge drinking according to the Substance Abuse and Mental Health
Services Administration [3], heavy drinking, i.e., one drink per day on average for a
woman, and more than two drinks per day on average for a man, any alcohol con-
sumption by youth aged <21years, and by pregnant women over the 30days prior
to the questions being asked [44]. The study documented that excessive drinking
and alcohol dependence were most common among men from 18 to 24years old,
with binge drinking being the most usual pattern in individuals from families with
an annual income of at least $75,000.00. Dependence was prevalent in individuals
from families with an annual income of less than $25,000, with a prevalence of
10.5% in binge drinkers, 10.2% in excessive drinkers, and 1.3% in non-binge drink-
ers. The study results documented that most individuals who drink excessively do
not meet the criteria for alcohol dependence; however, complications that result
from intoxication happen independently from that diagnosis. Furthermore, although
ALD develops only in 15% of persons who drink alcohol excessively, the global
mortality attributed to cirrhosis from alcohol was reported as 156,900 deaths in
women, and 336,400in men in 2010, reported to represent 0.7% for women and
1.2% for men of all global deaths, respectively [45]. Indeed, studies have docu-
mented that one of the predicting variables of cirrhosis development from alcohol is
drinking patterns [46, 47]. Decompensated liver disease from alcohol is relatively
common in patients seen in the hospitals where the author works, and, notably, the
number of patients considered for liver transplantation from this type of liver dis-
ease has increased; thus, it is useful for the clinician to be aware of the relevance of
drinking patterns and their associations to refer patients for early treatment and
preventive interventions [48, 49].
A vulnerability threshold beyond which there is a substantial risk of developing
liver disease from alcohol has also been documented [50]. From the Dyonisos
Study, a reputable source on the prevalence of chronic liver disease in Northern
Italy, it was documented from 6534 participants that the threshold for the develop-
ment of cirrhosis or non-cirrhotic liver damage was the intake of more than 30g of
alcohol per day in men and women. This group consisted of 1349 persons at risk
from whom 5.5% had evidence of liver injury, with a prevalence of what the inves-
tigators dened as “pure” alcoholic cirrhosis of 0.43%, 30 from the whole cohort,
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which was 2.3% of the individuals at risk, with a ratio of nine men to one woman,
versus 44 (3.3%) of the individuals at risk, who showed persistent signs of non-
cirrhotic liver damage. After the age of 50years, the cumulative risk for developing
cirrhosis and non-cirrhotic liver damage was signicantly higher in subjects who
drank at separate times from eating food versus in those who reported drinking at
mealtimes only, consistent with a recent study [51]. Thus, 30g of alcohol per day,
especially in various forms, and daily consumption over the years, increase the risk
of developing alcohol induced liver damage as concluded from these data [50].
Along the idea of a threshold required for developing liver disease from alcohol was
the publication with data from 1976 to 1978. Subjects aged 30–79years were fol-
lowed for 12years from a group of 13,285 from whom complete clinical informa-
tion was available. Two hundred sixty-one subjects had alcohol induced liver
disease, and 124 had alcohol induced cirrhosis, which yielded an overall incidence
of 0.2% per year in men and 0.03% per year in women with a sharp and signicant
increase in the relative risk to develop liver disease from alcohol at the intake of
7–13 drinks per week in women, and 14–27in men. Notably, women were more
vulnerable than men to develop liver disease at any given amount of alcohol con-
sumed [52].
In summary, alcohol drinking patterns and a dose threshold beyond which liver
disease develops itself contribute to the pathogenesis of liver disease, which appears
to be modied by environmental factors and genetic backgrounds combined with
the local toxic effects of alcohol in the liver, at least in part.
Natural History ofAlcoholic Liver Disease
A model that addressed the rate of decompensation of liver disease from a study that
used data on clinical signs from general practices from 1987 to 2002in the United
Kingdom and that included 4537 patients with cirrhosis, 50.9% of whom had cir-
rhosis from alcohol, documented that the rate of decompensation overall was 11%
per year but, higher, 31% (95% CI: 28.8%, 33.4%), in the rst year post diagnosis
of cirrhosis, and in patients with cirrhosis from alcohol, 37.6% (95% CI: 34.1%,
41.5%) compared with 25.2% (95% CI: 22.6%, 28.2%) for those with non-alcohol-
related cirrhosis also in the rst year; the rate of decompensation after the rst year
did not vary as per etiology of liver disease, being 7.3% per year (95% CI: 6.5%,
8.2%), adjusted for age and gender for patients with liver disease from alcohol, and
5.5% per year (95% CI: 4.8%, 6.2%) for those with non-alcohol-related cirrhosis
[53]. Although the information on abstinence was not provided in the publication,
abstinence likely was one of the most important factors that improved the survival
after the rst year, as reported from studies that had access to histological data and
that assessed the progression of liver injury versus its degree [54–56]. A study of
100 consecutive patients with cirrhosis from alcohol followed from 1995 to 2000
documented that abstinence 1month post diagnosis was associated with a 7-year
survival of 72% versus 44% for the patients who did not abstain [55]. Another study
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was a retrospective review of 192 consecutive patients, 60 with compensated dis-
ease, in whom liver related mortality was documented as 13% at 5years, and 43%
in the 132 who were decompensated. Patients with severe brosis had a 10year
mortality of 45% versus no mortality in those with F0 to F2; mortality was reported
as signicantly lower in patients who abstained from alcohol than in those who did
not by the use of the log-rank test, p=0.017 [56].
An important study on the natural history of ALD from 88 patients with steatosis
from alcohol followed for a median of 10.5years from 1978 to 1985 revealed that
nine (10%), eight of whom had continued to drink at least 40units (one unit equals
8g of pure alcohol) of alcohol per week, had developed cirrhosis. An additional
seven had developed brosis, but there was no information regarding alcohol use in
these seven patients. Mixed macro and microvesicular fat (Fig.8.1), and the pres-
ence of giant mitochondria on liver histology at baseline independently predicted
disease progression; these features identied patients at high risk for disease pro-
gression. Although alcohol abstinence is the pillar of the limited therapeutic inter-
ventions to treat alcoholism and prevent ALD or its progression, the ndings provide
a rationale for proposing a liver biopsy, which should always be individualized and
strong collaboration with alcohol rehabilitation programs to facilitate abstinence.
Pharmacological therapy, including naltrexone, an opioid antagonist, and baclofen,
a gamma-aminobutyric acid (GABA)-B receptor agonist, is indicated [57]. A study
from Denmark also identied alcoholic fatty liver disease as having a higher prob-
ability of progression to cirrhosis than NAFLD.Patients who had had liver biopsies
from 1976 to 1987 were identied. Over 9years (range 0.6 to 23), 22 of 106 (20%)
patients with alcoholic fatty liver disease developed cirrhosis versus one of 109
(0.9%) over 16.7years (range 0.2–21.9) in the NAFLD group. The death rate was
Fig. 8.1 Microvesicular
(top arrow) and
macrovesicular steatosis
(bottom arrow) in a patient
with alcohol induced liver
disease (Hematoxylin and
Eosin stain, 40X)
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also higher in patients with ALD than in those with NAFLD [58]. Thus, ALD from
the steatosis stage to the cirrhotic stage progresses faster than steatosis from nonal-
coholic disease; however, there is no mention of the report of abstinence versus
continuous alcohol intake over the follow-up period in that study. Another publica-
tion, from a retrospective review conducted in Iceland and that included patients
who had had a liver biopsy from 1984 to 2009, identied 94 patients with steatosis
from alcohol with a median of 20year survival similar to the median survival of
24years for patients with NAFLD. Seven percent of the group with NAFLD devel-
oped cirrhosis, signicantly different from the 20% of patients with steatosis from
alcohol; in addition, in 36% of patients in the latter group, the cause of death was
liver related, versus cardiovascular disease in the NAFLD group. As previously
reported, the degree of brosis, i.e., more, not less, was associated with risk of pro-
gression [59]. These data suggest that fat from alcohol induced liver injury is associ-
ated with a worse prognosis than fat from NAFLD.
Portal pressure has been proposed as the most important prognostic variable in
cirrhosis; however, there was a lack of prognostic usefulness in the hepatic venous
pressures. Hemodynamic measures were documented in a group of 87 patients with
cirrhosis from alcohol prospectively studied from 1991 to 1993 at an index hospital
admission and followed for a mean of 35months (range of 1–76months), during
which 56 (64%) patients died at 5years. Only age and bilirubin were signicantly
different from those who lived. Again, on Cox regression analysis, age and mea-
sures of liver function, e.g., Child–Pugh score, were the only prognostic factors for
mortality [60]. Of much interest, and along the same line of interpretation from the
data provided and as previously stated, the most signicant predictive measure of
survival at 5years reported from a group of 122 hospitalized patients with cirrhosis
and excessive intake of alcohol was the Child–Pugh class, with a 66%, 50%, and
25% for class A, B, and C, respectively [61]. In addition, the absence of alcoholic
hepatitis, documented by histology, and continuous alcohol intake were signi-
cantly associated with increased risk ratios of death, the former results interpreted
to suggest that the absence of a reversible condition, i.e., alcoholic hepatitis, was a
poor prognostic factor, or, conversely, that the presence of alcoholic hepatitis, by
virtue of its reversibility, was associated with a better prognosis than its absence [61].
The importance of relatively increased age and continuous alcohol use as
independent predictors of a fatal outcome was supported by a study that followed
100 consecutively admitted patients with cirrhosis from alcohol for 15years
until death or year 2000. The group’s mean age was 58years, 35% of patients
were women, 67 of whom had ascites, and 34% variceal bleeding on admission.
Seventy-one percent and 90% died at 5 and 15years, respectively, with bleeding
and liver failure being the two most common causes of death [62]; however,
Child–Pugh class was not identied as a prognostic factor for a bad outcome
[62]. Furthermore, from an analysis that pooled 118 studies of the natural history
of cirrhosis and that included 109 (46%) of patients with cirrhosis from alcohol,
it was reported that alcohol as the etiology of cirrhosis was found independently
predictive of survival in only one of the 48 studies (2%) in which it was included
as a variable. Child–Pugh score, which was studied in 67 studies, was a predictor
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