Approach Considerations
The diagnosis of alcoholic hepatitis is straightforward and requires no further diagnostic studies in patients presenting with a history of alcohol abuse, typical symptoms and physical findings, evidence of liver functional impairment, and compatible liver enzyme levels. In milder cases of alcoholic hepatitis, a mild elevation of the aspartate aminotransferase (AST) level may be the only diagnostic clue. However, early detection of fibrosis using hepatic elastography is essential. [3]
Studies have indicated that serum C-reactive protein (CRP) is an accurate marker of alcoholic hepatitis (ie, sensitivity, 41%; specificity, 99%; positive predictive value [PPV], 98%; negative predictive value [NPV], 88%). [20]
An electrolyte panel may demonstrate electrolyte disorders from the effects of vomiting, portal hypertension with decreased circulating volume, alcoholic ketoacidosis, or respiratory alkalosis. In addition, hypophosphatemia and hypomagnesemia are common consequences of coexistent malnutrition.
In August 2012, the Centers for Disease Control and Prevention (CDC) expanded their existing, risk-based testing guidelines to recommend a 1-time blood test for hepatitis C virus (HCV) infection in baby boomers—the generation born between 1945 and 1965, who account for approximately three fourths of all chronic HCV infections in the United States—without prior ascertainment of HCV risk (see Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965). [19] One-time HCV testing in this population could identify nearly 808,600 additional people with chronic infection. All individuals identified with HCV should be screened and/or managed for alcohol abuse, followed by referral to preventative and/or treatment services, as appropriate.
Imaging studies are rarely required for the diagnosis of alcoholic hepatitis, but they can be useful in excluding other causes of liver disease. Ultrasonography is generally the preferred modality due to its low cost, noninvasiveness, and wide availability. Similar and complementary information can be obtained by computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the abdomen; however, these two imaging studies are more expensive than ultrasonography and are usually required only in atypical cases. CT scanning and MRI are more sensitive and accurate than ultrasonography if liver cancer is suspected.
Complete Blood Count
A complete blood count (CBC) commonly reveals some degree of neutrophilic leukocytosis with bandemia. Usually, this is moderate; however, rarely, it is severe enough to provide a leukemoid picture.
Alcohol is a direct marrow suppressant, and moderate anemia may be observed. In addition, alcohol use characteristically produces a moderate increase in the mean corpuscular volume.
Thrombocytosis may be observed as part of the inflammatory response; conversely, myelosuppression or portal hypertension with splenic sequestration of platelets may produce thrombocytopenia.
Screening Blood Tests
Screening blood tests to exclude other conditions (appropriate in any patient with alcoholic hepatitis) may include the following:
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Hepatitis B surface antigen (HBsAg) detects hepatitis B
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Anti–hepatitis C virus by enzyme-linked immunosorbent assay (ELISA) detects hepatitis C
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Ferritin and transferrin saturation detect hemochromatosis
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Marked elevation of aminotransferase levels should raise concern for viral hepatitis or drug hepatotoxicity; in particular, people who are alcoholics may develop severe liver necrosis from standard therapeutic doses of acetaminophen
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Rapid deterioration of liver function (see Liver Tests) should raise the possibility of hepatocellular carcinoma (HCC), which can be tested for by determination of alpha-fetoprotein (AFP) levels as well as findings on an imaging study of the liver
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Jaundice with fever can be caused by gallstones producing cholangitis and is suggested by a disproportionate elevation of the alkaline phosphatase (ALP) level
Liver Tests
Liver enzyme levels exhibit a characteristic pattern. In most patients, the aspartate aminotransferase (AST) level is moderately elevated, whereas the alanine aminotransferase (ALT) level is in the reference range or only mildly elevated. This is the opposite of what is observed in most other liver diseases.
An AST/ALT ratio greater than 1 is almost universal in persons with alcoholic hepatitis. Even in severe disease, the elevations of aminotransferase levels are modest, and an AST level greater than 500 U/L should raise suspicion of an alternative diagnosis. An AST/ALT ratio greater than 1 may accompany cirrhosis of any cause and, therefore, is less diagnostically specific in the setting of cirrhosis.
Alkaline phosphatase (ALP) level elevations are typically mild in persons with alcoholic hepatitis. Levels greater than 500 U/L occur in a small percentage of patients, but abnormalities of this magnitude suggest a coexisting infiltrative or biliary obstructive process.
The gamma-glutamyl transpeptidase (GGTP) level is elevated markedly by alcohol use. Although a normal value helps to exclude alcohol as a cause of liver disease, an elevated level is of no value in distinguishing between simple alcoholism and alcoholic hepatitis.
Liver function tests
Common liver function tests include albumin level, bilirubin level, and prothrombin time (PT). Hypoalbuminemia occurs because of decreased hepatic synthetic function and coexisting protein-energy malnutrition (PEM). Hyperbilirubinemia is typically a mixture of unconjugated and conjugated bilirubin, with the latter predominating. Bilirubinuria is normally present in patients who are icteric. Coagulopathy predominantly affects the extrinsic pathway of coagulation (measured by PT). It is usually unresponsive to vitamin K.
The severity of hyperbilirubinemia and coagulopathy reflects the severity of alcoholic hepatitis and is of prognostic value.
Serum biomarkers
Ash test
The diagnostic value of serum biomarkers, such as the Ash test (ie, the 6 components of the FibroTest-ActiTest plus AST), was tested and validated in 275 patients with alcoholic hepatitis. [21] Both the sensitivity and the specificity of the Ash test in predicting alcoholic steatohepatitis were impressive (0.80 and 0.84, respectively). [21]
Carbohydrate-deficient transferrin (CDT)
Carbohydrate-deficient transferrin is perhaps the most reliable marker of chronic alcoholism, irrespective of the presence of liver disease. [22] Carbohydrate-deficient transferrin has been proposed as a reliable biomarker in the differentiation of nonalcoholic steatohepatitis (NASH) from alcoholic hepatitis. [23]
Ultrasonography
In general, real-time ultrasonography is the preferred imaging study in evaluating patients with suspected alcoholic hepatitis, because it is inexpensive, noninvasive, and widely available. This modality provides a good evaluation of the liver and other viscera, and it permits guided liver biopsy.
On ultrasonograms, the liver in patients with alcoholic hepatitis appears enlarged and diffusely hyperechoic. Features suggestive of coexistent portal hypertension and/or cirrhosis include the presence of varices, splenomegaly, and ascites.
Ultrasonography is also helpful in excluding gallstones, bile duct obstruction, and hepatic or biliary neoplasms. Jaundice with fever can be caused by gallstones producing cholangitis; ultrasonographic examination of the abdomen is usually sufficient to exclude this possibility. However, if stones are found or fever persists, cholangiography may be necessary.
Rapid deterioration of liver function should raise the possibility of hepatocellular carcinoma, which can be tested for by performing imaging studies (eg, ultrasonography, computed tomography [CT] scanning, magnetic resonance imaging [MRI]) of the liver.
Liver Biopsy
Liver biopsy is not always required in the evaluation of alcoholic hepatitis, but it may be useful in establishing the diagnosis, in determining the presence or absence of cirrhosis, and in excluding other causes of liver disease.
The 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) practice guideline recommends considering liver biopsy for patients whose diagnosis is reasonably uncertain and for patients likely to undergo medical treatment for severe alcoholic hepatitis. The risk of performing the biopsy should be weighed against the risk associated with the probable course of therapy, or the possible risk of an investigational treatment. [4]
Percutaneous liver biopsy
Percutaneous biopsy can be performed at the bedside by an experienced practitioner, usually a gastroenterologist or a hepatologist. Real-time ultrasonographic guidance may be desirable to optimize the biopsy site selection and to reduce the risk of complications.
Usually, a biopsy should be avoided in the presence of severe thrombocytopenia or coagulopathy because of the risk of serious (possibly fatal) hemorrhage.
Transjugular liver biopsy
If biopsy information is considered essential and the risk of percutaneous biopsy appears excessive, an alternative approach is to perform a biopsy angiographically via a catheter passed into the hepatic vein under fluoroscopic guidance. In principle, the risk of hemorrhage should be reduced, because the puncture site is contained within the venous system.
At the time of transjugular liver biopsy, the angiographer can determine the transhepatic venous pressure gradient. In alcoholic hepatitis and cirrhosis, the pressure measurement obtained with a catheter wedged retrograde in a branch of the hepatic vein accurately reflects the portal venous pressure.
Histologic Features
In alcoholic hepatitis, liver injury is characteristically most prominent in the centrilobular (perivenular) areas (zone 3 of Rappaport). Hepatocytes exhibit ballooning with necrosis. Focal accumulation of polymorphonuclear leukocytes, as shown in the image below, is noted in the areas of injury. Lymphocytes may also be present, especially in the portal tracts.
Liver biopsy sample shows typical findings of perivenular polymorphonuclear infiltrate and ballooning degeneration of hepatocytes (hematoxylin and eosin [H&E] stain). Courtesy of H. Robert Lippman, MD.
Ropy eosinophilic hyaline inclusions termed Mallory bodies may be observed in the perinuclear cytoplasm. With electron microscopy, Mallory bodies may be observed to be composed of fibril clumps that histochemically are identifiable as intermediate filaments. Mallory bodies are characteristic of alcoholic hepatitis, but are not always present, and occasionally, they can be observed in a variety of other disorders.
Macrovesicular steatosis, perivenular fibrosis, and frank cirrhosis commonly coexist with alcoholic hepatitis.
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Liver biopsy sample shows typical findings of perivenular polymorphonuclear infiltrate and ballooning degeneration of hepatocytes (hematoxylin and eosin [H&E] stain). Courtesy of H. Robert Lippman, MD.
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Ethanol (ETOH) and cytokine production. CYP = cytochrome P; IL = interleukin; NF-κB = nuclear factor-kappa B; ROS = reactive oxygen species; TNF = tumor necrosis factor.
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Mechanisms of cytokine injury. IL = interleukin; NO = nitric oxide; O2- = superoxide anion; OH- = hydroxyl radical; PMN = polymorphonuclear lymphocyte; TNF = tumor necrosis factor.
