Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol.
Signs and symptoms
Patients who are severely affected present with subacute onset of fever, hepatomegaly, leukocytosis, marked impairment of liver function (eg, jaundice, coagulopathy), and manifestations of portal hypertension (eg, ascites, hepatic encephalopathy, variceal hemorrhage). However, milder forms of alcoholic hepatitis often do not cause any symptoms.
See Clinical Presentation for more detail.
Diagnosis
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.
See Workup for more detail.
Management
In most patients with alcoholic hepatitis, the illness is mild. The short-term prognosis is good, and no specific treatment is required. Hospitalization is not always necessary. Alcohol use must be stopped, and care should be taken to ensure good nutrition; providing supplemental vitamins and minerals, including folate and thiamine, is reasonable.
In contrast, patients with severe acute alcoholic hepatitis are at a high risk of early death, at a rate of 50% or greater within 30 days. Patients with severe alcoholic hepatitis may benefit over the short term from specific therapies directed toward reducing liver injury, enhancing hepatic regeneration, and suppressing inflammation. For the long term, the goals include improvement in liver function, prevention of progression to cirrhosis, and reduction of mortality. Only prolonged alcohol abstinence is of demonstrated benefit in all these areas.
Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol.[1] The pathogenesis is not completely understood.[2] The relative risk of cirrhosis rises significantly for alcohol intake above 60 g/day for men and 20 g/day for women over a decade.[3]
Patients who are severely affected present with a subacute onset of fever, hepatomegaly, leukocytosis, marked impairment of liver function (eg, jaundice, coagulopathy), and manifestations of portal hypertension (eg, ascites, hepatic encephalopathy, variceal hemorrhage). However, milder forms of alcoholic hepatitis often do not cause any symptoms.
Upon microscopic examination, shown below, the liver exhibits characteristic centrilobular ballooning necrosis of hepatocytes, neutrophilic infiltration, megamitochondria, and Mallory hyaline inclusions. Steatosis (fatty liver) and cirrhosis frequently accompany alcoholic hepatitis.
View Image
Liver biopsy sample shows typical findings of perivenular polymorphonuclear infiltrate and ballooning degeneration of hepatocytes (hematoxylin and eos....
Disease that is sufficiently severe to cause an acute development of encephalopathy is associated with substantial early mortality, which may be ameliorated by treatment with glucocorticoids.
Alcoholic hepatitis usually persists and progresses to cirrhosis if heavy alcohol use continues. If alcohol use ceases, alcoholic hepatitis resolves slowly over weeks to months, sometimes without permanent sequelae but often with residual cirrhosis.
The American Association for the Study of Liver Diseases (AASLD) and the American College of Gastroenterology issued guidelines in 2010 for the diagnosis, therapy, and preventive care of alcoholic liver disease (ALD).[4]
See also Alcoholic Fatty Liver, Alcohol and Substance Abuse Evaluation, Alcohol Toxicity, Delirium Tremens, Autoimmune Hepatitis, Hepatitis B, Hepatitis C, and Hepatitis in Pregnancy.
Although the association of alcohol and liver disease has been known since antiquity, the precise mechanism of alcoholic liver disease remains in dispute.[1] Genetic, environmental, nutritional, metabolic, and immunologic factors, as well as cytokines and viral disease have been invoked.
Ethanol metabolism
Most tissues of the body, including the skeletal muscles, contain the necessary enzymes for the oxidative or nonoxidative metabolism of ethanol. However, the major site of ethanol metabolism is the liver. Within the liver, 3 enzyme systems—the cytosolic alcohol dehydrogenase (ADH) system, microsomal ethanol-oxidizing system (MEOS), and peroxisomal catalase system—can oxidize ethanol.
Cytosolic ADH uses nicotinamide adenine dinucleotide (NAD) as an oxidizing agent. ADH exists in numerous isoenzyme forms in the human liver and is encoded by 3 separate genes, designated as ADH1, ADH2, and ADH3. Variations in ADH isoforms may account for significant differences in ethanol elimination rates.
The microsomal ethanol-oxidizing system (MEOS) uses nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen. The central enzyme of MEOS is cytochrome P-450 2E1 (CYP2E1). This enzyme, in addition to catalyzing ethanol oxidation, is also responsible for the biotransformation of other drugs, such as acetaminophen, haloalkanes, and nitrosamines. Ethanol upregulates CYP2E1, and the proportion of alcohol metabolized via this pathway increases with the severity and duration of alcohol use.
Peroxisomal catalase uses hydrogen peroxide as an oxidizing agent.
The product of all 3 reactions is acetaldehyde, which is then further metabolized to acetate by acetaldehyde dehydrogenase (ALDH). Acetaldehyde is a reactive metabolite that can produce injury in a variety of ways.
Genetic factors
Although the evidence to prove a genetic predilection to alcoholism is adequate, the role of genetic factors in determining susceptibility to alcoholic liver injury is much less clear. Most people who are alcoholics do not develop severe or progressive liver injury. Attempts to link persons who are susceptible with specific human leukocyte antigen (HLA) groups have yielded inconsistent results, as have studies of genetic polymorphisms of collagen, ADH, ALDH, and CYP2E1.
Similar conclusions were reached in a meta-analysis of 50 studies pertaining to the association of alcoholic liver disease and genetic polymorphism.[5] Nonetheless, the fact remains that only a small fraction of even heavy alcoholics develop severe liver disease (ie, cirrhosis). Thus, future case-control studies investigating the genetic basis of alcohol-induced liver disease are urgently needed.
The genetic factor that most clearly affects susceptibility is male or female sex. For a given level of ethanol intake, women are more susceptible than men to developing alcoholic liver disease (see Epidemiology).
Malnutrition
Most patients with alcoholic hepatitis exhibit evidence of protein-energy malnutrition (PEM). In the past, nutritional deficiencies were assumed to play a major role in the development of liver injury. This assumption was supported by several animal models in which susceptibility to alcohol-induced cirrhosis could be produced by diets deficient in choline and methionine. This view changed in the early 1970s after key studies by Lieber and DeCarli performed in baboons demonstrated that alcohol ingestion could lead to steatohepatitis and cirrhosis in the presence of a nutritionally complete diet.[6] However, subsequent studies have suggested that enteral or parenteral nutritional supplementation in patients with alcoholic hepatitis may improve survival.
Toxic effects on cell membranes
Ethanol and its metabolite, acetaldehyde, have been shown to damage liver cell membranes. Ethanol can alter the fluidity of cell membranes, thereby altering the activity of membrane-bound enzymes and transport proteins. Ethanol damage to mitochondrial membranes may be responsible for the giant mitochondria (megamitochondria) observed in patients with alcoholic hepatitis. Acetaldehyde-modified proteins and lipids on the cell surface may behave as neoantigens and trigger immunologic injury.
Hypermetabolic state of the hepatocyte
Hepatic injury in alcoholic hepatitis is most prominent in the perivenular area (zone 3) of the hepatic lobule. This zone is known to be sensitive to hypoxic damage. Ethanol induces a hypermetabolic state in the hepatocytes, partially because ethanol metabolism via MEOS does not result in energy capture via formation of ATP. Rather, this pathway leads to the loss of energy in the form of heat. In some studies, antithyroid drugs, such as propylthiouracil (PTU), that reduce the basal metabolic rate of the liver have shown to be beneficial in the treatment of alcoholic hepatitis.
Generation of free radicals and oxidative injury
Free radicals, superoxides and hydroperoxides, are generated as byproducts of ethanol metabolism via the microsomal and peroxisomal pathways. In addition, acetaldehyde reacts with glutathione and depletes this key element of the hepatocytic defense against free radicals. Other antioxidant defenses, including selenium, zinc, and vitamin E, are often reduced in individuals with alcoholism. Peroxidation of membrane lipids accompanies alcoholic liver injury and may be involved in cell death and inflammation.
Steatosis
Oxidation of ethanol requires conversion of nicotinamide adenine dinucleotide (NAD) to the reduced form NADH. Because NAD is required for the oxidation of fat, its depletion inhibits fatty acid oxidation, thus causing accumulation of fat within the hepatocytes (steatosis). Some of the excess NADH may be reoxidized in the conversion of pyruvate to lactate. Accumulation of fat in the hepatocytes may occur within days of alcohol ingestion; with abstinence from alcohol, the normal redox state is restored, the lipid is mobilized, and steatosis resolves.
Although steatosis has generally been considered a benign and reversible condition, rupture of lipid-laden hepatocytes may lead to focal inflammation, granuloma formation, and fibrosis, and it may contribute to progressive liver injury. Nonoxidative metabolism of ethanol may lead to the formation of fatty acid ethyl esters, which may also be implicated in the pathogenesis of alcohol-induced liver damage.[7]
Formation of acetaldehyde adducts
Acetaldehyde may be the principal mediator of alcoholic liver injury. The deleterious effects of acetaldehyde include impairment of the mitochondrial beta-oxidation of fatty acids, formation of oxygen-derived free radicals, and depletion of mitochondrial glutathione. In addition, acetaldehyde may bind covalently with several hepatic macromolecules, such as amines and thiols, in cell membranes, enzymes, and microtubules to form acetaldehyde adducts. This binding may trigger an immune response through the formation of neoantigens, impair the function of intracellular transport through precipitation of intermediate filaments and other cytoskeletal elements, and stimulate hepatic stellate cells to produce collagen.
The levels of acetaldehyde in the liver represent a balance between its rate of formation (determined by the alcohol load and activities of the three alcohol-dehydrogenating enzymes) and its rate of degradation by ALDH. ALDH is downregulated by long-term ethanol abuse, with resultant acetaldehyde accumulation.
Role of the immune system
Active alcoholic hepatitis often persists for months after cessation of drinking. In fact, its severity may worsen during the first few weeks of abstinence. This observation suggests that an immunologic mechanism may be responsible for perpetuation of the injury. The levels of serum immunoglobulins, especially the immunoglobulin A (IgA) class, are increased in persons with alcoholic hepatitis. Antibodies directed against acetaldehyde-modified cytoskeletal proteins can be demonstrated in some individuals. Autoantibodies, including antinuclear and anti–single-stranded or anti–double-stranded DNA antibodies, have also been detected in some patients with alcoholic liver disease.
B and T lymphocytes are noted in the portal and periportal areas, and natural killer lymphocytes are noted around hyalin-containing hepatocytes. Patients have decreased peripheral lymphocyte counts with an associated increase in the ratio of helper cells to suppressor cells, signifying that lymphocytes are involved in a cell-mediated inflammatory process. Lymphocyte activation upon exposure to liver extracts has been demonstrated in patients with alcoholic hepatitis. Immunosuppressive therapy with glucocorticoids appears to improve survival and accelerate recovery in patients with severe alcoholic hepatitis.
Cytokines
Tumor necrosis factor-alpha (TNF-alpha) can induce programmed cellular death (apoptosis) in liver cells. Several studies have demonstrated extremely high levels of TNF and several TNF-inducible cytokines, such as interleukin (IL)–1, IL-6, and IL-8, in the sera of patients with alcoholic hepatitis. Inflammatory cytokines (TNF, IL-1, IL-8) and hepatic acute-phase cytokines (IL-6) have been postulated to play a significant role in modulating certain metabolic complications in alcoholic hepatitis, and they are probably instrumental in the liver injury of alcoholic hepatitis and cirrhosis, as shown in the images below.
Mechanisms of cytokine injury. IL = interleukin; NO = nitric oxide; O2- = superoxide anion; OH- = hydroxyl radical; PMN = polymorphonuclear lymphocyte....
Role of concomitant viral disease
Alcohol consumption may exacerbate liver injury caused by other pathogenic factors, including hepatitis viruses. Approximately 20% of patients presenting with alcoholic hepatitis have concomitant hepatitis C virus infection.[8] Extensive epidemiologic studies suggest that the risk of cirrhosis in patients with chronic hepatitis C infection is greatly exacerbated by heavy alcohol ingestion. Possible mechanisms include the impairment of immune-mediated viral killing or enhanced virus gene expression due to the interaction of alcohol and hepatitis C virus.
Acetaminophen-alcohol interactions
Long-term alcohol abuse has been established as potentiating acetaminophen toxicity via the induction of CYP2E1 and depletion of glutathione. Alcoholic patients may develop severe, even fatal, toxic liver injury after ingestion of standard therapeutic doses of acetaminophen.[9]
The prevalence of alcohol-related liver disease is high, with a rising rate of worsening mortality.[10] Alcohol abuse is the most common cause of serious liver disease in Western societies, causing 80% of hepatotoxic deaths and 50% of liver cirrhosis.[3] In the United States alone, alcoholic liver disease affects more than 2 million people (ie, approximately 1% of the population). The true prevalence of alcoholic hepatitis, especially of its milder forms, is unknown, because patients may be asymptomatic and may never seek medical attention.
Globally, the prevalence of alcoholic hepatitis appears to differ widely among different countries. In the Western hemisphere, when liver biopsies were performed in people who drank moderate to heavy amounts of alcohol and were asymptomatic, the prevalence of alcoholic hepatitis was found to be approximately 25-30%.
Racial and age differences in incidence
Although no genetic predilection is noted for any particular race, alcoholism and alcoholic liver disease are more common in minority groups, particularly among Native Americans. Likewise, since the 1960s, death rates of alcoholic hepatitis and cirrhosis have consistently been far greater for the nonwhite population than the white population. The nonwhite male rate of alcoholic hepatitis is 1.7 times the white male rate, 1.9 times the nonwhite female rate, and almost 4 times the white female rate.
Alcoholic hepatitis can develop at any age. However, its prevalence parallels the prevalence of ethanol abuse in the population, with a peak incidence in individuals aged 20-60 years.
Sexual differences in incidence
Women are more susceptible than men to the adverse effects of alcohol. Women develop alcoholic hepatitis after a shorter period and smaller amounts of alcohol abuse than men, and alcoholic hepatitis progresses more rapidly in women than in men.
The estimated minimum daily ethanol intake required for the development of cirrhosis is 40 g for men and 20 g for women older than 15-20 years. Furthermore, for patients who continue to drink after a diagnosis of alcoholic liver disease, the 5-year survival rate is approximately 30% for women compared with 70% for men.
To date, no single factor can account for this increased female susceptibility to alcoholic liver damage. Lower gastric mucosal alcohol dehydrogenase (ADH) content in women has been suggested to possibly lead to less first-pass clearance of alcohol in the stomach. A higher prevalence of autoantibodies has been found in the sera of alcoholic females compared with alcoholic males, but their clinical significance is questionable. Perhaps hormonal influences on the metabolism of alcohol or the higher prevalence of immunologic abnormalities is responsible for the differences described in the prevalence of alcoholic liver damage between men and women.
The long-term prognosis of individuals with alcoholic hepatitis depends heavily on whether patients have established cirrhosis and whether they continue to drink. With abstinence, patients with this disease exhibit progressive improvement in liver function over months to years, and the histologic features of active alcoholic hepatitis resolve. If alcohol abuse continues, alcoholic hepatitis invariably persists and progresses to cirrhosis over months to years. In one study, the estimated 5-year survival after hospitalization for severe alcoholic hepatitis was 31.8%. Abstinence was the only independent predictor of long-term survival.[11]
Annualized rates of progression of precirrhotic disease to cirrhosis are reported to be 1% (0-8%) for patients with normal histology, 3% (2-4%) for hepatic steatosis, 10% (6-17%) for steatohepatitis, and 8% (3-19%) for fibrosis.[12] The annualized mortality for patients with steatosis or cirrhosis, respectively are 6% (4-7%) and 8% (5-13%). Alcohol-related hepatic steatohepatitis requiring inpatient admission is the most dangerous subtype of alcohol-related liver disease.[12]
Mild alcoholic hepatitis is a benign disorder with negligible short-term mortality. However, when alcoholic hepatitis is of sufficient severity to cause hepatic encephalopathy, jaundice, or coagulopathy, mortality can be substantial.
The overall 30-day mortality rate in patients hospitalized with alcoholic hepatitis is approximately 15%; however, in patients with severe liver disease, the rate approaches or exceeds 50%. In those lacking encephalopathy, jaundice, or coagulopathy, the 30-day mortality rate is less than 5%. Overall, the 1-year mortality rate after hospitalization for alcoholic hepatitis is approximately 40%.
In one study, the overall mortality among patients with severe alcoholic hepatitis was 66%. Age, white blood cell (WBC) count, prothrombin time (PT), and female sex were all independent risk factors for the dismal outcome.[13]
Prognostic scoring systems
During the past several decades, various formulas and algorithms have been proposed for predicting the outcome of severe alcoholic hepatitis. The single most reliable indicator of severity is the presence of hepatic encephalopathy.
The American Association for the Study of Liver Diseases (AASLD) guideline recommends using prognostic scoring systems such as the Maddrey discriminant function (MDF) to stratify illness severity and the risk of poor outcome, both initially and over the course of the illness.[4]
The discriminant function (DF) of Maddrey and coworkers is based on PT and bilirubin levels, and it is calculated as follows: DF = (4.6 × PT prolongation) + total serum bilirubin in mg/dL.
Values greater than 32 indicate severe disease and predict a 30-day mortality rate of approximately 50%, assuming only supportive treatment is given. However, subsequent studies have found the DF to be an inexact predictor of mortality in patients with alcoholic hepatitis, especially in those who receive glucocorticoids.
Other formulas have been proposed for the assessment of prognosis of alcoholic hepatitis, but none has become popular among clinicians. The Combined Clinical and Laboratory Index of the University of Toronto permits a linear estimate of acute mortality in persons with alcoholic hepatitis. Its major disadvantages are the large number (14) of variables that must be scored and the complexity of the calculation itself.
In contrast to the Combined Clinical and Laboratory Index, a much simpler formula for assessing mortality was proposed in a large series of 142 patients with histologically proven alcoholic hepatitis based on PT, serum bilirubin level, and serum albumin level.[14] According to this study, the mortality rate in patients with a serum bilirubin level greater than 2 mg/dL, a serum albumin level less than 2.5 g/dL, and a PT greater than 5 seconds was 75%. Conversely, patients who did not meet all 3 criteria had a much lower mortality rate (approximately 25%).
Model for end-stage liver disease (MELD) score
Several retrospective studies have shown that the MELD score is useful in predicting the 30- and 90-day mortality in patients with alcoholic hepatitis (see the MELD Score calculator). Moreover, the MELD score seems to contain some practical and statistical advantages over Maddrey's DF in predicting mortality among these patients. In a cohort of 73 patients with alcoholic hepatitis at the Mayo Clinic, the MELD score was the only independent predictor of mortality.[15] Likewise, in another much larger retrospective study of 202 patients with alcoholic hepatitis, the MELD score was found superior to not only Maddrey's DF but also to the classic Child-Turcotte-Pugh (CTP) score.[16]
Glasgow alcoholic hepatitis score (GAHS)
The GAHS is one of the most recently described predictors of outcome in patients with alcoholic hepatitis. This scoring system uses five different variables, including age, bilirubin level, blood urea nitrogen (BUN) level, PT, and WBC count. The overall accuracy of GAHS, which was validated in 195 patients with alcoholic hepatitis, was 81%, when predicting 28-day outcome.[17] In contrast, the modified DF had an overall accuracy of only 50%.[17]
Asymmetric dimethylarginine (ADMA) score
The ADMA score is the most recently proposed predictor of adverse clinical outcome in patients with severe alcoholic hepatitis. In a small prospective study of 27 patients with alcoholic hepatitis, the ADMA score was a better predictor of outcome than the CTP score, the DF, or the MELD score.[18]
Other factors that correlate with poor prognosis include older age, impaired renal function, encephalopathy, and a rise in the WBC count in the first 2 weeks of hospitalization.
Complications
Most complications of alcoholic hepatitis are identical to those of cirrhosis.
Variceal hemorrhage
Acute variceal bleeding constitutes one of the most devastating emergencies, not only in gastroenterology but also in medicine at large. Resuscitation of the patient and protection of the airway are the two most important steps in the treatment of acute variceal bleeding. Cessation of the acute bleeding is usually achieved in more than 90% of patients with the combination of interventional endoscopy (sclerotherapy or banding ligation) and the intravenous infusion of pharmaceutical agents that lower the pressure within the portal system (somatostatin or one of its long-acting analogues [eg, octreotide]). Alternatively and for patients who continue to bleed in spite of interventional endoscopy and drug therapy, more invasive options, such as balloon tamponade, a transjugular intrahepatic portosystemic shunt, and an emergency portal-caval shunt, may be used.
Hepatic encephalopathy
The development of encephalopathy in patients with alcoholic hepatitis is invariably associated with a grave prognosis. Treatment consists of close monitoring of the patient and the administration of lactulose or nonabsorbable antibiotics. Low energy or low protein intake is not indicated, except transiently in severe cases. The use of benzodiazepine receptor antagonists (ie, flumazenil [Romazicon]) is still experimental. Rarely, rapidly progressive worsening of encephalopathy leading to deep coma may be associated with cerebral edema, as observed in fulminant hepatic failure. In selected instances, aggressive treatment with intracranial pressure monitoring and liver-assist devices may be considered.
Coagulopathy and thrombocytopenia
Profound hypoprothrombinemia may ensue during the course of severe alcoholic hepatitis, especially in patients with variceal bleeding. Administer fresh frozen plasma (FFP) to temporarily restore the depleted hepatic prothrombin stores. The value of parenteral administration of vitamin K is dubious, because the hepatocytes are incapable of synthesizing new prothrombin. Platelet transfusions are not usually necessary to correct thrombocytopenia, unless the patient is actively bleeding or requires an invasive procedure.
Ascites
Acute onset of ascites may develop in patients with alcoholic hepatitis, even in the absence of overtly decompensated liver disease and portal hypertension. The ascites is typically transudative, with a very low albumin concentration (< 1 g/dL). In patients who are hemodynamically stable with normal renal function, bed rest and salt restriction may be sufficient to mobilize fluid. The addition of diuretics (typically spironolactone and furosemide) permits clearing of fluid in most patients. In some individuals who do not respond to these measures, periodic large-volume paracentesis with intravenous albumin supplementation may be required. With continued abstinence, the salt-retaining tendency may improve; in many instances, the diuretics can be withdrawn safely after a period of months without any reaccumulation of ascites.
Spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis may develop in patients with alcoholic hepatitis and ascites, especially in those with concomitant gastrointestinal bleeding. Following a confirmatory diagnostic paracentesis, broad-spectrum antibiotic therapy with a second- or third-generation cephalosporin is the treatment of choice.
Iron overload
Several histopathologic studies have shown that as many as 50% of patients with alcoholic liver disease have increased hepatic iron content compared with healthy controls. This excess deposition of iron may play a significant role in the progression of the alcoholic liver damage. Portosystemic shunts, especially the side-to-side variety, enormously increase the deposition of iron in the liver. Occasionally, this excessive iron deposition leads to a clinical and pathologic entity that is analogous to primary hemochromatosis. Attempts to treat alcoholic liver disease with phlebotomy to reduce iron overload have been hampered by the development of anemia, and no clear benefit has been observed.
Given the addictive nature of alcohol in most patients who use it heavily, counseling complete abstinence is prudent. Refer patients to a program of rehabilitation and support, and strongly encourage them to attend. Also, fully inform patients regarding the serious potential health consequences of continued ethanol use.
For patient education see Infections Center, Digestive Disorders Center, Mental Health Center, as well as Alcoholism, Hepatitis B, Hepatitis C, and Cirrhosis.
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.
Heavy alcohol use is a prerequisite for the development of alcoholic hepatitis. The history is usually apparent; however, in some patients, alcohol use may be covert.
Clues to the presence of alcoholism include a history of multiple motor vehicle accidents, convictions for driving while intoxicated, and poor interpersonal relationships. Alcoholism exhibits a genetic predisposition, and a history of alcoholism in a close relative may also indicate that a patient is at risk.
Presentation
Patients with clinically symptomatic alcoholic hepatitis typically present with nonspecific symptoms of nausea, malaise, and low-grade fever. The clinical presentation may be precipitated by complications of impaired liver function or portal hypertension, such as upper gastrointestinal hemorrhage from esophageal varices, confusion and lethargy from hepatic encephalopathy, or increased abdominal girth from ascites.
A person who uses alcohol heavily may come to medical attention because of an intercurrent medical illness that produces altered mental status or persistent vomiting, which, in turn, triggers alcohol withdrawal symptoms. In such instances, the clinician must be alert to the presence of a precipitating illness (eg, subdural hematoma, acute pancreatitis, gastrointestinal hemorrhage) and to the likelihood of alcohol withdrawal symptoms (eg, seizures, delirium tremens) in addition to the problems associated with alcoholic hepatitis.
2010 AASLD screening and diagnostic recommendations for ALD
The 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) practice guideline includes the following recommendations for screening and diagnosis[4] :
After discussion of alcohol use with the patient, if abuse or excess use is suspected, screen the patient for alcohol abuse using a structured questionnaire such as the Alcohol Use Disorders Identification Test (AUDIT)
If the patient's history or a screening test is positive for alcohol abuse, use laboratory testing to verify the diagnosis of ALD and rule out other considerations
If ALD is present, examine the patient for evidence of other alcohol-related organ damage
Physical examination
Patients with alcoholic hepatitis are commonly febrile with tachycardia. Mild tachypnea with primary respiratory alkalosis may be observed. The liver is usually enlarged, often with mild hepatic tenderness. Hepatomegaly results from both steatosis and swelling of the injured hepatocytes.
Manifestations of hepatic failure or portal hypertension may include scleral icterus with darkening of the urine, splenomegaly, asterixis (a flapping tremor characteristic of metabolic encephalopathies), peripheral edema, and bulging flanks with shifting abdominal dullness (indicating the presence of ascites).
Spider angiomata, proximal muscle wasting, altered hair distribution, and gynecomastia may be observed, although these findings most commonly reflect coexistent cirrhosis.
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.
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 to exclude other conditions (appropriate in any patient with alcoholic hepatitis) may include the following:
Hepatitis B surface antigen (HBsAg) detects hepatitis B
Anti–hepatitis C virus by enzyme-linked immunosorbent assay (ELISA) detects hepatitis C
Ferritin and transferrin saturation detect hemochromatosis
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
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
Jaundice with fever can be caused by gallstones producing cholangitis and is suggested by a disproportionate elevation of the alkaline phosphatase (ALP) level
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]
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 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.
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.
View Image
Liver biopsy sample shows typical findings of perivenular polymorphonuclear infiltrate and ballooning degeneration of hepatocytes (hematoxylin and eos....
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.
In most patients with alcoholic hepatitis, the illness is mild. The short-term prognosis is good, and no specific treatment is required. Hospitalization is not always necessary. Alcohol use must be stopped, and care should be taken to ensure good nutrition; providing supplemental vitamins and minerals, including folate and thiamine, is reasonable. Patients who are coagulopathic should receive vitamin K parenterally. Anticipate symptoms of alcohol withdrawal, and manage them appropriately.
In contrast, patients with severe acute alcoholic hepatitis are at a high risk of early death, at a rate of 50% or greater within 30 days. In multiple studies, the strongest factor predictive of short-term mortality was hepatic encephalopathy. In some studies, a combination of hyperbilirubinemia and coagulopathy has also been found to independently predict a high short-term mortality rate. Individuals with these findings or with other complications, such as azotemia or gastrointestinal bleeding, should be hospitalized. Usually, observing the patient in an intensive care unit (ICU) until liver function is stable and the patient is clinically improving is prudent.
Patients with severe alcoholic hepatitis may benefit over the short term from specific therapies directed toward reducing liver injury, enhancing hepatic regeneration, and suppressing inflammation. Glucocorticosteroids are widely used for this purpose, although their benefits have not been proven unequivocally. Various other treatments remain experimental. For the long term, goals include improvement of liver function, prevention of progression to cirrhosis, and reduction of mortality. Only prolonged alcohol abstinence is of demonstrated benefit in all these areas.
Among future therapeutic directions, gene therapy is perhaps the most appealing modality. Various genes involved in hepatic fibrogenesis, inflammatory response, and oxidative stress are overexpressed in alcoholic hepatitis. Moreover, some candidate genes correlate well with the histologic findings and disease severity, thus suggesting that they may be potential targets for such therapy.[24]
Surgical considerations
Patients with acute alcoholic hepatitis are at a high risk of developing hepatic failure following general anesthesia and major surgery. Because postoperative mortality rates are high, surgery should be avoided in the setting of acute alcoholic hepatitis unless it is absolutely necessary. If patients remain abstinent, alcoholic hepatitis usually resolves over time, permitting surgery to be undertaken with a substantially reduced risk.
Transfer
Patients with alcoholic hepatitis of mild to moderate severity can be treated in a primary care setting. In general, for patients with severe alcoholic hepatitis or cirrhosis, observation by a gastroenterologist or a hepatologist is desirable, particularly if the illness is of sufficient severity or complexity to require intensive care.
If patients become comatose or have complications that may require surgical intervention, the treating physician should consider emergent transfer to a tertiary care center with experience in the treatment of liver failure. In selected cases, the use of novel liver-assist devices (artificial livers) may provide transient improvement in the manifestations of liver failure.
Cessation of alcohol use is the mainstay of treatment of alcoholic hepatitis. The 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline states that complete abstinence should be enjoined on all alcoholic hepatitis patients.[4]
In general, alcoholic hepatitis resolves or improves greatly following 6-12 months of alcohol abstinence, and continued improvement may be observed for several years. Mild alcoholic hepatitis often resolves completely, but, following severe alcoholic hepatitis, residual cirrhosis can usually be demonstrated. If alcohol abuse persists, alcoholic hepatitis invariably persists and progresses to cirrhosis, and the prognosis is dramatically worse.
Some experts have questioned whether complete abstinence is necessary or whether reduced amounts of alcohol would be sufficient for recovery in most patients. Given the addictive nature of alcohol in most patients who use it heavily, counseling complete abstinence is prudent. Patients should be referred to a program of rehabilitation and support, and they should be strongly encouraged to attend. Also, patients should be fully informed regarding the serious potential health consequences of continued ethanol use.
For patients with milder alcoholic hepatitis, a general diet containing 100 g/d of protein is appropriate. Provide supplemental multivitamins and minerals, including folate and thiamine. Salt restriction may be required in patients with ascites.
Additional treatment includes nutritional support. The 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline recommends testing all patients with alcoholic hepatitis for protein-energy malnutrition (PEM) and for vitamin and mineral deficiencies.[4]
Protein-energy malnutrition is almost universal in patients hospitalized for alcoholic hepatitis. In a large Veterans Administration Cooperative Study of Alcoholic Hepatitis, the severity of protein-energy malnutrition correlated with the severity of alcoholic hepatitis and the predicted mortality rate.[25] In patients with alcoholic hepatitis and severe protein-energy malnutrition, the mortality rate was 50%, compared with a mortality rate of less than 10% in patients with mild protein-energy malnutrition.[25]
Oral intake vs parenteral/enteral hyperalimentation
Some studies have suggested that improved energy and protein intake may improve the survival rate in patients with severe alcoholic hepatitis. However, complications associated with parenteral hyperalimentation (eg, sepsis, hemothorax) or enteral hyperalimentation (eg, aspiration pneumonia) may outweigh the benefits of these approaches. Thus, if patients are able to take food orally, this is the route of choice, and formal nutritional support can be reserved for those instances in which patients are unable to ingest enough by mouth to meet their needs. Energy (caloric) intake should be carefully measured to ensure adequate consumption. The use of nutritional supplements and appetite stimulants may be appropriate.
The 2010 AASLD ALD guideline states that patients with advanced disease should receive aggressive enteral nutritional therapy.[4] Patients with mild to moderate alcoholic hepatitis (Maddrey discriminant function [MDF] score < 32, no liver encephalopathy) that improves during the first week of hospitalization (ie, lower serum bilirubin level or decreased MDF) and who are treated with nutritional therapy and abstinence will probably neither need nor benefit from other interventions, but these individuals should be monitored closely.[4]
Protein restriction vs normal protein intake
Except in patients with severe encephalopathy, protein restriction is unnecessary and should be avoided because a protein-deficient diet impairs liver regeneration and worsens liver function. Even in the presence of hepatic encephalopathy, patients are usually able to ingest a minimum of 60-100 g/d of dietary protein if other measures to control encephalopathy have been aggressively pursued. In rare instances, restricting dietary proteins may be necessary. In these cases, alternatives include provision of high-quality protein via the parenteral route or provision of oral amino acid supplements that are selectively enriched with branched-chain amino acids.
Use of medications in alcoholic hepatitis has been considered controversial. Many treatments discussed in the Medication section are still investigational.[26] However, according to the 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline[4] : (1) Naltrexone or acamprosate may be used, in addition to counseling, to assist patients who have achieved abstinence to avoid relapsing; and (2) in patients with severe disease (Maddrey discriminant function [MDF] score ≥32), unless steroids are contraindicated, prednisolone should be considered. Pentoxifylline may be considered, especially if prednisolone cannot be used.
Prednisolone and pentoxifylline are recommended for the treatment of severe alcoholic hepatitis,[1] but uncertainty about their benefit persists.
Results of the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial involving 1,103 subjects showed that treatment with the steroid prednisolone reduced 28-day mortality in patients with severe alcoholic hepatitis, whereas treatment with the oral phosphodiesterase inhibitor pentoxifylline did not.[27, 28] However, the benefit of prednisolone did not extend beyond 28 days. There was no difference in the mortality rates between the two treatments at 1 year. Mortality at 28 days was 13.5% with prednisolone and pentoxifylline combined, 14.3% with prednisolone and placebo, 19.4% with pentoxifylline and placebo, and 16.7% with double placebo. For all patients treated with prednisolone, the mortality rate was 13.9%; for those treated only with pentoxifylline or placebo, the rate was 18.0%. Mortality rates were similar in patients who received pentoxifylline treatment (16.4%) and those who did not (15.5%).[27, 28]
Significant predictors of 28-day mortality included prednisone use, prothrombin time ratio, bilirubin level, age, white blood cell count, urea level, creatinine level, and hepatic encephalopathy.[27, 28] Neither treatment was significantly associated with a survival benefit beyond 28 days. Infections were significantly more frequent in the prednisolone group than in the no-prednisolone group. Patients who did not reduce or increased their alcohol use had a 3-fold increased risk of death compared with those who abstained.[27, 28]
Tort claims regarding steroid-induced aseptic necrosis of the hip are very common. Physicians treating patients with alcoholic hepatitis for longer than the recommended period should discuss the issue with the patient and the patient's family, and obtain consent. Patients with mild forms of alcoholic hepatitis should not be treated with steroids.
Orthotopic liver transplantation is widely used in patients with end-stage liver disease.[1, 29] Most patients with active alcoholic hepatitis are excluded from transplantation because of ongoing alcohol abuse. In most liver transplantation programs in the United States, patients must abstain from alcohol for at least 6 months before they can be considered for transplantation, and a thorough psychosocial evaluation must demonstrate that patients have a low likelihood of reverting to alcohol abuse.
Patients with alcoholic hepatitis may be informed that their liver injury can be expected to subside, and liver function will improve following at least 6 months of abstinence. If they still develop cirrhosis and its complications, they can be considered for transplantation if they remain committed to sustained abstinence. The prospect of liver transplantation can be a powerful motivational tool for encouraging abstinence.
Challenges to liver transplantation policies
Current policies pertaining to liver transplantation in patients with end-stage alcoholic liver disease (ie, cirrhosis), especially those with severe alcoholic hepatitis, have been challenged.[30, 31]
First, the societal aspects of the issue (ie, the public perception and reservation regarding the use of donated livers for self-inflicted disease) should not be any different than those of intravenous (IV) drug addicts with the hepatitis C virus or even the fast-food generation of obese persons with nonalcoholic steatohepatitis (NASH).
Second, the current fixed interval of ethanol abstinence, often at the behest of third-party payers, as a prerequisite for transplantation remains controversial as a predictor of future alcoholic relapse (ie, recidivism).[32, 33]
Finally, other investigators have proposed the conduct of pilot studies, on only a small cohort of patients, to determine whether liver transplantation improves the survival of patients with severe alcoholic hepatitis.[34]
2010 AASLD ALD recommendation
The recommendation of the 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline report is that patients with end-stage alcoholic liver disease be evaluated for liver transplantation in the same way as other possible candidates, after medical and psychosocial factors have been carefully evaluated.[4] A formal assessment of the probability of long-term abstinence should be included in the evaluation.[4]
Largely, mild and moderate alcoholic hepatitis can be managed on a hospital medical floor, requiring only a brief hospital stay. In fact, patients with the mildest forms of the disease may never seek medical attention, or they can be treated safely in outpatient settings. By contrast, severe acute alcoholic hepatitis requires intensive medical care and often a multidisciplinary approach.
Nutrition services and gastroenterology/hepatology
Adequate nutritional support is of paramount importance for the survival and recovery of patients with alcoholic hepatitis. The complexity of the disease and the wide variation in nutritional regimens and modalities mandate consultation with a nutritionist. Customarily, the gastroenterology service of the hospital should be able to handle this issue and should be instrumental in treatment.
In patients with alcoholic hepatitis who have developed cirrhosis, especially those with coexistent chronic viral hepatitis B or C, consider periodic surveillance for hepatocellular carcinoma. A common algorithm includes the determination of serum alpha-fetoprotein (AFP) levels at 6-month intervals along with annual diagnostic ultrasonography. The finding of a liver nodule or an elevated AFP level should lead to referral to a liver specialist and additional diagnostic studies.
In general, for patients with severe alcoholic hepatitis or cirrhosis, observation by a gastroenterologist or a hepatologist is desirable, particularly if the illness is of sufficient severity or complexity to require intensive care.
Nephrology
The onset of acute renal failure may indicate the development of hepatorenal syndrome or, alternatively, an episode of acute tubular necrosis resulting either from the use of nephrotoxic drugs or from acute intravascular volume changes. In these instances, obtaining consultation with a nephrologist is advisable.
Neurology
If a patient with alcoholic hepatitis exhibits mental status changes, focal neurologic findings, or seizures, consider consultation with a neurologist.
Infectious disease
The fever and leukocytosis that accompany alcoholic hepatitis often raise concerns regarding possible sepsis or other infectious processes. Routine evaluation with urinalysis, chest radiography, and cultures of blood and urine is appropriate, and findings from these tests are usually negative. If concerns persist, consultation with an infectious disease specialist is appropriate.
In the absence of complications, patients generally can be discharged from acute medical inpatient care facilities once alcohol withdrawal symptoms have cleared; liver function has begun to improve; and the complications of liver failure, such as encephalopathy, have resolved with appropriate treatment.
In patients who have a potential for rehabilitation, transferring them to an inpatient substance abuse treatment program rather than discharging them from the hospital may be appropriate.
Patients recently discharged from the hospital following an acute bout of alcoholic hepatitis should generally be observed within 2 weeks of their discharge. Subsequent periodic follow-up visits, at intervals ranging from weeks to several months, are appropriate to monitor patients' responses to treatment, including obtaining electrolyte levels and liver test results, and to encourage sobriety.
In patients with alcoholic hepatitis who have developed cirrhosis, especially those with coexistent chronic viral hepatitis B or C, consider periodic surveillance for hepatocellular carcinoma. A common algorithm includes determination of the serum alpha-fetoprotein (AFP) level at 6-month intervals along with annual diagnostic ultrasonography. The finding of a liver nodule or an elevated AFP level should lead to referral to a liver specialist and additional diagnostic studies.
Immunizing patients with alcoholic liver disease against common infectious pathogens, including hepatitis A virus, hepatitis B virus, pneumococci, and influenza A virus, is prudent.
2018 European Association for the Study of the Liver (EASL)
The EASL released guidelines on the management of alcohol-related liver disease in April 2015.[35] Their recommendations are outlined below.
Excess alcohol consumption should be addressed using pricing-based policies and regulation of availability.
Advertising and marketing of alcohol either directly or indirectly should be banned.
Primary care facilities for managing alcohol use disorder (AUD) need to be made widely available.
Screening for harmful alcohol consumption should be done by general practitioners (GPs) and in emergency departments.
Screening for alcoholic liver disease (ALD) should be done in high-risk populations, such as those in alcohol rehabilitations clinics, or the harmful drinkers identified by their GP.
Patients identified through screening should undergo brief intervention and referral to a multidisciplinary team.
The term alcohol use disorder (defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) criteria) should be used in preference to alcoholic, alcohol abuse, alcohol dependence, or risky drinker.
AUDIT (Alcohol Use Disorders Inventory Test) or AUDIT-consumption (AUDIT-C) should be used to screen patients for AUD and dependence.
Patients with AUD should be screened for concurrent psychiatric disorders and other addictions.
Benzodiazepines should be used to treat alcohol withdrawal syndrome (AWS) but should not be prescribed beyond 10–14 days because of the potential for abuse and/or encephalopathy.
Gastroenterology/hepatology centers should have access to services to provide effective psychosocial therapies.
Pharmacotherapy should be considered in patients with AUD and ALD.
Liver biopsy is required where there is diagnostic uncertainty, where precise staging is required, or in clinical trials.
Screening of patients with AUD should include determination of liver function tests (LFTs) and a measure of liver fibrosis.
Abstinence can be accurately monitored by measurement of ethyl glucuronide (EtG) in urine or hair.
A recent onset of jaundice in patients with excessive alcohol consumption should prompt clinicians to suspect alcoholic hepatitis (AH).
Available prognostic scores should be used to identify severe forms of AH, at risk of early mortality.
In the absence of active infection, corticosteroids (prednisolone 40 mg/day or methylprednisolone 32 mg/day) should be considered in patients with severe AH to reduce short-term mortality. However, corticosteroids do not influence medium to long-term survival.
N-acetylcysteine (for 5 days, intravenously) may be combined with corticosteroids in patients with severe AH.
A careful evaluation of nutritional status should be performed and patients should aim to achieve a daily energy intake ≥35–40 kcal/kg body weight (BW) and 1.2–1.5 g/kg protein, and to adopt the oral route as first-line intervention.
Systematic screening for infection should be performed before initiating therapy, during corticosteroid treatment, and during the follow-up period.
Early non-response (at day 7) to corticosteroids should be identified, and strict rules for the cessation of therapy should be applied.
In case of non-response to corticosteroids, highly selected patients should be considered for early liver transplantation.
Patients with alcohol-related cirrhosis should be advised and encouraged to achieve complete abstinence from alcohol to reduce the risk of liver-related complications and mortality.
Identification and management of cofactors, including obesity and insulin resistance, malnutrition, cigarette smoking, iron overload, and viral hepatitis, are recommended.
General recommendations for screening and management of complications of cirrhosis should be applied to alcoholic cirrhosis.
Liver transplantation (LT) confers a survival benefit. LT should be considered in patients with ALD (classified as Child-Pugh C and/or model for end-stage liver disease (MELD) ≥15), as it confers a survival benefit.
The selection of patients with AUD should not be based on the 6-month criterion alone.
The duration of abstinence before listing should depend on the degree of liver insufficiency in selected patients with a favorable addiction and psychological profile and supportive relatives.
Patients with AUD on the transplant waiting list should be checked for alcohol use by regular clinical interviews and use of laboratory tests to confirm abstinence.
A multidisciplinary approach evaluating not only medical but also psychological suitability for transplantation is mandatory before and after LT.
The integration of an addiction specialist may decrease the risk of relapse in heavy-drinking individuals.
Early LT should be proposed to a minority of patients with severe AH not responding to medical therapy after a careful selection process.
Patients should be screened regularly for cardiovascular and neurologic disease, psychiatric disorders, and neoplasms before and after LT.
Risk factors for cardiovascular disease and neoplasms, particularly cigarette smoking, should be controlled.
Early reduction in calcineurin inhibitor therapy may be considered to decrease the risk of de novo cancer after LT.
Use of medications in alcoholic hepatitis has been considered controversial. Many treatments discussed in this section remain investigational.[26]
The 2010 American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guideline does indicate that the following drugs may be considered[4] :
Naltrexone or acamprosate may be used, in addition to counseling, to assist patients who have achieved abstinence to avoid relapsing.
Prednisolone should be considered, unless steroids are contraindicated, in patients with severe disease (Maddrey discriminant function [MDF] score ≥ 32); pentoxifylline may also be considered, especially if prednisolone cannot be used. In a clinical trial, the use of prednisolone and pentoxifylline in combination did not result in improved 6-month survival over use of prednisolone alone in patients with severe alcoholic hepatitis.[36]
Note that tort claims regarding steroid-induced aseptic necrosis of the hip are very common. When patients with alcoholic hepatitis are treated with these agents for longer than the recommended period, physicians should discuss the issue with the patient and the patient's family, and obtain consent. Patients with mild forms of alcoholic hepatitis should not be treated with steroids.
The conclusion of the 2010 AASLD ALD guideline report was that the use of complementary and alternative medications for alcoholic hepatitis has not demonstrated convincing benefits, and should be considered investigational only.[4]
Monoclonal antibodies
Infliximab (Remicade) is a monoclonal antibody against tumor necrosis factor–alpha (TNF-alpha) that has been used successfully in immunologically mediated inflammatory diseases, such as Crohn disease and rheumatoid arthritis. In two small pilot studies on subjects with alcoholic hepatitis, infliximab improved the MDF scores, serum bilirubin and C-reactive protein (CRP) levels, and, more importantly, patient survival.[37, 38]
In contrast, a subsequent randomized, double-blinded, controlled trial of 36 subjects with severe alcoholic hepatitis failed to confirm the findings of the pilot studies.[39] In fact, the trial was discontinued because of the high rate of infections and because of mortality in the infliximab group. This study was criticized for the concomitant use of corticosteroids, the high dose of infliximab (10 mg/kg vs 5 mg/kg), and the selection of infliximab instead of an anti-TNF agent with a limited duration and action (ie, etanercept).
Better-designed controlled clinical trials are probably necessary to resolve the controversy and avoid a possible type I error. Currently, corticosteroids are the only recommended pharmaceutical therapy for severe alcoholic hepatitis (ie, MDF score >32).
Hemorheologic agents
Pentoxifylline (Trental) is a hemorheologic agent that lowers blood viscosity and has been shown to decrease portal hypertension in experimental animals with cirrhosis as well as has been found to have inhibitory effects on TNF. Following two encouraging pilot studies in a small number of subjects, a large, randomized, double-blinded, placebo-controlled trial in 101 subjects with acute alcoholic hepatitis showed significant improvement in short-term survival.[40] The benefit of pentoxifylline appears to be related to a significant decrease in the risk of developing hepatorenal syndrome.
Anabolic steroids
Anabolic steroids (eg, oxandrolone) have been used to treat alcoholic hepatitis because of their ability to stimulate protein synthesis and cell repair. These agents may also enhance nutrition through increased appetite.
In a large study of 273 subjects with severe alcoholic hepatitis, although treatment with both oxandrolone and nutritional supplementation showed no benefit on survival when the results of all subjects were analyzed, when subjects were stratified according to their nutritional status upon admission to the hospital, a significant improvement in short-term and long-term survival was noted in those with moderate malnutrition.[41] The survival rate in subjects who were severely malnourished did not improve.[41]
The above landmark study was confirmed in a meta-analysis of 5 randomized control trials that included 499 patients with alcoholic hepatitis who were treated with anabolic-androgenic steroids: anabolic steroids had no significant effect on mortality, liver-related mortality, liver complications, or liver histology.[42]
Thiocarbamide compounds
The 2010 AASLD ALD guideline states that propylthiouracil (PTU) should not be used.[4] Investigators reported the combined results of 6 randomized clinical trials, which included 710 patients, in a meta-analytical study in which PTU had no beneficial effect on all-cause mortality, liver-related mortality, liver complications, or liver histology.[43]
Hepatotropic hormones
Insulin and glucagon are hepatotropic hormones that may play an important role in promoting liver cell regeneration in response to injury. In two clinical trials, the administration of insulin and glucagon along with glucose (to prevent hypoglycemia) led to a modest improvement of liver function in patients with alcoholic hepatitis; however, insulin-induced severe hypoglycemia resulted in several deaths.
Other promoters of hepatic regeneration include prostaglandins and malotilate, which appeared to improve survival in a multicenter European trial. Peptide growth factors, such as hepatocyte growth factor, are candidates for future study.
Alkaloid agents
The 2010 AASLD ALD guideline states that colchicine should not be used.[4] This agent interferes with the transcellular movement and transport of collagen from the cytoplasm to the extracellular space, thus inhibiting fibrogenesis. In the 2 randomized double-blinded trials in the literature, colchicine was ineffective in treating patients with severe alcoholic hepatitis. By contrast, of 7 studies on the use of colchicine in patients with cirrhosis (mostly alcoholic), 4 studies demonstrated improvement and 3 studies demonstrated a tendency toward improvement.
Chelating agents
Penicillamine inhibits collagen synthesis in vitro by decreasing cross-linking and has been used successfully for other liver diseases (eg, Wilson disease) for its copper-chelating properties. However, no controlled trial with this agent has been performed in alcoholic hepatitis.
Sulfhydryl agents
Sulfhydryl agents can act as free-radical scavengers and promote the formation of reduced glutathione, an important element of hepatic antioxidant defense. The 2010 AASLD ALD guideline recommends only investigational use of S-adenosyl-l-methionine (SAM).[4] This agent protects against alcoholic liver injury in animal models. A randomized, double-blinded, placebo-controlled trial in patients with alcoholic hepatitis resulted in improved survival of patients who received SAM compared with controls.
Antidotes
N-acetyl-L-cysteine (NAC) is widely used as an antidote for acetaminophen hepatotoxicity. Data from limited case-controlled studies suggest a beneficial effect of NAC in alcoholic liver disease. The beneficial effect is particularly apparent in patients who are alcoholics and who also consume therapeutic doses of acetaminophen; however, preliminary evidence from prospective randomized trials did not show benefit.
Antioxidants
Vitamin E, a potent antioxidant substance, has been found to be hepatoprotective in both experimental animals and humans. However, a double-blinded trial among patients with alcoholic liver disease failed to improve liver chemistry, the hospitalization rate, and the cumulative mortality rate when the patients were administered 500 mg of vitamin E daily compared with the placebo-treated control group.
Cyanidanol-3 (catechin) is a naturally occurring flavonoid with antioxidant properties. As a hepatoprotective agent, it has been studied extensively in experimental toxic liver injury. Cyanidanol gained popularity in Europe in the mid 1980s and was used for a wide variety of liver diseases. Unfortunately, prospective randomized trials in subjects with alcoholic hepatitis failed to show any benefit. Moreover, the administration of cyanidanol is associated with adverse effects, such as allergic hyperthermia and autoimmune hemolytic anemia.
Several other antioxidant agents have been used in the treatment of alcoholic hepatitis, albeit with little success. In a randomized clinical trial, corticosteroids were far superior to a "cocktail" of antioxidants in improving the usually measured clinical parameters and liver histology.[44]
Nutritional supplements
Polyunsaturated lecithin (PPC, phosphatidyl choline) has been studied because of the empiric observation that choline deficiency in rats (which impairs endogenous lecithin synthesis) increases the sensitivity to alcoholic liver injury. The precise mechanism is unknown. Beneficial effects have also been demonstrated in preventing alcoholic liver injury in baboons.
PPC failed to demonstrate any hepatoprotective effects in alcohol-induced liver injury in a multicenter Veterans Affairs cooperative study among 789 subjects.[45] In fact, approximately 20% of these subjects showed progressive liver fibrosis with continued moderated amounts of alcohol ingestion.[45] Thus, PPC does not appear to have a viable role in acute alcoholic hepatitis.
Calcium channel blockers
Several preliminary reports on alcoholic hepatitis have indicated a beneficial effect of calcium channel blockers (eg, diltiazem, verapamil); however, the only randomized double-blinded trial of amlodipine failed to demonstrate any improvement in patients with alcoholic hepatitis.
Bile acids
Hepatoprotective bile acids include ursodeoxycholic acid (Ursodiol), a tertiary bile acid that has been used extensively either as monotherapy or as an adjuvant therapy in various cholestatic liver diseases, such as primary biliary cholangitis and primary sclerosing cholangitis. Preliminary data from a small clinical trial in patients with alcoholic hepatitis showed a significant improvement in liver chemistry test results.
Herbal agents
Herbal agents have also been tried in alcoholic hepatitis. Silymarin is the active ingredient in milk thistle; it is a member of the flavonoids and has shown remarkable hepatoprotective effects in experimental toxic liver injury. The precise mechanism of its hepatoprotective mediation is not known, but it is probably related to its antioxidant properties. In humans with mild alcoholic hepatitis, silymarin improves liver chemistry test results. In a single controlled trial among 170 subjects with alcoholic liver disease, silymarin reduced the liver-related deaths. However, in a meta-analysis of 13 clinical trials (about half of them double-blind), it was concluded that milk thistle did not significantly influence the clinical course of patients with alcoholic hepatitis.[46]
Clinical Context:
Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing the increased capillary permeability. This agent may be preferable to other glucocorticoids (eg, prednisone), because hepatic metabolism is not required.
Clinical Context:
Prednisolone decreases autoimmune reactions, possibly by suppressing key components of the immune system. This agent does not need to undergo hepatic metabolism.
Strong evidence of immunologic and inflammatory liver injury in alcoholic hepatitis provides the rationale for the use of glucocorticosteroids. Over the past 30 years, more than 50 clinical trials have been published evaluating the use of glucocorticosteroids in treating alcoholic hepatitis. In most studies, treatment consists of the equivalent of 30-40 mg/d of prednisolone for 30 days, followed by a rapid taper and withdrawal over the subsequent 2-4 weeks.
Study results have not been uniform. Larger studies demonstrate a significant benefit in severe alcoholic hepatitis, including reduction in mortality. Two meta-analyses of 12 randomized, prospective, placebo-controlled trials support the conclusion that glucocorticosteroid treatment reduces early mortality in patients with severe acute alcoholic hepatitis.
All studies conclude that in mild alcoholic hepatitis, no benefit can be demonstrated with glucocorticosteroid treatment; therefore, this treatment is only appropriate in individuals with severe alcoholic hepatitis characterized by encephalopathy, hyperbilirubinemia, and/or coagulopathy.
Glucocorticosteroids may suppress inflammatory and immune-mediated hepatic destruction, but their marked anti-anabolic effect suppresses regeneration and may slow healing. They may increase the complications and mortality associated with gastrointestinal bleeding, pancreatitis, or sepsis, and they should be withheld or used judiciously if any of these are present.
When Louvet et al investigated whether the presence of infection in patients with severe alcoholic hepatitis contraindicates corticosteroid treatment, the investigators determined that infection was not independently associated with patient survival and although infection screening is warranted in patients with severe alcoholic hepatitis, it should not contraindicate steroid use.[47] Prednisolone was administered to 246 patients suffering from severe alcoholic hepatitis, including to 63 patients in whom infection—specifically, spontaneous bacterial peritonitis or bacteremia (n=28), pulmonary infection (n=8), urinary tract infection (n=20), or other infection (n=7)—was present at hospital admission.
Patients suffering from infection before corticosteroid administration had a 2-month survival rate (70.9%) that was similar to that of the study's other patients (71.6%). Louvet et al also observed that postadmission infection developed more frequently in patients who were nonresponders to corticosteroid therapy (42.5%) than it did in responders (11.1%).[47] In addition, in a multivariate analysis, only the Lille model yielded an independent prediction of infection upon steroid use.[48, 49]
What is alcoholic hepatitis?What are the signs and symptoms of alcoholic hepatitis?How is alcoholic hepatitis diagnosed?What are the treatment options for alcoholic hepatitis?What is the presentation of alcoholic hepatitis?What is the prognosis of alcoholic hepatitis?What are the etiologic factors of alcoholic hepatitis?What is the pathophysiology of alcoholic hepatitis?What is the role of genetic factors in the etiology of alcoholic hepatitis?What is the role of malnutrition in the etiology of alcoholic hepatitis?How does ethanol damage the liver in alcoholic hepatitis?What is the role of the hypermetabolic state of the hepatocyte in the pathophysiology of alcoholic hepatitis?What is the role of free radicals in the pathophysiology of alcoholic hepatitis?What is the role of steatosis in the pathophysiology of alcoholic hepatitis?What is the role of acetaldehyde adducts in the pathophysiology of alcoholic hepatitis?What is the role of the immune system in the pathophysiology of alcoholic hepatitis?What is the role of cytokines in the pathophysiology of alcoholic hepatitis?What is the role of hepatitis C in the etiology of alcoholic hepatitis?What is the role of acetaminophen in the etiology of alcoholic hepatitis?What is the prevalence of alcoholic hepatitis?Which patient groups are at highest risk for alcoholic hepatitis?How does the incidence of alcoholic hepatitis vary by sex?What is the prognosis of alcoholic hepatitis?Which prognostic scoring systems are used for alcoholic hepatitis?What is the efficacy of model for end-stage liver disease (MELD) scoring system for alcoholic hepatitis?What is the efficacy of Glasgow alcoholic hepatitis score (GAHS) prognostic scoring system for alcoholic hepatitis?What is the efficacy of asymmetric dimethylarginine (ADMA) prognostic scoring system for alcoholic hepatitis?How is variceal hemorrhage managed in alcoholic hepatitis?How is hepatic encephalopathy managed in alcoholic hepatitis?How is coagulopathy and thrombocytopenia managed in alcoholic hepatitis?How are ascites managed in patients with alcoholic hepatitis?How is spontaneous bacterial peritonitis managed in alcoholic hepatitis?How is iron overload managed in alcoholic hepatitis?What should be included in patient education for alcoholic hepatitis?What is a prerequisite for the development of alcoholic hepatitis?What are symptoms of alcoholic hepatitis?What are the guidelines for screening and diagnosis of alcoholic hepatitis?What are the physical findings characteristic of alcoholic hepatitis?Which conditions need to be distinguished from alcoholic hepatitis?What are the differential diagnoses for Alcoholic Hepatitis?What is the role of lab testing in the evaluation of alcoholic hepatitis?What is the role of imaging studies in the evaluation of alcoholic hepatitis?Which complete blood count (CBC) results are characteristic of alcoholic hepatitis?Which screening blood tests are indicated in the workup of alcoholic hepatitis?What is the role of liver tests in the workup of alcoholic hepatitis?Which liver function tests are performed in the workup of alcoholic hepatitis?Which serum biomarkers are performed in the workup of alcoholic hepatitis?What is the role of ultrasonography in the workup of alcoholic hepatitis?What is the role of liver biopsy in the workup of alcoholic hepatitis?How is percutaneous liver biopsy performed in the workup of alcoholic hepatitis?When is a transjugular liver biopsy indicated for evaluation of alcoholic hepatitis?Which histologic features are characteristic of alcoholic hepatitis?What are the treatment options for alcoholic hepatitis?Why should surgery be avoided during an episode of acute alcoholic hepatitis?When is transfer to a tertiary care center indicated in the treatment of alcoholic hepatitis?What is the mainstay of treatment for alcoholic hepatitis?Which dietary modifications are beneficial in the treatment of alcoholic hepatitis?What is the role of parenteral hyperalimentation in the treatment of alcoholic hepatitis?When is protein restriction indicated in the treatment of alcoholic hepatitis?What is the role of drug treatment for alcoholic hepatitis?What is the role of liver transplantation in the treatment of alcoholic hepatitis?What are the controversies surrounding liver transplantation policies for alcoholic hepatitis?What are the American Association for the Study of Liver Diseases (AASLD) alcoholic liver disease (ALD) guidelines for liver transplantation evaluation in patients with alcoholic hepatitis?Which specialist consultations are needed for the treatment of alcoholic hepatitis?What is the role of the gastroenterologists and hepatologist in the treatment of alcoholic hepatitis?What is the role of the nephrologist in the treatment of alcoholic hepatitis?What is the role of the neurologist in the treatment of alcoholic hepatitis?When should an infectious disease specialist be consulted in the treatment of alcoholic hepatitis?What is included in long-term monitoring of alcoholic hepatitis?When are medications indicated for the treatment of alcoholic hepatitis?What is the role of infliximab (Remicade) in the treatment of alcoholic hepatitis?What is the role of pentoxifylline (Trental) in the treatment of alcoholic hepatitis?What is the role of anabolic steroids in the treatment of alcoholic hepatitis?What is the role of propylthiouracil (PTU) in the treatment of alcoholic hepatitis?What is the role of hepatotropic hormones in the treatment of alcoholic hepatitis?What is the role of colchicine in the treatment of alcoholic hepatitis?What is the role of penicillamine in the treatment of alcoholic hepatitis?What is the role of S-adenosyl-l-methionine (SAM) in the treatment of alcoholic hepatitis?What is the role of N-acetyl-L-cysteine (NAC) in the treatment of alcoholic hepatitis?What is the role of antioxidants in the treatment of alcoholic hepatitis?What is the role of polyunsaturated lecithin (PPC, phosphatidyl choline) in the treatment of alcoholic hepatitis?What is the role of calcium channel blockers in the treatment of alcoholic hepatitis?What is the role of ursodeoxycholic acid (Ursodiol) in the treatment of alcoholic hepatitis?What is the role of herbal agents in the treatment of alcoholic hepatitis?Which medications in the drug class Corticosteroids are used in the treatment of Alcoholic Hepatitis?
Douglas M Heuman, MD, FACP, FACG, AGAF, Chief of Hepatology, Hunter Holmes McGuire Department of Veterans Affairs Medical Center; Professor, Department of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Disclosure: Received grant/research funds from Novartis for other; Received grant/research funds from Bayer for other; Received grant/research funds from Otsuka for none; Received grant/research funds from Bristol Myers Squibb for other; Received none from Scynexis for none; Received grant/research funds from Salix for other; Received grant/research funds from MannKind for other.
Coauthor(s)
Anastasios A Mihas, MD, DMSc, FACP, FACG, Professor, Department of Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine; Consulting Staff, Virginia Commonwealth University Hospitals and Clinics; Chief of GI Clinical Research, Director of GI Outpatient Service, Associate Director of Hepatology, Hunter Holmes McGuire Veterans Affairs Medical Center
Disclosure: Nothing to disclose.
Patrick D Hung, MD, Senior Fellow, Department of Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Disclosure: Nothing to disclose.
Chief Editor
BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
George Y Wu, MD, PhD Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine
George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical Investigation, and Association of American Physicians
Osterweil N. STOPAH: Only steroid reduces alcoholic hepatitis death risk. Medscape Medical News from WebMD. November 14, 2014. Available at http://www.medscape.com/viewarticle/834928. Accessed: November 20, 2014.
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.
Mechanisms of cytokine injury. IL = interleukin; NO = nitric oxide; O2- = superoxide anion; OH- = hydroxyl radical; PMN = polymorphonuclear lymphocyte; TNF = tumor necrosis factor.
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.
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.
){kind=link}
){kind=link}
){kind=link}