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Clinical manifestations and diagnosis of alcohol-associated fatty

liver disease and cirrhosis
AUTHOR: Scott L Friedman, MD
SECTION EDITOR: Bruce A Runyon, MD, FAASLD
DEPUTY EDITOR: Kristen M Robson, MD, MBA, FACG

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2024.

This topic last updated: May 01, 2023.

INTRODUCTION

Alcohol-associated liver disease (ALD) includes several liver disorders, including alcoholic hepatitis, alcohol-
associated steatosis, alcohol-associated steatohepatitis, and alcohol-associated cirrhosis. Patients with excessive
alcohol intake (eg, ≥30 grams per day [one standard drink contains 14 grams of alcohol ( figure 1)]) are at
increased risk of cirrhosis, although many individuals will not develop cirrhosis despite alcohol consumption.
Unfortunately, among those who do develop liver disease, symptoms have often presented only after severe,
life-threatening liver disease has already developed.

This topic will review the clinical manifestations and diagnosis of alcohol-associated steatohepatitis and alcohol-
associated cirrhosis. The pathophysiology and management of ALD are discussed separately. (See
"Pathogenesis of alcohol-associated liver disease" and "Management of alcohol-associated steatosis and
alcohol-associated cirrhosis".)

Issues related to liver transplantation for patients with ALD are presented separately. (See "Liver transplantation
for alcohol-associated liver disease".)

Treatment of alcohol use disorder is presented separately. (See "Alcohol use disorder: Treatment overview".)

The clinical manifestations, diagnosis, and management of alcoholic hepatitis are presented separately. (See
"Alcoholic hepatitis: Clinical manifestations and diagnosis" and "Management and prognosis of alcoholic
hepatitis".)

EPIDEMIOLOGY

Prevalence — Alcohol use disorder is common worldwide, with an estimated lifetime prevalence of 18 percent
among adults in the United States. In a large study using data from the National Health and Nutrition
Examination Survey, the prevalence of alcohol-associated fatty liver disease among adults in the United States
was 4 percent [1]. Mortality related to alcohol-associated liver disease (ALD) in the United States was estimated
at 5.5 per 100,000 persons in 2012 [2,3]. (See "Risky drinking and alcohol use disorder: Epidemiology, clinical
features, adverse consequences, screening, and assessment".)
Rates of ALD are higher in areas with greater per capita alcohol consumption compared with areas with low
levels of consumption. Areas with high rates of alcohol consumption and ALD include Eastern Europe, Southern
Europe, and the United Kingdom [4]. Environmental factors such as colder climate and fewer sunlight hours
have been linked to increased alcohol consumption [5]. Alarm over the rising impact of ALD has provoked
national response in the United Kingdom to address this crisis [6], in addition to concern from the World Health
Organization [7] and international thought leaders [8]. Moreover, alcohol consumption in late adolescence
increases the risk of severe liver disease later in life [9].

The coronavirus disease 2019 (COVID-19) pandemic has been associated with a marked increase in
hospitalizations related to alcohol-associated liver disease [10]. While underlying reasons have not been fully
characterized, this trend has been attributed to disruption of services for alcohol rehabilitation, in addition to
economic and psychologic stress related to the pandemic. Issues related to liver disease in adults with COVID-19
are discussed separately. (See "COVID-19: Issues related to liver disease in adults".)

Risk factors — The primary risk factor for alcohol-associated liver disease is alcohol consumption above the
threshold that puts an individual at risk for health consequences (ie, risky alcohol use). The thresholds for
alcohol consumption vary based on patient age, patient biologic sex, and drinking pattern [11]. This is discussed
in more detail separately. (See "Risky drinking and alcohol use disorder: Epidemiology, clinical features, adverse
consequences, screening, and assessment", section on 'Terminology'.)

However, many individuals whose alcohol consumption exceeds these thresholds do not develop liver disease.
Other factors associated with increased risk of alcohol-associated liver injury have included [12-14]:

● Tobacco use [15]

● Higher body mass index
● Coexisting conditions (eg, chronic viral hepatitis, nonalcohol-associated fatty liver disease [NAFLD])

Metabolic and lifestyle factors have been linked to risk of alcohol-associated cirrhosis. In a case-control study
including 1293 patients with alcohol-associated cirrhosis and 754 individuals with similar lifetime alcohol
exposure but without liver disease, patients with cirrhosis were more likely to have diabetes (odds ratio [OR]
3.09, 95% CI 2.02-4.72) and higher premorbid body mass index (OR 1.06, 95% CI 1.03-1.09) [16]. On multivariate
analysis, patients with cirrhosis were less likely to be coffee drinkers or tea drinkers (OR 0.64, 95% CI 0.50-0.83
and OR 0.70, 95% CI 0.51-0.95, respectively). If these findings are confirmed, lifestyle interventions such as
weight loss may be used to reduce the risk of alcohol-associated cirrhosis (see "Benefits and risks of caffeine
and caffeinated beverages", section on 'Cirrhosis'). The pathogenesis of ALD including genetic factors is
discussed separately. (See "Pathogenesis of alcohol-associated liver disease".)

NATURAL HISTORY

The spectrum of ALD ranges from alcohol-associated fatty liver or steatosis to alcohol-associated
steatohepatitis, and eventually to alcohol-associated cirrhosis that may lead to hepatocellular carcinoma.
Hepatic steatosis is seen in approximately 90 percent of heavy drinkers and is typically macrovesicular [17-19]. It
may be seen within two weeks of regular alcohol ingestion and resolves rapidly with abstinence [20,21]. In a
study of four patients with normal baseline liver biopsies, ingestion of 98 to 138 grams of alcohol per day
resulted in moderate to marked steatosis in all four after 16 to 18 days [20]. It has been estimated that a third of
patients with steatosis will develop hepatic inflammation (steatohepatitis) if they continue to drink [22]. ALD is
increasing in many parts of Asia [23].
Once steatohepatitis has developed, the risk of cirrhosis is increased compared with simple steatosis. In one
study, over a five-year period, cirrhosis developed in 16 percent of patients with steatohepatitis and in 7 percent
of patients with simple steatosis [24]. Higher rates of progression to cirrhosis are seen among patients with
steatohepatitis who continue to drink or who present with symptomatic alcoholic hepatitis (up to 50 percent for
both groups) [25-28]. Overall, it is estimated that 8 to 20 percent of patients with steatosis will eventually
progress to cirrhosis [29].

Hepatic decompensation is common among patients with alcohol-associated cirrhosis. In a population-based

study from Denmark that included 446 patients with alcohol-associated cirrhosis, the risk of complications
(ascites development, variceal bleeding, or hepatic encephalopathy) was approximately 25 percent after one
year and 50 percent after five years [30]. Once hepatic decompensation develops, the expected five-year
transplant-free survival rate is 60 percent for those who stop drinking alcohol and 30 percent for those who
continue to drink alcohol [25,31-33].

CLINICAL MANIFESTATIONS

The clinical manifestations of ALD depend on the severity of disease. Patients with simple steatosis are often
asymptomatic, patients with alcoholic hepatitis typically present with jaundice, and patients who have
developed cirrhosis may have peripheral stigmata of liver disease or signs of hepatic decompensation [34]. (See
"Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

The clinical manifestations in patients with alcoholic hepatitis are reviewed separately. (See "Alcoholic hepatitis:
Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Signs and symptoms — Patients with alcohol-associated fatty liver are typically asymptomatic [35]. Patients
who have developed cirrhosis may report jaundice, weakness, peripheral edema, abdominal distension, or
symptoms of gastrointestinal bleeding, such as hematemesis or melena. Patients with hepatic encephalopathy
may note disturbances in their sleep pattern and confusion. (See "Cirrhosis in adults: Etiologies, clinical
manifestations, and diagnosis", section on 'Clinical manifestations' and "Cirrhosis in adults: Overview of
complications, general management, and prognosis", section on 'Major complications' and "Hepatic
encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Formal health-related, quality-of-life metrics in patients with all forms of liver disease, including alcohol-
associated liver disease, are increasingly being employed [36].

Physical examination findings — Physical examination findings in patients with ALD range from a normal
physical examination to evidence of cirrhosis with hepatic decompensation ( table 1). Patients with steatosis
may have a normal examination or hepatomegaly. Patients who have developed cirrhosis may have stigmata of
chronic liver disease (eg, spider angiomata, palmar erythema, gynecomastia). With hepatic decompensation,
patients may develop ascites, peripheral edema, or hepatic encephalopathy. (See "Cirrhosis in adults: Etiologies,
clinical manifestations, and diagnosis", section on 'Physical examination' and "Cirrhosis in adults: Overview of
complications, general management, and prognosis", section on 'Major complications'.)

Patients with ALD often have coexisting dysfunction in other organs and may have signs of cardiomyopathy,
neuropathies, pancreatic dysfunction, and skeletal muscle wasting. (See "Alcohol-induced cardiomyopathy",
section on 'Clinical manifestations' and "Overview of the chronic neurologic complications of alcohol", section on
'Clinical features' and "Chronic pancreatitis: Clinical manifestations and diagnosis in adults", section on 'Clinical
manifestations'.)
Laboratory tests — There are several characteristic laboratory abnormalities in patients with ALD, but none are
diagnostic ( table 2). The classic finding is moderately elevated aminotransferases, with an aspartate
aminotransferase (AST) to alanine aminotransferase (ALT) ratio >1 (and often >2).

Liver test abnormalities — Serum aminotransferase levels may be normal or moderately elevated in the
setting of alcohol-associated fatty liver disease and alcohol-associated cirrhosis [37,38]. The AST elevation is
usually less than eight times the upper limit of normal, and the ALT elevation is typically less than five times the
upper limit of normal. The degree of elevation does not correlate with the severity of the underlying liver
disease [35].

Unlike other forms of liver disease in which the serum ALT level often is higher than the serum AST level, the
most common pattern of liver biochemical test abnormalities in ALD is a disproportionate elevation of the AST
compared with the ALT, resulting in a ratio greater than one [37-41]. As an example, in a study that included 38
patients with ALD, the mean AST was 92 international units/L, and the ALT was 80 international units/L (AST to
ALT ratio of 1.2) [42]. The relatively lower elevation of serum ALT has been ascribed in part to hepatic deficiency
of pyridoxal 5'-phosphate in patients with alcohol use disorder, which is a cofactor for the enzymatic activity of
ALT [41]. According to this hypothesis, the altered ratio reflects a failure to appropriately increase the ALT, rather
than a disproportionate elevation in AST.

An AST to ALT ratio >1 is occasionally seen in patients with nonalcoholic steatohepatitis (NASH) and is frequently
seen in patients who have developed nonalcohol-associated cirrhosis. However, if the ratio is greater than two,
the transaminase elevations are likely due to ALD since values greater than two are rarely seen in other forms of
liver disease [39,40]. In a study of 271 patients with biopsy-confirmed liver disorders, more than 90 percent of
the patients whose AST to ALT ratio was ≥2 had ALD [43]. The percentage increased to greater than 96 percent
when the ratio was ≥3. (See "Approach to the patient with abnormal liver tests", section on 'Laboratory tests'.)

The gamma-glutamyl transpeptidase (GGT) is often elevated in patients with ALD [38,44]. In a study that
included 123 patients with alcohol use disorder, all of the patients with liver disease had elevations of the GGT
approximately 8 to 10 times the upper limit of normal [44]. The GGT elevations persisted after eight weeks of
abstinence. However, GGT elevations are not specific for ALD. For example, elevated GGT levels may be seen in
patients with biliary or pancreatic disease and in patients taking certain medications such as barbiturates and
phenytoin. (See "Enzymatic measures of hepatic cholestasis (alkaline phosphatase, 5'-nucleotidase, gamma-
glutamyl transpeptidase)", section on 'Gamma-glutamyl transpeptidase'.)

Elevated bilirubin levels are frequently seen in patients with decompensated cirrhosis from any cause, including
ALD. Elevation of the bilirubin in a patient who does not have cirrhosis should raise concern for alcoholic
hepatitis. Patients who are malnourished or who have cirrhosis may have low albumin levels. (See "Cirrhosis in
adults: Etiologies, clinical manifestations, and diagnosis", section on 'Laboratory findings' and "Alcoholic
hepatitis: Clinical manifestations and diagnosis", section on 'Laboratory tests' and "Tests of the liver's
biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)", section on 'Albumin'.)

Hematologic abnormalities — Hematologic findings in patients with ALD may include thrombocytopenia,
anemia, an elevated mean corpuscular volume (MCV), a decreased lymphocyte count, an elevated erythrocyte
sedimentation rate (ESR), and an elevated international normalized ratio (INR) [37,45]. Macrocytosis suggests
longstanding disease and may result from vitamin B12 or folate deficiency, alcohol toxicity, or increased lipid
deposition in red cell membranes. Similarly, thrombocytopenia may result from primary bone marrow
hypoplasia (which can be due to alcohol and is usually brief) or splenic sequestration (due to portal
hypertension and an enlarged spleen). (See "Hematologic complications of alcohol use".)
In one study that included 40 patients with alcohol-associated liver disease, the following mean laboratory test
results were noted [45]:

● Hemoglobin and hematocrit: 12 g/dL and 33.7 percent, respectively

● MCV: 91.6 fL
● Lymphocyte percentage: 24.8 percent
● ESR: 25.9
● INR: 1.6

Other abnormalities — Additional laboratory findings that may be seen in patients who have progressed to
cirrhosis include hyponatremia and an elevated creatinine in patients with hepatorenal syndrome. (See
"Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Laboratory findings' and
"Hepatorenal syndrome", section on 'Clinical presentation'.)

Radiographic imaging — Transabdominal ultrasound, abdominal computed tomography, and abdominal

magnetic resonance imaging may show signs of hepatic steatosis or cirrhosis in patients with ALD. (See
'Imaging studies' below.)

DIAGNOSIS

Alcohol-associated liver disease may be suspected in a patient with a compatible history who has elevated
serum aminotransferases, a suggestion of fatty liver on imaging tests, or is found to have steatosis on liver
biopsy. Liver tests are generally normal or modestly elevated, and jaundice is unusual. The diagnosis is
established after excluding other causes of fatty liver or cirrhosis [46,47]. (See 'When to consider alcohol-
associated liver disease' below.)

Our approach to the diagnosis of alcohol-associated liver disease is generally consistent with society guidelines
[12,48,49]. (See 'Society guideline links' below.)

The evaluation includes:

● Obtaining a very detailed history to quantify alcohol use and drinking patterns and to identify other
potential sources of hepatic injury (see 'History' below).

● Performing a physical examination to identify stigmata of chronic liver disease (see 'Physical examination'
below).

● Obtaining laboratory tests to look for signs of hepatic inflammation and to assess hepatic synthetic
function, including (see 'Standard laboratory evaluation' below):

• Liver blood tests – Serum aminotransferases, bilirubin, alkaline phosphatase, gamma-glutamyl

transaminase
• Complete blood count
• Serum albumin level
• Coagulation studies – Prothrombin time, international normalized ratio (INR)

● Obtaining laboratory tests to identify other causes of chronic hepatic injury, including (see 'Tests for other
causes of liver disease' below):

• Hepatitis B surface antigen, anti-hepatitis B core antibody

 • Antibodies to hepatitis C virus (HCV)
• Serum ferritin and transferrin saturation for hemochromatosis
• Total IgG or gamma-globulin level, antinuclear antibody, anti-smooth muscle antibody, anti-liver/kidney
microsomal-1 (anti-LKM-1) antibodies for autoimmune hepatitis

Clinical and laboratory features are often adequate for establishing the diagnosis of ALD in a patient with a
history of excessive alcohol use, provided the patient does not have risk factors for other causes of liver disease
and testing for other common causes of liver disease is negative. In a study of patients with chronically elevated
liver biochemical tests, the sensitivity and specificity of clinical findings for diagnosing ALD were 91 and 97
percent, respectively, when liver biopsy was used as the gold standard [50].

Liver imaging may provide evidence of hepatic steatosis or cirrhosis, but it is not able to differentiate ALD from
other causes. Ultrasound is always indicated to confirm that the liver is homogeneous and to exclude other
causes of abnormal liver tests (eg, biliary obstruction, hepatic mass). More detailed liver imaging (eg, computed
tomography [CT] or magnetic resonance imaging [MRI]) is obtained for patients with suspected cirrhosis or
ultrasound evidence of biliary tract obstruction (eg, jaundice, elevation of liver tests in a cholestatic pattern).
(See 'Imaging studies' below.)

A liver biopsy may be required if the diagnosis remains uncertain following a noninvasive evaluation. In
addition, it can establish the severity of liver disease. (See 'Liver biopsy' below.)

There is increasing interest in clinical trials for the disease, which has generated more rigorous, standardized
criteria for establishing a diagnosis of alcoholic hepatitis, which should allow more consistent inclusion and
characterization of patients in therapeutic trials [51,52]. These include: onset of jaundice within prior eight
weeks; ongoing consumption of >40 (female) or 60 (male) grams alcohol per day for six months or more, with
less than 60 days of abstinence before the onset of jaundice; aspartate aminotransferase >50, aspartate
aminotransferase/alanine aminotransferase >1.5-fold, and both values <400 International Units/L; serum
bilirubin (total) >3 mg/dL; and liver biopsy confirmation in patients with confounding factors. In addition,
stratification should be based on severity as assessed by Maddrey discriminant function >32, assuming a control
prothrombin time of 12 seconds and Model for end stage liver disease (MELD) score >20. In addition, the
authors have defined common data elements and end points to be assessed in an effort to further standardize
clinical trial design for experimental therapies [51].

When to consider alcohol-associated liver disease — Alcohol-associated liver disease should be suspected in
patients with a history of significant alcohol consumption who present with:

● Abnormal aminotransferases (particularly if the aspartate aminotransferase [AST] is greater than the
alanine aminotransferase [ALT])
● Hepatomegaly
● Radiographic imaging suggesting hepatic steatosis or fibrosis/cirrhosis
● A liver biopsy showing steatosis or cirrhosis

Several definitions have been proposed for what constitutes significant alcohol consumption [53]. We define
significant alcohol consumption as an average consumption of >210 grams of alcohol per week in men or >140
grams of alcohol per week in women over at least a two-year period. This is generally consistent with guidelines
from the National Institute on Alcohol Abuse and Alcoholism and the United Kingdom [54,55].

A standard drink in the United States (12 oz [360 mL] of beer, 5 oz [150 mL] of wine, 1.5 oz [45 mL] of 80-proof
spirits) contains approximately 14 grams of alcohol ( figure 1), so the limits above roughly translate to >15
drinks per week for men and >10 drinks per week for women.
History — The history should include questioning to assess a patient's alcohol use and to elicit risk factors for
other causes of liver disease. Obtaining an accurate alcohol use history in patients with suspected alcohol-
associated liver disease can be difficult since many patients do not readily admit to heavy alcohol use. In some
cases, speaking with the patient's family or friends may help in obtaining a more accurate history. Patients
should be asked about their pattern of alcohol use, the type of alcohol consumed, and the amount of alcohol
ingested. Several screening tools exist to identify patients with alcohol use disorder. (See "Screening for
unhealthy use of alcohol and other drugs in primary care", section on 'Screening tests' and 'Differential
diagnosis' below and "Approach to the patient with abnormal liver tests".)

To identify risk factors for other causes of liver disease, the patient should also be carefully questioned about
medication use (including herbal supplements and over-the-counter medications), possible parenteral
exposures to viral hepatitis (including transfusions, intravenous and intranasal drug use, tattoos, and sexual
activity), occupational exposures to hepatotoxins, family history of liver disease, and whether the patient has a
history of diseases that may be associated with liver disease (such as the metabolic syndrome, celiac disease, or
autoimmune disorders). (See "Approach to the patient with abnormal liver tests", section on 'History'.)

Physical examination — Patients with suspected alcohol-associated liver disease (ALD) should be examined for
hepatomegaly and signs of chronic liver disease such as spider angiomata, ascites, splenomegaly, and
gynecomastia. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Physical
examination'.)

Physical findings in patients with ALD may vary from normal to evidence of cirrhosis or hepatic decompensation
( table 1). Patients with ALD may also have extrahepatic manifestations of alcohol use disorder such as
cardiomyopathy, neuropathies, pancreatitis, and skeletal muscle wasting. As a result, a thorough physical
examination should be carried out to identify problems outside of the liver. (See "Overview of the risks and
benefits of alcohol consumption", section on 'Alcohol effect on specific conditions' and "Alcohol-induced
cardiomyopathy" and "Overview of the chronic neurologic complications of alcohol".)

Laboratory tests — Laboratory testing in patients with suspected ALD includes testing for evidence of hepatitis
and liver synthetic dysfunction. In addition, patients should be tested for other causes of liver disease that may
coexist with ALD or may offer alternative explanations for a patient's liver disease. There are several
characteristic laboratory abnormalities in patients with ALD, but none are diagnostic ( table 2). (See
'Laboratory tests' above.)

Standard laboratory evaluation — Laboratory tests that should be obtained in patients with suspected ALD
include liver tests (serum aminotransferases, bilirubin, alkaline phosphatase, gamma-glutamyl transaminase), a
complete blood count, serum albumin, and coagulation studies (prothrombin time, INR). In addition, patients
with ascites should undergo paracentesis to confirm that the ascites is due to portal hypertension (serum-to-
ascites albumin gradient ≥1.1 g/dL [11 g/L]). (See 'Laboratory tests' above and "Evaluation of adults with ascites",
section on 'Determining the cause of the ascites'.)

There are no laboratory tests that reliably differentiate ALD from other causes of liver disease. However, an AST
to ALT ratio >2 is highly suggestive of ALD. (See 'Liver test abnormalities' above.)

Tests for other causes of liver disease — Patients with suspected ALD should also be tested for other causes
of hepatitis that may be responsible for the patients liver disease or may coexist with ALD. The combination of
alcohol use with other liver diseases such as hereditary hemochromatosis, nonalcoholic steatohepatitis, chronic
viral hepatitis, and autoimmune liver disease can lead to an accelerated rate of fibrosis compared with the
disorders in isolation [56].
In order to rule out other common causes of chronic hepatitis, patients should be tested for the following:

● Hepatitis B surface antigen, anti-hepatitis B core antibody

● Antibodies to hepatitis C virus
● Serum ferritin and transferrin saturation for hemochromatosis
● Total IgG or gamma-globulin level, antinuclear antibody, anti-smooth muscle antibody, anti-liver/kidney
microsomal-1 (anti-LKM-1) antibodies for autoimmune hepatitis

Ferritin production and the plasma ferritin concentration are increased in the absence of iron overload in certain
liver diseases, including ALD and acute or subacute hepatitis (from any cause) [57]. As a result, in patients with
acute or subacute hepatitis testing should be deferred until the patient has recovered from the acute episode.
In addition, the serum transferrin saturation in ALD may reach or exceed 60 percent, perhaps because alcohol
suppresses liver transferrin synthesis. As a result, if ferritin levels or the transferrin saturation are high,
additional testing for hemochromatosis is indicated. (See "Approach to the patient with suspected iron
overload", section on 'Diagnosis' and "Approach to the patient with suspected iron overload".)

Additional testing will depend upon the patient's symptoms and risk factors for other causes of liver disease and
may include testing for (see "Approach to the patient with abnormal liver tests"):

● Nonalcoholic fatty liver disease (see "Clinical features and diagnosis of metabolic dysfunction-associated
steatotic liver disease (nonalcoholic fatty liver disease) in adults")
● Wilson disease (see "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on
'When to suspect Wilson disease')
● Alpha-1 antitrypsin deficiency (see "Clinical manifestations, diagnosis, and natural history of alpha-1
antitrypsin deficiency", section on 'Evaluation and diagnosis')
● Hyperthyroidism (see "Diagnosis of hyperthyroidism", section on 'Clinical manifestations')
● Celiac disease (see "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults",
section on 'Clinical manifestations')
● Primary biliary cholangitis (see "Clinical manifestations, diagnosis, and prognosis of primary biliary
cholangitis", section on 'Clinical manifestations')
● Primary sclerosing cholangitis (see "Primary sclerosing cholangitis in adults: Clinical manifestations and
diagnosis", section on 'Clinical manifestations')

In some cases, if the clinical picture is only partially consistent with ALD (eg, liver disease in a patients with
moderate alcohol use or an AST to ALT ratio <1), but no alternative causes are identified noninvasively, a liver
biopsy may be required. (See 'Liver biopsy' below.)

Imaging studies — Imaging studies can be used to assess for hepatic parenchymal changes, but they cannot
confirm that the changes are the result of ALD. Ultrasound, CT, and MRI can be used to diagnose fatty change,
cirrhosis, or neoplastic diseases of the liver. They can also rule out obstructive biliary pathology.

Ultrasound — Ultrasound can detect hepatic steatosis, but will miss many patients with <30 percent steatosis
[58,59]. Ultrasonography in patients with fatty liver may reveal a liver with a hyperechoic texture [58-60]. In
patients with fibrosis, the ultrasound may reveal a coarse echo pattern. If cirrhosis has developed, nodules may
be seen, causing an irregular outline of the liver surface.

Studies of ultrasound for evaluation of hepatic steatosis and fibrosis have found the following:

● In a study of 235 patients with suspected liver disease, the sensitivity of a hyperechoic pattern on
ultrasound for hepatic steatosis was 64 percent, with a specificity of 97 percent [58]. Among patients with
 ≥30 percent steatosis, the sensitivity was 91 percent, with a specificity of 93 percent.

● In a study that included 35 patients with significant hepatic fibrosis (advanced fibrosis or cirrhosis), the
sensitivity of ultrasound for significant fibrosis was 57 percent [59]. Among patients with established
cirrhosis, the sensitivity was 71 percent. The overall specificity was 88 percent.

Computed tomography — Hepatic steatosis is readily detected by CT scan [61]. Liver attenuation in patients
with hepatic steatosis is lower than that seen in the spleen. On non-contrast-enhanced images, the attenuation
value of normal liver is between 45 and 65 HU and is typically 8 HU higher than that of the spleen. However, in
patients with hepatic steatosis, the attenuation value of the liver is typically 10 to 25 HU less than the spleen.
With severe steatosis, liver attenuation may be less than unenhanced hepatic venous structures. The relative
densities of the liver and spleen are highly variable on contrast-enhanced CT, so the diagnosis of steatosis is
based on non-contrast-enhanced images.

CT findings in patients with cirrhosis may include atrophy of the right lobe of the liver, hypertrophy of the
caudate lobe, hypertrophy of the lateral segment of the left lobe, parenchymal nodularity, attenuation of
hepatic vasculature, splenomegaly, venous collaterals, and ascites [62]. In some cases, the liver may be diffusely
atrophic or hepatomegaly may be seen.

In a study that included 35 patients with cirrhosis (20 patients), alcoholic hepatitis alone (one patient), or hepatic
steatosis (14 patients) along with 10 control patients, CT scan had a sensitivity for cirrhosis of 78 percent and for
fatty liver of 81 percent. There was only one control patient with false-positive results (specificity of 90 percent).

Magnetic resonance imaging and spectroscopy — Gradient echo magnetic resonance (MR) pulse sequences
are sensitive for detecting hepatic steatosis [61]. Water and fat are imaged in and out of phase. With in-phase
imaging, the signal intensities are additive, whereas when out-of-phase, the signal intensities cancel each other
out. If there is a significant amount of intracellular fat, the signal intensity on the out-of-phase images will be
lower than that seen on the in-phase images. In a study of 33 patients with diabetes (and thus at risk for
nonalcohol-associated fatty liver disease), the sensitivity of in-phase and out-of-phase MRI for hepatic steatosis
was 95 percent, with a specificity of 98 percent [63]. On T1-weighted and T2-weighted images, focal hepatic
steatosis may result in higher signal intensity compared with normal liver.

Regenerative nodules in patients with cirrhosis may appear hypointense, isointense, or hyperintense related to
the background liver on T1-weighted images [62]. On T2-weighted images, the signal intensity of the
regenerative nodules does not increase (unlike hepatocellular carcinoma). The nodules on T2-weighted images
are often hypointense or isointense.

On MRI, specific features that are suggestive of alcohol-associated cirrhosis versus cirrhosis from viral hepatitis
include a higher volume index of the caudate lobe, smaller size of regenerative nodules of the liver, and more
frequent visualization of the right posterior hepatic notch [64]. In a study that included 23 patients with chronic
hepatitis, diffusion-weighted MRI had a sensitivity for detecting advanced fibrosis or cirrhosis of 83 percent,
with a specificity of 80 percent.

MR spectroscopy is a specialized MRI sequence that allows assessment of the chemical composition of tissue.
Proton MR spectroscopy can be used to quantify lipid content [65]. It has been used to estimate hepatic fat
volume fractions and correlates well with histology [66]. However, the technique is not widely available.

An experimental tool for diagnosing ALD is hepatic phosphorus 31 MR spectroscopy, which can calculate hepatic
energy metabolism and phospholipid membrane metabolism [67]. Patients with cirrhosis from alcohol have
lower phosphodiester to adenosine triphosphate (ATP) ratios than patients with cirrhosis from other causes [68].
 Other noninvasive methods to detect fibrosis — Other methods for the detection of hepatic fibrosis,
including transient elastography and magnetic resonance elastography, are discussed in detail elsewhere. (See
"Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)

Liver biopsy

Patients who may need a liver biopsy — Clinical and laboratory features are often adequate for establishing
the diagnosis of ALD in a patient with a history of significant alcohol use, provided the patient does not have risk
factors for other causes of liver disease and testing for other common causes of hepatitis is negative. However,
a liver biopsy may be required if the diagnosis remains uncertain following a noninvasive evaluation. In
addition, it can establish the severity of liver disease.

The decision to perform a biopsy should consider the confidence of the clinical diagnosis and the role that the
biopsy findings would have in guiding therapeutic options. As a general rule, a biopsy may be indicated in:

● Any patient with serum aminotransferase elevations that persist for more than six months without a clear
explanation, even if the patient is asymptomatic.

● Patients who have elevated aminotransferases and evidence of clinically significant hepatic dysfunction
(eg, abnormal prothrombin time, hypoalbuminemia). If a coagulopathy is present, transjugular biopsy is
usually safer than percutaneous biopsy. (See "Transjugular liver biopsy".)

● Patients in whom the diagnosis of ALD is uncertain based on clinical and laboratory findings.

● Patients who may have more than one cause of liver disease (such as alcohol and hepatitis C virus) in
whom a liver biopsy may help determine the relative contribution of these factors ( picture 1).

● Patients in whom a more detailed understanding of prognosis is desired. (See "Management of alcohol-
associated steatosis and alcohol-associated cirrhosis", section on 'Prognosis'.)

Histologic findings — Early changes in patients with ALD seen under the electron microscope include
accumulation of membrane-bound large droplet (macrovesicular) steatosis, proliferation of smooth
endoplasmic reticulum, and gradual distortion of mitochondria [69]. This is most often seen in the pericentral
region of hepatic lobules (zone 3) [70]. Fat accumulation can be seen easily by light microscopy; inflammatory
changes are minimal at this stage apart from occasional lipogranulomata in pericentral zones [71].

Fat in ALD is typically macrovesicular and composed of neutral triglycerides. However, small droplets of
triglycerides may resemble microvesicular fat (and indeed are sometimes referred to as such on pathology
reports) but are not the same as the lipid droplets that form microvesicular fat in other disorders such as acute
fatty liver of pregnancy ( picture 2), tetracycline toxicity, and Reye's syndrome. Microvesicular fat in these
conditions (which is composed of free fatty acids that are hepatotoxic) can only be detected by special stains
and not on standard light microscopy.

Steatosis may progress to steatohepatitis. As with steatosis, inflammation is typically first seen in zone 3. As the
disease progresses, the histologic changes may extend to the portal tracts. The findings may vary among
patients with regard to their extent and severity. The presence of neutrophils is a hallmark of alcohol-associated
steatohepatitis and is unusual in chronic viral hepatitis. Their role in pathogenesis is discussed separately. (See
"Pathogenesis of alcohol-associated liver disease".)

Mallory-Denk bodies (previously called Mallory bodies or Mallory's hyaline) are eosinophilic accumulations of
intracellular protein aggregates within the cytoplasm of hepatocytes ( picture 4B). They represent
condensations of intracellular "intermediate filaments" or cytokeratins that are normal components of the
hepatocyte cytoskeleton [72]. The mechanisms underlying Mallory-Denk body formation in ALD are unclear.
Furthermore, they are not specific for alcohol-associated steatohepatitis and can be seen in nonalcoholic
steatohepatitis (NASH) [73], Indian childhood cirrhosis (thought in part to be due to high copper intake),
starvation, after jejunoileal bypass surgery, or after the use of certain drugs (such as amiodarone or
perhexiline). (See "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease
(nonalcoholic fatty liver disease) in adults".)

Mallory-Denk bodies do not appear to have a pathogenic role in the hepatic injury. However, their presence is an
important marker of alcohol-induced injury. In a large, multicenter Veterans Administration study, Mallory-Denk
bodies were detected in 76 percent of those with alcoholic hepatitis and in 95 percent of those who also had
cirrhosis [74].

Alcohol-associated fibrosis, like the other lesions seen in ALD, first appears in zone 3 and may progress to
become panlobular, particularly in those who continue to drink [75]. Early zone 3 fibrosis, also called hyaline
necrosis, predicts a high likelihood of eventual cirrhosis [76,77]. Since patients with alcohol use disorder often
deny having a drinking problem, the presence of zone 3 fibrosis can sometimes be used to convince a patient
who drinks heavily that his or her drinking is a problem and that eventual progression to end-stage liver disease
is virtually certain with continued alcohol use.

The term "fibrosis" in this setting denotes the accumulation of scar or extracellular matrix and is potentially
reversible in the absence of continued alcohol use. By contrast, true cirrhosis ( picture 3A-B) is characterized
by the presence of regenerative nodules and is generally thought to be irreversible, even in the absence of
further alcohol ingestion. Cirrhosis in ALD may be micronodular or macronodular [78,79]. In addition, some
patients with micronodular cirrhosis will later progress to macronodular cirrhosis [79]. (See "Cirrhosis in adults:
Etiologies, clinical manifestations, and diagnosis", section on 'Etiologies and classification'.)

DIFFERENTIAL DIAGNOSIS

There are numerous causes of hepatic steatosis and cirrhosis other than ALD. In particular, nonalcoholic
steatohepatitis should be considered since its clinical and histologic features are very similar to those seen in
patients with ALD.

Differential diagnosis of hepatic steatosis — The differential diagnosis of hepatic steatosis includes [80]:

● Alcohol-associated liver disease

● Nonalcoholic fatty liver disease (NAFLD)
● Hepatitis C virus infection (particularly genotype 3)
● Wilson disease
● Lipodystrophy
● Starvation
● Parenteral nutrition
● Abetalipoproteinemia
● Medications (amiodarone, tetracycline, methotrexate, tamoxifen, glucocorticoids, valproate, anti-retroviral
agents for HIV)
● Reye syndrome
● Acute fatty liver of pregnancy
● HELLP (hemolytic anemia, elevated liver enzymes, low platelet count) syndrome
 ● Inborn errors of metabolism (LCAT deficiency, cholesterol ester storage disease, Wolman disease)

Some of these entities may be suggested by the patient's medical and social history. Other causes may be
suspected based upon the patient's age such as abetalipoproteinemia, Reye syndrome, and inborn errors of
metabolism, which are seen in children, or Wilson disease, which is typically seen in patients under the age of 40
years. Other causes may be suggested by the physical examination such as Kayser-Fleischer rings in patients
with Wilson disease.

Based on the likelihood of a given diagnosis, specific testing can be performed to narrow the differential
diagnosis. (See 'Laboratory tests' above.)

Differential diagnosis of cirrhosis — Many causes of chronic liver disease may result in cirrhosis, including
chronic viral hepatitis, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, and
autoimmune hepatitis. As with hepatic steatosis, a specific etiology for a patient's cirrhosis can often be
determined through a combination of history, physical examination findings, and laboratory evaluation
( table 3). (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Determining
the cause of cirrhosis'.)

Differentiating alcohol-associated from nonalcoholic liver disease — Nonalcoholic fatty liver disease
(NAFLD) is the primary consideration in patients who deny alcohol use disorder but have clinical features
suggestive of alcohol-associated liver disease (such as elevated aminotransferases in the absence of serum
markers of viral hepatitis).

However, it can be difficult to distinguish NAFLD from alcohol-associated liver disease based upon clinical or
histologic features [81]. Some histologic features of NAFLD (such as macrovesicular steatosis and inflammation
with Mallory-Denk bodies) are indistinguishable from alcohol-associated liver disease ( picture 4A-B) [73,82].
On the other hand, features more common in alcohol-associated liver disease than in NAFLD include canalicular
cholestasis, marked ductular reaction, acute inflammation in the portal regions, and periportal fibrosis [83].
Steatosis is not always seen in alcohol-associated liver disease, whereas NAFLD is generally associated with a
greater degree of steatosis and nuclear vacuolization.

The presence of obesity does not help differentiate alcohol-associated fatty liver disease from NAFLD. While
obesity is a known risk factor for NAFLD, it can also increase the risk of developing steatosis in heavy drinkers
[31].

A predictive model (the alcohol-associated liver disease to NAFLD index [ANI]) has been proposed to distinguish
alcohol-associated from nonalcoholic liver disease [84]. The model is based upon aminotransferase levels, mean
corpuscular volume (MCV), body mass index (BMI), and sex:

ANI = -58.5 + 0.637 (MCV) + 3.91 (AST/ALT) – 0.406 (BMI) + 6.35 for men

An ANI greater than zero favors a diagnosis of alcohol-associated liver disease, whereas an ANI less than zero
favors a diagnosis of NAFLD. The probability of the patient having alcohol-associated liver disease rather than
NAFLD is then calculated using the value obtained for the ANI:

Probability = eANI/(1+eANI)

The ability of the model to accurately categorize patients ranged from good to excellent in validation cohorts
[84].
SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world
are provided separately. (See "Society guideline links: Cirrhosis" and "Society guideline links: Alcohol-associated
liver disease".)

SUMMARY AND RECOMMENDATIONS

● Clinical features – The clinical manifestations of alcohol-associated liver disease depend on the severity of
disease ( table 1). (See 'Clinical manifestations' above.)

• Physical examination findings – Patients with steatosis may have a normal examination or
hepatomegaly. Patients who have developed cirrhosis may have stigmata of chronic liver disease (eg,
spider angiomata, palmar erythema, gynecomastia). With hepatic decompensation, patients may
develop ascites, peripheral edema, or hepatic encephalopathy.

• Laboratory tests – There are several characteristic laboratory abnormalities in patients with alcohol-
associated liver disease, but none is diagnostic ( table 2). The classic finding is moderately elevated
aminotransferases, with an aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio >1
(and often >2). (See 'Laboratory tests' above.)

• Imaging – Ultrasound, computed tomography, and magnetic resonance imaging may demonstrate
hepatic parenchymal changes, but they cannot confirm that the changes are the result of alcohol-
associated liver disease (See 'Imaging studies' above.)

● Diagnostic evaluation – Alcohol-associated liver disease may be suspected in a patient with a compatible
history who has elevated serum aminotransferases, a suggestion of fatty liver on imaging tests, or is found
to have steatosis on liver biopsy. (See 'When to consider alcohol-associated liver disease' above.)

Clinical and laboratory features are often adequate for establishing a diagnosis of alcohol-associated liver
disease. The evaluation includes (see 'Diagnosis' above):

• Obtaining a history to quantify alcohol use and identify other potential sources of hepatic injury (see
'History' above)

• Performing a physical examination to identify stigmata of chronic liver disease (see 'Physical
examination' above)

• Obtaining laboratory tests to look for signs of hepatic inflammation and to assess hepatic synthetic
function (see 'Standard laboratory evaluation' above)

• Obtaining laboratory tests to identify other causes of hepatic injury (see 'Tests for other causes of liver
disease' above)

A liver biopsy may be required if the diagnosis of alcohol-associated liver disease remains uncertain
following a noninvasive evaluation. In addition, it can establish the severity of liver disease. (See 'Liver
biopsy' above.)

Use of UpToDate is subject to the Terms of Use.

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Topic 3617 Version 43.0
GRAPHICS

What is a standard drink?

US: United States; oz.: ounces.

* It can be difficult to estimate the number of standard drinks in a single mixed drink made with hard liquor. Depending on
factors such as the type of spirits and the recipe, a mixed drink can contain from 1 to 3 or more standard drinks.

Reproduced with content from: National Institutes on Alcohol Abuse and Alcoholism. Rethinking Drinking: Alcohol and your health. Available at:
http://rethinkingdrinking.niaaa.nih.gov.

Graphic 56818 Version 5.0

Physical findings in alcohol abuse

Abdominal wall collaterals (caput medusa)

Ascites

Cutaneous telangiectasias

Digital clubbing

Disheveled appearance

Dupuytren's contractures

Gynecomastia

Jaundice

Malnutrition

Palmar erythema

Peripheral neuropathy

Splenomegaly

Testicular atrophy

Graphic 82583 Version 1.0

Laboratory abnormalities in alcoholic liver disease

Abnormality Diagnostic characteristics*

Serum AST>ALT (ratio usually >2.0, both usually <300 Sensitivity and specificity have not been well studied, but
international units/L, and almost never >500 international may vary with the magnitude of the ratio
units/L)

Elevated serum AST Sensitivity 50 percent

Specificity 82 percent

Elevated serum ALT Sensitivity 35 percent

Specificity 86 percent

Elevated serum GGT Sensitivity approximately 70 percent

Specificity approximately 60 to 80 percent

High MCV Sensitivity approximately 30 to 50 percent

Specificity approximately 85 to 90 percent

Elevated carbohydrate-deficient transferrin Sensitivity approximately 60 to 70 percent (lower values

have been reported)

Specificity approximately 80 to 90 percent

AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: gamma-glutamyl transpeptidase; MCV: mean
corpuscular volume.

* The sensitivity and specificity figures all assume chronic alcohol use, although the definitions have varied among studies.

Graphic 64489 Version 2.0

Biopsy showing cirrhosis due to hepatitis C and alcohol

Needle biopsy of the liver (100x) of a 57-year-old female with cirrhosis from both hepatitis C virus infection and chronic
alcohol consumption. Hematoxylin and eosin stain demonstrates prominent steatosis as well as portal and peri-portal
inflammation and fibrosis.

Courtesy of Jeremy Ditelberg, MD.

Graphic 55740 Version 2.0

Acute fatty liver of pregnancy

Trichrome stain of a liver biopsy from a patient with acute fatty liver of pregnancy. Left panel: Low power view shows pallor
of the hepatocytes surrounding the central vein (CV). Right panel: High power view reveals disruption of the plate pattern
with "dropped out" hepatocytes, lobular disarray, and vacuolated, pale hepatocytes (microvesicular fat).

Courtesy of Caroline A. Riely, MD.

Graphic 80340 Version 2.0

Mallory-Denk bodies in alcoholic hepatitis

High power view of a liver biopsy in alcoholic hepatitis shows macrovesicular fat and Mallory-Denk bodies (arrows), which
are eosinophilic accumulations of intracellular material. Similar changes can occur in metabolic dysfunction-associated
steatohepatitis, formerly termed nonalcoholic steatohepatitis.

Courtesy of Robert Odze, MD.

Graphic 75188 Version 4.0

Alcoholic steatohepatitis and cirrhosis in a 35-year-old woman (low power, Masson
trichrome)

This section of the liver biopsy demonstrated more inflammation and scarring than what was seen in other sections from
the same patient.

Courtesy of Marshall M Kaplan, MD.

Graphic 82544 Version 2.0

Alcoholic steatohepatitis and cirrhosis in a 35-year-old woman (low power, Masson
trichrome)

This section demonstrates more scarring and advanced cirrhosis than in the other sections from the same patient. There
was more sampling variation in this biopsy than is typically seen in alcoholic liver disease.

Courtesy of Marshall M. Kaplan, MD.

Graphic 65537 Version 1.0

Common causes of abnormal liver blood tests

Disease Tests and findings

Alcoholic liver disease History of alcohol abuse

AST/ALT >2 with both being less than 500 international unit/mL if alcoholic hepatitis is present

Chronic hepatitis C ELISA assay for anti-HCV

PCR for HCV RNA if confirmatory test is necessary

Primary biliary Antimitochondrial antibodies as an isolated finding

cholangitis
IgM elevation

Primary sclerosing Strong association with inflammatory bowel disease

cholangitis
Cholangiography to establish the diagnosis

Antinuclear and antismooth muscle antibodies and ANCA; these are not diagnostic

Autoimmune hepatitis Hypergammaglobulinemia

Antinuclear and smooth muscle antibodies and ANCA in type 1; anti-LKM-1 in type 2

Chronic hepatitis B HBsAg and HBeAg and, in some cases, HBV DNA by hybridization or bDNA assay

Hereditary Family history of cirrhosis

hemochromatosis
Transferrin saturation and plasma ferritin should be performed but may be elevated by liver
disease itself

Diagnosis established by genetic testing or liver biopsy and calculation of hepatic iron index

Wilson disease Family or personal history of cirrhosis at a young age

Serum ceruloplasmin reduced in 95 percent of patients

Liver biopsy shows increased copper content, which may also be seen in cholestatic liver diseases

Alpha-1 antitrypsin Family or personal history of cirrhosis at a young age

deficiency
Serum AAT; phenotyping if low or borderline values

Nonalcoholic fatty liver History of diabetes mellitus or metabolic syndrome

disease
Diagnosis may be suspected by abnormal liver biochemical tests and hepatic imaging showing
fatty infiltration and is confirmed by liver biopsy

Congestive History of right-sided heart failure, constrictive pericarditis, mitral stenosis, tricuspid
hepatopathy regurgitation, cor pulmonale, cardiomyopathy

Right upper quadrant ultrasonography with Doppler studies of the portal and hepatic veins and
hepatic artery, electrocardiogram, and cardiac ultrasound

AAT: alpha-1 antitrypsin; ANCA: antineutrophil cytoplasmic antibody; anti-LKM-1: anti-liver-kidney microsomal 1 antibodies;
ALT: alanine aminotransferase; AST: aspartate aminotransferase; DNA: deoxyribonucleic acid; ELISA: enzyme-linked
immunosorbent assay; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV:
hepatitis C virus; Ig: immunoglobulin; PCR: polymerase chain reaction; RNA: ribonucleic acid.

Graphic 55647 Version 7.0

Metabolic dysfunction-associated steatohepatitis on biopsy

Histologic changes in metabolic dysfunction-associated steatohepatitis (MASH), formerly termed nonalcoholic

steatohepatitis (NASH).

(A) The hepatocyte in the center contains a large vacuole of fat and deeply staining eosinophilic strands of cytoplasmic
hyalin. Numerous neutrophils and phagocytic cells containing golden brown pigmented material (bile components and
cellular debris) are present in the sinusoids.

(B) MASH with cirrhosis. Trichrome stain shows regenerating nodules with fat surrounded by fibrous tissue.

Graphic 51497 Version 3.0

Contributor Disclosures
Scott L Friedman, MD Equity Ownership/Stock Options: Blade Therapeutics [Fibrosis therapeutics using protease
inhibitors]; DeuteRx [NASH]; Fibrocor Therapeutics [Fibrosis therapeutics]; Galectin [NASH]; Galmed [NASH therapeutics];
Glympse Bio [NASH diagnostics]; Gordian Biotechnology [NASH therapeutics]; HepGene [NASH diagnostics]; In Sitro [NASH
therapeutics]; Metrea [NASH therapeutics]; Morphic Therapeutics [Fibrosis therapeutics]; NorthSea Therapeutics [NASH
therapeutics]; Satellite Bio [Liver regenerative treatments]; Scholar Rock [Antifibrotic therapeutics]; Surrozen [Regenerative
therapies]. Grant/Research/Clinical Trial Support: Abalone Bio [Novel antifibrotics]; Cincerra [Animal studies]; Galmed [NASH
therapeutics]; Morphic Therapeutics [Cell culture or animal studies]; Novo Nordisk [Culture studies]; Plonyr Therapeutics
[Novel antifibrotics]; ProSciento Research [NASH]. Consultant/Advisory Boards: 89 Bio [NASH therapeutics]; AboMab [NASH];
Axcella Health [NASH therapeutics]; Can-Fite BioPharma [NASH therapeutics]; Escient Pharmaceuticals [Liver therapeutics];
Fate Therapeutics [Liver disease]; Fibrocor Therapeutics [Fibrosis therapeutics]; Galmed [NASH therapeutics]; Glycotest [Liver
cancer diagnostics]; Glympse Bio [NASH diagnostics]; Gordian Biotechnology [NASH therapeutics]; HepGene [NASH
diagnostics]; In Sitro [NASH therapeutics]; Merck Pharmaceuticals [NASH therapeutics]; Metrea [NASH therapeutics]; Morphic
Therapeutics [Fibrosis therapeutics]; NorthSea Therapeutics [NASH therapeutics]; Novartis [NASH therapeutics]; Pfizer
[Antiinflammatory and antifibrotic drugs]; Resolution Therapeutics [Fibrosis therapeutics]; Scholar Rock [Antifibrotic
therapeutics]; Surrozen [Liver therapeutics]; Yaqrit therapeutics [Novel therapies of liver failure]. All of the relevant financial
relationships listed have been mitigated. Bruce A Runyon, MD, FAASLD No relevant financial relationship(s) with ineligible
companies to disclose. Kristen M Robson, MD, MBA, FACG No relevant financial relationship(s) with ineligible companies to
disclose.

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