Clinical manifestations and diagnosis of alcohol-associated steatosis and cirrhosis

INTRODUCTION — 

Liver disease related to harmful alcohol use ranges from steatosis (fatty changes) in the liver to inflammation, fibrosis, and ultimately cirrhosis. Harmful alcohol use is a risk factor for liver disease, although many individuals will not develop cirrhosis despite harmful alcohol consumption. Among those who develop liver disease, symptoms often present only after severe, life-threatening liver disease has already developed.

This topic will discuss the clinical features and diagnosis of chronic alcohol-associated liver disease (ALD). Other aspects of ALD are discussed separately:

●Pathogenesis (see "Pathogenesis of alcohol-associated liver disease")

●Management of alcohol associated-steatosis and cirrhosis (see "Management of alcohol-associated steatosis and alcohol-associated cirrhosis")

●Liver transplantation for ALD (see "Liver transplantation for alcohol-associated liver disease")

The diagnosis and treatment of alcohol use disorder are presented separately. (See "Risky drinking and alcohol use disorder: Epidemiology, clinical features, adverse consequences, screening, and assessment" and "Alcohol use disorder: Treatment overview".)

The clinical manifestations, diagnosis, and management of alcohol-associated hepatitis are presented separately. (See "Clinical features and diagnosis of alcohol-associated hepatitis" and "Management and prognosis of alcoholic hepatitis".)

TERMINOLOGY — 

Steatotic (fatty) liver disease is a comprehensive term defined as hepatic steatosis identified on radiologic imaging or by liver biopsy. Alcohol-associated liver disease (ALD) represents alcohol-induced liver injury such as steatosis, liver fibrosis, cirrhosis, or alcohol-associated hepatitis that is secondary to active or previous harmful alcohol use [1]. Harmful drinking as a risk factor for liver disease is typically defined as >2 drinks per day (approximately 30 g) or >14 drinks per week for females and >3 drinks per day (approximately 40 g) or >21 drinks per week for males during the previous 12 months or longer. One standard drink contains 14 g of alcohol (figure 1) [1,2].

ALD can be further classified as [1,3]:

●Alcohol-associated steatosis – Liver imaging demonstrates steatosis without fibrosis or cirrhosis

●Alcohol-associated steatohepatitis – Steatohepatitis related to alcohol requires histologic evidence of inflammation and hepatocellular injury with neutrophil infiltration, which is the histologic hallmark of alcohol-induced injury. Histologic findings of liver inflammation are a risk factor for liver disease progression. (See 'Histologic findings' below.)

●Alcohol-associated cirrhosis – Histologic or clinical signs of cirrhosis are present (eg, imaging consistent with cirrhosis, features of portal hypertension such as ascites, variceal bleeding)

●Metabolic dysfunction- and alcohol-associated liver disease (MetALD) – Patients with liver steatosis, at least one metabolic risk factor (eg, obesity, diabetes mellitus, dyslipidemia, hypertension), and a history of moderate (but not heavy) alcohol use have metabolic dysfunction- and alcohol-associated liver disease (MetALD). This category recognizes that steatotic liver disease can involve a combination of metabolic dysfunction and alcohol. Moderate amounts of alcohol are defined as 20 to 50 g daily for females and 30 to 60 g daily for males [4]. This range of alcohol intake defines a spectrum between metabolic dysfunction-associated steatotic liver disease (MASLD)-predominant and alcohol-predominant disease. (See "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults".)

●Alcohol-associated hepatitis – Alcohol-associated hepatitis is a clinical syndrome manifested by the onset of jaundice within the previous eight weeks, ongoing harmful alcohol use for six months or greater, and elevated aminotransferases and total serum bilirubin levels [5]. (See "Clinical features and diagnosis of alcohol-associated 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 ALD among adults in the United States was 4 percent [6]. Mortality related to alcohol-associated cirrhosis in the United States was estimated at 7.3 per 100,000 persons in 2019 [7]. (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 [8]. Environmental factors such as colder climate and fewer sunlight hours have been linked to increased alcohol consumption [9]. Alarm over the rising impact of ALD has provoked national response in the United Kingdom to address this crisis [10], in addition to concern from the World Health Organization [8] and international thought leaders [11].

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 or harmful alcohol use). The thresholds for alcohol consumption vary based on patient age, patient biologic sex, and drinking pattern [12]. However, a commonly-used definition of harmful alcohol use is [1,2]:

●For females, >2 drinks per day (approximately 30 g) or >14 drinks per week

●For males, >3 drinks per day (approximately 40 g) or >21 drinks per week

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 g of alcohol (figure 1) [13].

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 are [14,15]:

●Tobacco use [16]

●Higher body mass index [17]

●Coexisting liver conditions (eg, chronic viral hepatitis)

●Genetic polymorphisms including patatin-like phospholipase domain protein 3 (PNPLA3), membrane-bound O-acyltransferase domain 7 (MBOAT7), transmembrane 6 superfamily member 2 (TM6SF2), and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) [18,19] (see "Pathogenesis of alcohol-associated liver disease")

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) [17]. 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'.).

CLINICAL FEATURES

Patient presentation — The clinical features of ALD vary with disease severity. Most patients with ALD are asymptomatic or report nonspecific symptoms such as fatigue [20]. In addition, progression from liver steatosis to steatohepatitis or cirrhosis often occurs in the absence of symptoms.

Asymptomatic patients are usually identified when laboratory testing shows elevated aminotransferases or when abdominal imaging shows liver steatosis as an incidental finding. At the other end of the spectrum are patients who present with manifestations of decompensated cirrhosis such as jaundice, peripheral edema, abdominal distension from ascites, hematemesis, or melena. Patients with hepatic encephalopathy may have 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'.)

Physical examination findings — Physical examination findings in patients with ALD range from a normal physical examination to evidence of decompensated cirrhosis. Patients with steatosis may have a normal examination or hepatomegaly. Patients who have developed cirrhosis may have spider angioma, splenomegaly, muscle wasting, palmar erythema, or gynecomastia [21]. Patients with decompensated cirrhosis may develop ascites, peripheral edema, or hepatic encephalopathy. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Physical examination'.)

Patients with ALD often have skeletal muscle wasting or coexisting dysfunction in other organs:

●Cardiomyopathy – (See "Alcohol-induced cardiomyopathy", section on 'Clinical manifestations'.)

●Neuropathies – (See "Overview of the chronic neurologic complications of alcohol".)

●Pancreatic disorders – (See "Chronic pancreatitis: Clinical manifestations and diagnosis in adults", section on 'Clinical manifestations'.)

Laboratory features

Liver biochemistries and tests — Serum aminotransferase levels may be normal or moderately elevated in patients with ALD [22,23]. The AST elevation is usually <8 times the upper limit of normal, whereas the ALT elevation is typically <5 times the upper limit of normal. The magnitude of elevation does not correlate with the severity of the underlying liver disease.

The most common pattern of liver biochemistries in ALD is a disproportionate elevation of AST compared with ALT, resulting in a ratio >1 (and often >2) [22-27]. The relatively lower elevation of serum ALT may result from hepatic deficiency of pyridoxal 5'-phosphate in patients with alcohol use disorder, which is a cofactor for the enzymatic activity of ALT [26]. According to this hypothesis, the altered ratio reflects a failure to appropriately increase the ALT, rather than a disproportionate elevation in AST.

In addition, if the AST to ALT ratio is >2, the aminotransferase elevations are likely due to ALD because ratio values greater than two are uncommon in other hepatocellular liver diseases [25]. In a study of 271 patients with biopsy-confirmed liver disease, more than 90 percent of the patients whose AST to ALT ratio was >2 had ALD [28]. 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 [23,29,30]. In a study that included 123 patients with alcohol use disorder, all patients with liver disease had elevated GGT by approximately 8 to 10 times the upper limit of normal [29]. GGT elevations persisted after eight weeks of abstinence, whereas other studies suggested that GGT normalized following two to six weeks of abstinence [30]. In addition, GGT elevations are not specific for ALD. As an 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 total bilirubin levels are frequently seen in patients with decompensated cirrhosis from any cause, including ALD.

Patients who are nutritionally deficient or have cirrhosis may have low albumin levels. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Laboratory findings' 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 [22,31,32] (see "Hematologic complications of alcohol use"):

●Anemia – Anemia defined as hemoglobin or hematocrit below the age- and sex-specific reference ranges.

●Thrombocytopenia – Mild thrombocytopenia (eg, platelet count 70,000 to 149,000/microL) is more common in ALD than severe thrombocytopenia (ie, platelet count <30,000/microL). Contributing factors may include direct toxicity to platelet precursor cells (megakaryocytes) and hypersplenism causing platelet sequestration.

●Leukopenia – Leukopenia is typically due to a fall in the neutrophil count as neutrophils are the most abundant white blood cells.

●Macrocytosis – Macrocytosis (ie, elevated mean corpuscular volume above the reference range) may result from vitamin B12 or folate deficiency, alcohol toxicity, or increased lipid deposition in red cell membranes. (See "Hematologic complications of alcohol use".)

●Elevated international normalized ratio (INR). (See "Hemostatic abnormalities in patients with liver disease".)

Other abnormalities — Other laboratory findings that may be seen in patients with alcohol-associated 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: Clinical presentation and diagnosis", section on 'Clinical presentation'.)

DIAGNOSTIC EVALUATION

When to suspect alcohol-associated liver disease — ALD may be suspected in patients with a history of harmful alcohol use (ie, >2 drinks per day [>14 drinks per week] for females and >3 drinks per day [>21 drinks per week] for males) who have elevated serum aminotransferases, and/or liver steatosis by radiographic imaging or liver biopsy (figure 1) [1,2,13]. Aminotransferase levels are usually <400 international units/L with the ratio of AST to ALT >1 (and often >2) [33,34]. Some patients with ALD may have hepatomegaly. (See 'Clinical features' above.)

Liver imaging provides evidence of hepatic steatosis or cirrhosis, but it is not able to differentiate ALD from other causes. (See 'Diagnostic imaging' below and 'Differential diagnosis' below.)

Initial evaluation

History and physical examination — The history includes a description of symptoms, medication use (including herbal supplements and over-the-counter medications), assessing risk factors for other causes of liver disease (eg, exposure to viral hepatitis), existing medical conditions (eg, type 2 diabetes mellitus), family history of liver disease, and alcohol consumption (including type of alcohol, amount, pattern, and duration of use). Obtaining an accurate alcohol use history in patients with suspected ALD may be limited since some patients may not readily admit to heavy alcohol use. In some cases, speaking with the patient's caregivers may help in obtaining a more accurate history. The approach to screening for alcohol use disorder is discussed separately. (See "Screening for unhealthy use of alcohol and other drugs in primary care".)

The physical examination includes assessing for hepatomegaly, for stigmata of chronic liver disease (eg, jaundice, ascites, splenomegaly, gynecomastia) and for extrahepatic manifestations of alcohol use disorder such as skeletal muscle wasting, cardiomyopathy, and neuropathies. (See "Overview of the risks and benefits of alcohol consumption".)

Laboratory studies — For patients with suspected ALD, we measure the following laboratory studies to assess liver inflammation and liver function (see 'When to suspect alcohol-associated liver disease' above):

●Liver tests – Aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase, total bilirubin, gamma-glutamyl transpeptidase (GGT)

●Serum albumin

●Coagulation studies – Prothrombin time/international normalized ratio (INR)

●Complete blood count with platelets

We obtain the following tests to evaluate for other causes or coexisting liver disease:

●Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and total hepatitis B core antibody (anti-HBc) – (See "Hepatitis B virus: Screening and diagnosis in adults".)

Evaluating patients for immunity to hepatitis A virus infection and other preventive immunizations is discussed separately – (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis" and "Immunizations for adults with chronic liver disease".)

●Anti-hepatitis C virus antibody with reflex to hepatitis C viral RNA – (See "Screening and diagnosis of chronic hepatitis C virus infection".)

●Alpha-1 antitrypsin (AAT) level – (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)

●Plasma iron, ferritin, and total iron binding capacity – (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

Ferritin production and the plasma ferritin concentration are increased in the absence of iron overload in patients with ALD and acute hepatitis [35]. As a result, for patients with acute hepatitis, testing should be deferred until the patient has recovered from the acute episode. In addition, the serum transferrin saturation in patients with ALD may reach or exceed 60 percent, perhaps because alcohol suppresses liver transferrin synthesis. For patients with elevated ferritin or transferrin saturation, we obtain additional laboratory testing to evaluate for iron overload, and such testing is discussed separately. (See "Approach to the patient with suspected iron overload".)

In selected patients, we obtain the following laboratory tests to evaluate for other causes:

●Antimitochondrial antibody in females with cholestasis – (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis".)

●Immunoglobulin G (IgG) level, antinuclear antibody, anti-smooth muscle antibody, anti-liver/kidney microsomal-1 (anti-LKM-1) antibodies (for female patients and/or those with aminotransferases >5 times the upper limit of normal or history of autoimmune disease) – (See "Overview of autoimmune hepatitis", section on 'Diagnostic evaluation'.)

●Ceruloplasmin for patients <40 years of age or those with neurologic or psychiatric conditions – (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

We do not routinely measure blood biomarkers to assess for harmful alcohol use. However, biomarkers such as blood phosphatidylethanol (PEth) may be helpful for evaluating patients who cannot provide an accurate or detailed description of their alcohol use (eg, patients with encephalopathy). PEth has emerged as the mostly widely used biomarker for alcohol use, which can provide strong evidence for alcohol consumption in the preceding two to three weeks [36,37]. PEth values <20 ng/mL correspond to minimal or no alcohol consumption [38,39].

We do not measure carbohydrate-deficient transferrin (CDT) because it may be elevated in patients with nonalcohol-related liver diseases, such as primary biliary cholangitis [40,41]. A commonly used CDT threshold for harmful alcohol use is >2.6 percent [42]. (See "Risky drinking and alcohol use disorder: Epidemiology, clinical features, adverse consequences, screening, and assessment", section on 'Assessment'.)

Diagnostic imaging

Initial imaging — Our approach to initial imaging is informed by the availability of recent imaging studies:

●For patients in whom liver steatosis or fibrosis was initially suspected based on imaging (eg, transabdominal ultrasound, computed tomography [CT], magnetic resonance imaging [MRI]), additional imaging is not necessary to establish the diagnosis if other criteria are met (ie, harmful alcohol use and excluding other primary etiologies). However, we assess the stage of liver disease by evaluating the severity of fibrosis in such patients, as discussed below. (See 'Staging (evaluating for fibrosis)' below.)

●For patients with no recent liver imaging (ie, within 12 months), we obtain transabdominal ultrasound. If ultrasound shows abnormalities (eg, ascites, liver mass, portal vein thrombosis, biliary obstruction), we obtain additional imaging with CT or MRI. (See 'Other imaging tests' below and "Recent portal vein thrombosis in adults: Clinical features, diagnosis, and management".)

Transabdominal ultrasound is performed to confirm that the liver is homogeneous and to exclude other causes of elevated liver tests (eg, biliary obstruction, liver mass). For patients with early ALD, ultrasound shows liver steatosis as diffuse, hyperechoic texture. Ultrasound has an overall sensitivity of 60 to 94 percent and specificity of 88 to 95 percent for detecting liver steatosis. However, ultrasound is less accurate in patients with <30 percent steatosis [43-45]. 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.

Other imaging tests — Alternative diagnostic imaging tests include computed tomography (CT) and magnetic resonance imaging (MRI). We typically obtain additional imaging when the initial ultrasound examination is technically limited. We also obtain more detailed imaging with CT or MRI for patients with suspected cirrhosis or evidence of biliary tract obstruction (eg, cholestatic pattern of elevated liver biochemistries).

●Computed tomography (CT) – CT detects liver steatosis by demonstrating reduced liver attenuation relative to the spleen. On CT without contrast in patients with liver steatosis, the liver attenuation value is less than 40 Hounsfield units (HU) or at least 10 HU less than the spleen [44,46]. In contrast, the normal liver attenuation ranges from 45 to 65 HU and is typically 8 HU higher than that of the spleen. With severe steatosis, liver attenuation may be less than unenhanced hepatic venous structures. CT has a specificity of 100 percent for diagnosis liver steatosis when the liver-to-spleen attenuation ratio is less than 0.8 [47]. CT evaluation of liver steatosis is based on non-contrast-enhanced images because the relative densities of the liver and spleen are highly variable on contrast-enhanced CT.

For patients with cirrhosis, CT findings 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 [44]. In some cases, the liver may be diffusely atrophic or may be enlarged (ie, hepatomegaly).

●Magnetic resonance imaging (MRI) – Gradient echo MR pulse sequences are sensitive for detecting hepatic steatosis [48]. 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, the sensitivity of in-phase and out-of-phase MRI for liver steatosis was 95 percent, with a specificity of 98 percent [49]. On T1-weighted and T2-weighted images, focal liver steatosis may result in higher signal intensity compared with normal liver.

Regenerative nodules in patients with cirrhosis may appear hypointense, isointense, or hyperintense relative to background liver tissue on T1-weighted images [44]. On T2-weighted images, the signal intensity of the regenerative nodules does not increase. The nodules on T2-weighted images are often hypointense or isointense.

On MRI, specific features that are suggestive of alcohol-associated cirrhosis 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 [50]. 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 widely regarded as the reference standard for quantifying fat but is not used routinely in clinical practice [44].

Liver biopsy

Limited indications — Clinical, laboratory, and imaging findings are often adequate to establish a diagnosis of ALD. Thus, we typically reserve diagnostic liver biopsy for patients with suspected ALD if the diagnosis remains uncertain despite laboratory and imaging tests or if an alternate etiology is suspected. In addition, we may obtain a liver biopsy for any of the following:

●Patients with persistently elevated serum aminotransferases (>6 months) who do not improve with abstinence from alcohol.

●Patients with inconclusive noninvasive testing for advanced fibrosis. (See 'Staging (evaluating for fibrosis)' below.)

The interpretation of liver biopsy specimens in general and methods to obtain liver biopsy specimens are discussed separately. (See "Interpretation of nontargeted liver biopsy findings in adults" and "Approach to liver biopsy".)

Histologic findings — Histologic features of ALD include macrovesicular steatosis that is characterized by a single large vacuole or fat droplet occupying the entire hepatocyte and thereby pushing the nucleus to the edge of the cell (picture 1).

●Early changes – Early changes in ALD include fat accumulation seen easily by light microscopy and minimal inflammatory changes except for occasional lipogranulomas in the lobules or portal tracts [51].

Fat in ALD is typically macrovesicular and composed of neutral triglycerides. However, small droplets of triglycerides may resemble microvesicular fat, but they differ from 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 is composed of free fatty acids that are hepatotoxic, and it can only be detected by using special stains with high resolution microscopy. (See "Acute fatty liver of pregnancy".)

●Progression to steatohepatitis – Liver steatosis may progress to steatohepatitis. Inflammation is typically first seen in zone 3 (figure 2). As the disease progresses, the histologic changes may extend to the portal tracts. Specific features of steatohepatitis include hepatocyte ballooning degeneration, lobular inflammation (especially neutrophils), individual hepatocyte necrosis/dropout, and glycogenated hepatocyte nuclei [52]. Hepatocytes may also contain Mallory-Denk hyalines surrounded by neutrophils (termed Mallory-Denk bodies), which are more characteristic of alcohol-associated steatohepatitis than metabolic dysfunction-associated steatohepatitis (MASH) [53]. Mallory-Denk hyalines tend to be more numerous and larger in patients with alcohol-associated steatohepatitis (picture 3A-B). Mild portal mononuclear cell infiltrates may also be present. (See "Pathogenesis of alcohol-associated liver disease" and "Interpretation of nontargeted liver biopsy findings in adults", section on 'Hepatocellular injury'.)

●Fibrosis – Alcohol-associated fibrosis, like the other histologic changes seen in ALD, first appears in zone 3 and may progress to become panlobular, particularly in patients who continue to consume alcohol [54]. Early zone 3 fibrosis, also called hyaline necrosis, predicts a high likelihood of eventual cirrhosis.

The term "fibrosis" in this setting denotes the accumulation of scar or extracellular matrix and is potentially reversible in the absence of alcohol use. By contrast, cirrhosis (picture 4A-B) is characterized by the presence of regenerative nodules and is generally thought to be irreversible, even in the absence of alcohol. Cirrhosis in ALD may be micronodular or macronodular [55,56]. In addition, some patients with micronodular cirrhosis will later progress to macronodular cirrhosis [56]. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Etiologies and classification'.)

Establishing the diagnosis — The diagnosis of ALD is typically established on the basis of clinical, laboratory, and liver imaging features in a patient with a history of harmful alcohol use, in the absence of other primary etiologies (eg, viral hepatitis). We typically reserve diagnostic liver biopsy for patients with suspected ALD when the diagnosis remains uncertain despite laboratory and imaging tests.

DIFFERENTIAL DIAGNOSIS

Other causes of liver steatosis — The differential diagnosis of alcohol-associated steatosis includes other conditions associated with nonacute steatosis:

●Metabolic dysfunction-associated steatotic liver disease (MASLD; previously termed nonalcoholic fatty liver disease) – Patients with MASLD have liver steatosis with at least one risk factor for cardiometabolic dysfunction (figure 3) and minimal or no alcohol consumption (ie, <20 g daily for females and <30 g daily for males). (See 'Terminology' above and "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults".)

Distinguishing ALD from MASLD based on clinical and histologic features may be challenging [57]. Biomarkers for alcohol use disorder (eg, phosphatidylethanol [PEth]) may help identify individuals with harmful alcohol use who under report their alcohol ingestion. (See 'Laboratory studies' above.)

Some histologic features, such as macrovesicular steatosis and inflammation, are found in both ALD and MASLD (picture 5A-B) [58,59]. On the other hand, features more commonly seen in ALD include canalicular cholestasis, marked ductular reaction, acute inflammation in the portal regions, and periportal fibrosis [60]. Steatosis is not always seen in ALD, whereas MASLD is generally associated with a greater degree of steatosis and nuclear vacuolization.

●Chronic hepatitis C virus (HCV) infection – Liver steatosis related to hepatitis C genotype 3 can be excluded with anti-HCV antibody testing [61]. (See "Screening and diagnosis of chronic hepatitis C virus infection".)

●Parenteral nutrition – Use of parenteral nutrition has been linked to elevated liver enzymes and liver steatosis. (See "Nutrition support in critically ill adult patients: Parenteral nutrition", section on 'Complications'.)

●Drug-induced liver disease – Medications that have been associated with liver steatosis include amiodarone, methotrexate, tamoxifen, glucocorticoids. (See "Drug-induced liver injury".)

●Wilson disease – Patients with symptomatic Wilson disease may have elevated liver enzymes in addition to signs of copper overload (eg, Kayser-Fleischer rings, neurocognitive involvement) and family history of Wilson disease. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

●Other genetic diseases – Other genetic diseases such as lysosomal acid lipase deficiency (cholesterol ester storage disease), hypobetalipoproteinemia, and lipodystrophy are in the differential diagnosis of liver steatosis; however, these conditions typically present in pediatric patients.

Other causes of cirrhosis — Many causes of chronic liver disease may result in cirrhosis, including chronic viral hepatitis, autoimmune hepatitis, hereditary hemochromatosis, primary biliary cholangitis, and primary sclerosing cholangitis. A specific underlying condition that progressed to cirrhosis can often be determined through a combination of history, physical examination findings, and laboratory evaluation. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Determining the cause of cirrhosis'.)

STAGING (EVALUATING FOR FIBROSIS) — 

The goal of staging patients with ALD is to determine the severity of fibrosis which may predict long term outcomes [62]. We evaluate most patients with noninvasive studies and reserve liver biopsy for those with inconclusive findings.

We evaluate for fibrosis in patients with ALD who did not require a liver biopsy to establish the diagnosis, who do not have signs of portal hypertension (eg, ascites), and who do not have cirrhosis by imaging (algorithm 1). We typically evaluate for advanced fibrosis by assessing Fibrosis (FIB)-4 index followed by transient elastography if the FIB-4 score indicates higher risk for advanced fibrosis (ie, FIB-4 ≥3.25 points) [1,63].

The FIB-4 index predicts advanced fibrosis by combining biochemical values (platelet count, ALT, AST) and age (calculator 1 and calculator 2). For patients with ALD, a FIB-4 cutoff value of ≥3.25 points had a sensitivity and specificity of 58 percent and 91 percent, respectively, for detecting advanced fibrosis using liver biopsy as a reference [63].

Liver stiffness as measured by ultrasound-based elastography also informs further management, although cutoff values for diagnosing fibrosis vary among studies and underlying liver disease [63,64]. (See "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography".)

●Liver stiffness measurement <15 kPa by transient elastography corresponds to a low-risk fibrosis score and excludes clinically significant fibrosis.

●Liver stiffness measurement ≥15 kPa by transient elastography suggests clinically significant fibrosis or cirrhosis. Further management includes hepatology referral for screening and preventing complications of cirrhosis (eg, variceal bleeding, hepatocellular carcinoma). These issues are discussed separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

A liver stiffness measurement cutoff value of 15 kPa in individuals with ALD had a sensitivity and specificity of 86 and 84 percent, respectively, for detecting advanced fibrosis [63].

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: Alcohol-associated liver disease" and "Society guideline links: Cirrhosis".)

SUMMARY AND RECOMMENDATIONS

●Background – ALD represents alcohol-induced liver injury that is secondary to active or previous harmful alcohol use. Harmful drinking is typically defined as >2 drinks per day or >14 drinks per week for females and >3 drinks per day or >21 drinks per week for males during the previous 12 months or longer (figure 1).

ALD can be further classified as (see 'Terminology' above):

•Alcohol-associated steatosis – Liver imaging demonstrates steatosis without fibrosis or cirrhosis

•Alcohol-associated steatohepatitis – Steatohepatitis related to alcohol requires histologic evidence of inflammation and hepatocellular injury with neutrophil infiltration. (See 'Histologic findings' above.)

•Alcohol-associated cirrhosis – Histologic or clinical signs of cirrhosis are present (eg, cirrhosis on imaging, features of portal hypertension such as ascites, variceal bleeding)

•Metabolic dysfunction- and alcohol-associated liver disease (MetALD) – Patients with liver steatosis, at least one metabolic risk factor (eg, obesity, diabetes mellitus, dyslipidemia, hypertension), and a history of moderate (but not heavy) alcohol use have metabolic dysfunction- and alcohol-associated liver disease (MetALD). Moderate amounts of alcohol are defined as 20 to 50 g daily for females and 30 to 60 g daily for males. (See "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults".)

•Alcohol-associated hepatitis – Alcohol-associated hepatitis is a clinical syndrome manifested by the onset of jaundice within the previous eight weeks, ongoing harmful alcohol use for six months or greater, and elevated aminotransferases and total serum bilirubin levels. (See "Clinical features and diagnosis of alcohol-associated hepatitis".)

●Clinical features – The clinical features of ALD vary with the disease severity. Most patients with ALD are asymptomatic or report nonspecific symptoms such as fatigue. Asymptomatic patients come to attention because laboratory testing revealed elevated liver biochemistries or because steatosis was detected incidentally on liver imaging. (See 'Clinical features' above.)

The classic laboratory pattern is moderately elevated aminotransferases, with an AST to ALT ratio >1 (and often >2).

Liver ultrasound often shows a hyperechoic texture or a bright liver because of diffuse fatty infiltration.

●When to suspect ALD – ALD may be suspected in patients with a history of harmful alcohol use (ie, >2 drinks per day [>14 drinks per week] for females and >3 drinks per day [>21 drinks per week] for males) who have elevated serum aminotransferases and/or liver steatosis by radiographic imaging or liver biopsy. (See 'When to suspect alcohol-associated liver disease' above.)

●Diagnosis – The diagnosis of ALD is typically established on the basis of clinical, laboratory, and liver imaging features in a patient with a history of harmful alcohol use, in the absence of other primary etiologies. We typically reserve diagnostic liver biopsy for patients with suspected ALD when the diagnosis remains uncertain despite laboratory and imaging tests. (See 'Diagnostic evaluation' above.)

●Staging – For patients with ALD who did not require a liver biopsy to establish the diagnosis, we typically evaluate for advanced fibrosis by assessing Fibrosis (FIB)-4 index followed by transient elastography if the FIB 4 indicates higher risk for fibrosis (ie, FIB-4 ≥3.25 points) (algorithm 1). (See 'Staging (evaluating for fibrosis)' above.)

If the liver stiffness measured by ultrasound-based elastography suggests advanced fibrosis or cirrhosis, further management includes screening for and preventing complications of cirrhosis (eg, variceal bleeding, hepatocellular carcinoma). (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)