The Journal of Family Practice

ALCOHOLIC HEPATITIS, a severe manifestation of alcoholic liver disease, is rising in incidence. Complete abstinence from alcohol remains the cornerstone of treatment, while other specific interventions aim to decrease short-term mortality rates.

Despite current treatments, about 25% of patients with severe alcoholic hepatitis eventually die of it. For those who survive hospitalization, measures need to be taken to prevent recidivism. Although liver transplantation seems to hold promise, early transplantation is still largely experimental in alcoholic hepatitis and will likely be available to only a small subset of patients, especially in view of ethical issues and the possible wider implications for transplant centers.

New treatments will largely depend on a better understanding of the disease’s pathophysiology, and future clinical trials should evaluate therapies that improve short-term as well as long-term outcomes.

ACUTE HEPATIC DECOMPENSATION IN A HEAVY DRINKER

Excessive alcohol consumption is very common worldwide, is a major risk factor for liver disease, and is a leading cause of preventable death. Alcoholic cirrhosis is the eighth most common cause of death in the United States and in 2010 was responsible for nearly half of cirrhosis-related deaths worldwide.¹

Alcoholic liver disease is a spectrum. Nearly all heavy drinkers (ie, those consuming 40 g or more of alcohol per day, TABLE 1) have fatty liver changes, 20% to 40% develop fibrosis, 10% to 20% progress to cirrhosis, and of those with cirrhosis, 1% to 2% are diagnosed with hepatocellular carcinoma every year.²

Within this spectrum, alcoholic hepatitis is a well-defined clinical syndrome characterized by acute hepatic decompensation that typically results from long-standing alcohol abuse. Binge drinkers may also be at risk for alcoholic hepatitis, but good data on the association between drinking patterns and the risk of alcoholic hepatitis are limited.

Alcoholic hepatitis varies in severity from mild to life-threatening.³ Although its exact incidence is unknown, its prevalence in alcoholics has been estimated at 20%.⁴ Nearly half of patients with alcoholic hepatitis have cirrhosis at the time of their acute presentation, and these patients generally have a poor prognosis, with a 28-day death rate as high as 50% in severe cases.^5,6 Moreover, although alcoholic hepatitis develops in only a subset of patients with alcoholic liver disease, hospitalizations for it are increasing in the United States.⁷

Women are at higher risk of developing alcoholic hepatitis, an observation attributed to the effect of estrogens on oxidative stress and inflammation, lower gastric alcohol dehydrogenase levels resulting in slower first-pass metabolism of alcohol, and higher body fat content causing a lower volume of distribution for alcohol than in men.⁸ The incidence of alcoholic hepatitis is also influenced by a number of demographic and genetic factors as well as nutritional status and coexistence of other liver diseases.⁹ Most patients diagnosed with alcoholic hepatitis are active drinkers, but it can develop even after significantly reducing or stopping alcohol consumption.

FATTY ACIDS, ENZYMES, CYTOKINES, INFLAMMATION

Alcohol consumption induces fatty acid synthesis and inhibits fatty acid oxidation, thereby promoting fat deposition in the liver.

The major enzymes involved in alcohol metabolism are cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase. CYP2E1 is inducible and is up-regulated when excess alcohol is ingested, while alcohol dehydrogen-
ase function is relatively stable. Oxidative degradation of alcohol by these enzymes generates reactive oxygen species and acetaldehyde, inducing liver injury.¹⁰ Interestingly, it has been proposed that variations in the genes for these enzymes influence alcohol consumption and dependency as well as alcohol-driven tissue damage.

In addition, alcohol disrupts the intestinal mucosal barrier, allowing lipopolysaccharides from gram-negative bacteria to travel to the liver via the portal vein. These lipopolysaccharides then bind to and activate sinusoidal Kupffer cells, leading to production of several cytokines such as tumor necrosis factor alpha, interleukin 1, and transforming growth factor beta. These cytokines promote hepatocyte inflammation, apoptosis, and necrosis (FIGURE 1).¹¹

Besides activating the innate immune system, the reactive oxygen species resulting from alcohol metabolism interact with cellular components, leading to production of protein adducts. These act as antigens that activate the adaptive immune response, followed by B- and T-lymphocyte infiltration, which in turn contribute to liver injury and inflammation.¹²

THE DIAGNOSIS IS MAINLY CLINICAL

The diagnosis of alcoholic hepatitis is mainly clinical. In its usual presentation, jaundice develops rapidly in a person with a known history of heavy alcohol use. Other symptoms and signs may include ascites, encephalopathy, and fever. On examination, the liver may be enlarged and tender, and a hepatic bruit has been reported.¹³

Other classic signs of liver disease such as parotid enlargement, Dupuytren contracture, dilated abdominal wall veins, and spider nevi can be present, but none is highly specific or sensitive for alcoholic hepatitis.

Elevated liver enzymes and other clues

Laboratory tests are important in evaluating potential alcoholic hepatitis, although no single laboratory marker can definitively establish alcohol as the cause of liver disease. To detect alcohol consumption, biochemical markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), mean corpuscular volume, carbohydrate-deficient transferrin, and, more commonly, gamma-glutamyl transpeptidase are used.

In the acute setting, typical biochemical derangements in alcoholic hepatitis include elevated AST (up to 2 to 6 times the upper limit of normal; usually less than 300 IU/L) and elevated ALT to a lesser extent,¹⁴ with an AST-to-ALT ratio greater than 2. Neutrophilia, anemia, hyperbilirubinemia, and coagulopathy with an elevated international normalized ratio are common.

Patients with alcoholic hepatitis are also prone to develop bacterial infections, and about 7% develop hepatorenal syndrome, itself an ominous sign.¹⁵

Imaging studies are valuable in excluding other causes of abnormal liver test results in patients who abuse alcohol, such as biliary obstruction, infiltrative liver diseases, and hepatocellular carcinoma.

Screen for alcohol intake

Women are at higher risk of developing alcoholic hepatitis

During the initial evaluation of suspected alcoholic hepatitis, one should screen for excessive drinking. In a US Centers for Disease Control and Prevention study, only one of six US adults, including binge drinkers, said they had ever discussed alcohol consumption with a health professional.¹⁶ Many patients with alcoholic liver disease in general and alcoholic hepatitis in particular deny alcohol abuse or underreport their intake.¹⁷

Screening tests such as the CAGE questionnaire and the Alcohol Use Disorders Identification Test can be used to assess alcohol dependence or abuse.^18,19 The CAGE questionnaire consists of four questions:

• Have you ever felt you should cut down on your drinking?
• Have people annoyed you by criticizing your drinking?
• Have you ever felt guilty about your drinking?
• Have you ever had a drink first thing in the morning (an eye-opener) to steady your nerves or to get rid of a hangover?

A yes answer to two or more questions is considered clinically significant.

Is liver biopsy always needed?

Although alcoholic hepatitis can be suspected on the basis of clinical and biochemical clues, liver biopsy remains the gold standard diagnostic tool. It confirms the clinical diagnosis of alcoholic hepatitis in about 85% of all patients and in up to 95% when significant hyperbilirubinemia is present.²⁰

However, whether a particular patient needs a biopsy is not always clear. The American Association for the Study of Liver Diseases (AASLD) recommends biopsy in patients who have a clinical diagnosis of severe alcoholic hepatitis for whom medical treatment is being considered and in those with an uncertain underlying diagnosis.

Findings on liver biopsy in alcoholic hepatitis include steatosis, hepatocyte ballooning, neutrophilic infiltration, Mallory bodies (which represent aggregated cytokeratin intermediate filaments and other proteins), and scarring with a typical perivenular distribution as opposed to the periportal fibrosis seen in chronic viral hepatitis. Some histologic findings, such as centrilobular necrosis, may overlap alcoholic hepatitis and nonalcoholic steatohepatitis.

In addition to confirming the diagnosis and staging the disease, liver biopsy has prognostic value. The severity of inflammation and cholestatic changes correlates with poor prognosis and may also predict response to corticosteroid treatment in severe cases of alcoholic hepatitis.²¹

However, the utility of liver biopsy in confirming the diagnosis and assessing the prognosis of alcoholic hepatitis is controversial for several reasons. Coagulopathy, thrombocytopenia, and ascites are all common in patients with alcoholic hepatitis, often making percutaneous liver biopsy contraindicated. Trans-
jugular liver biopsy is not universally available outside tertiary care centers.

The major enzymes involved in alcohol metabolism are CYP2E1 and ADH

Needed is a minimally invasive test for assessing this disease. Breath analysis might be such a test, offering a noninvasive means to study the composition of volatile organic compounds and elemental gases and an attractive method to evaluate health and disease in a patient-friendly manner. Our group devised a model based on breath levels of trimethylamine and pentane. When we tested it, we found that it distinguishes patients with alcoholic hepatitis from those with acute liver decompensation from causes other than alcohol and controls without liver disease with up to 90% sensitivity and 80% specificity.²²

ASSESSING THE SEVERITY OF ALCOHOLIC HEPATITIS

Several models have been developed to assess the severity of alcoholic hepatitis and guide treatment decisions (TABLE 2). 

The MDF (Maddrey Discriminant Function)⁶ system was the first scoring system developed and is still the most widely used. A score of 32 or higher indicates severe alcoholic hepatitis and has been used as the threshold for starting treatment with corticosteroids.⁶

The MDF has limitations. Patients with a score lower than 32 are considered not to have severe alcoholic hepatitis, but up to 17% of them still die. Also, since it uses the prothrombin time, its results can vary considerably among laboratories, depending on the sensitivity of the thromboplastin reagent used.

The MELD (Model for End-stage Liver Disease) score. Sheth et al²³ compared the MELD and the MDF scores in assessing the severity of alcoholic hepatitis. They found that the MELD performed as well as the MDF in predicting 30-day mortality. A MELD score of greater than 11 had a sensitivity in predicting 30-day mortality of 86% and a specificity of 81%, compared with 86% and 48%, respectively, for MDF scores greater than 32.

Another study found a MELD score of 21 to have the highest sensitivity and specificity in predicting mortality (an estimated 90-day death rate of 20%). Thus, a MELD score of 21 is an appropriate threshold for prompt consideration of specific therapies such as corticosteroids.²⁴

The MELD score has become increasingly important in patients with alcoholic hepatitis, as some of them may become candidates for liver transplantation (see below). Also, serial MELD scores in hospitalized patients have prognostic implications, since an increase of 2 or more points in the first week has been shown to predict in-hospital mortality.²⁵

The GAHS (Glasgow Alcoholic Hepatitis Score)²⁶ was shown to identify patients with alcoholic hepatitis who have an especially poor prognosis and need corticosteroid therapy. In those with a GAHS of 9 or higher, the 28-day survival rate was 78% with corticosteroid treatment and 52% without corticosteroid treatment; survival rates at 84 days were 59% and 38%, respectively.²⁶

The ABIC scoring system (Age, Serum Bilirubin, INR, and Serum Creatinine) stratifies patients by risk of death at 90 days²⁷:

• Score less than 6.71: low risk (100% survival)
• A score 6.71–8.99: intermediate risk (70% survival)
• A score 9.0 or higher: high risk (25% survival). 

Both the GAHS and ABIC score are limited by lack of external validation.

The Lille score.²⁸ While the above scores are used to identify patients at risk of death from alcoholic hepatitis and to decide on starting corticosteroids, the Lille score is designed to assess response to corticosteroids after 1 week of treatment. It is calculated based on five pretreatment variables and the change in serum bilirubin level at day 7 of corticosteroid therapy. Lille scores range from 0 to 1; a score higher than 0.45 is associated with a 75% mortality rate at 6 months and indicates a lack of response to corticosteroids and that these drugs should be discontinued.²⁸

MANAGEMENT

Supportive treatment

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis. Early management of alcohol abuse or dependence is, therefore, warranted in all patients with alcoholic hepatitis. Referral to addiction specialists, motivational therapies, and anticraving drugs such as baclofen can be utilized.

Treat alcohol withdrawal. Alcoholics who suddenly decrease or discontinue their alcohol use are at high risk of alcohol withdrawal syndrome. Within 24 hours after the last drink, patients can experience increases in their heart rate and blood pressure, along with irritability and hyperreflexia. Within the next few days, more dangerous complications including seizures and delirium tremens can arise.

Alcohol withdrawal symptoms should be treated with short-acting benzodiazepines or clomethiazole, keeping the risk of worsening encephalopathy in mind.²⁹ If present, complications of cirrhosis such as encephalopathy, ascites, and variceal bleeding should be managed.

Usual presentation: Rapid onset of jaundice in a person with a history of heavy alcohol use

Nutritional support is important. Protein-calorie malnutrition is common in alcoholics, as are deficiencies of vitamin A, vitamin D, thiamine, folate, pyridoxine, and zinc.³⁰ Although a randomized controlled trial comparing enteral nutrition (2,000 kcal/day) vs corticosteroids (prednisolone 40 mg/day) in patients with alcoholic hepatitis did not show any difference in the 28-day mortality rate, those who received nutritional support and survived the first month had a lower mortality rate than those treated with corticosteroids (8% vs 37%).³¹ A daily protein intake of 1.5 g per kilogram of body weight is therefore recommended, even in patients with hepatic encephalopathy.¹⁵

Combining enteral nutrition and corticosteroid treatment may have a synergistic effect but is yet to be investigated.

Screen for infection. Patients with alcoholic hepatitis should be screened for infection, as about 25% of those with severe alcoholic hepatitis have an infection at admission.³² Since many of these patients meet the criteria for systemic inflammatory response syndrome, infections can be particularly difficult to diagnose. Patients require close clinical monitoring as well as regular pancultures for early detection. Antibiotics are frequently started empirically even though we lack specific evidence-based guidelines on this practice.³³

Corticosteroids

Various studies have evaluated the role of corticosteroids in treating alcoholic hepatitis, differing considerably in sample populations, methods, and end points. Although the results of individual trials differ, meta-analyses indicate that corticosteroids have a moderate beneficial effect in patients with severe alcoholic hepatitis.

For example, Rambaldi et al³⁴ performed a meta-analysis that concluded the mortality rate was lower in alcoholic hepatitis patients with MDF scores of at least 32 or hepatic encephalopathy who were treated with corticosteroids than in controls (relative risk 0.37, 95% confidence interval 0.16–0.86).

Therefore, in the absence of contraindications, the AASLD recommends starting corticosteroids in patients with severe alcoholic hepatitis, defined as an MDF score of 32 or higher.²¹ The preferred agent is oral prednisolone 40 mg daily or parenteral methylprednisolone 32 mg daily for 4 weeks and then tapered over the next 2 to 4 weeks or abruptly discontinued. Because activation of prednisone is decreased in patients with liver disease, prednisolone (the active form) is preferred over prednisone (the inactive precursor).³⁵ In alcoholic hepatitis, the number needed to treat with corticosteroids to prevent one death has been calculated³⁶ at 5.

As mentioned, response to corticosteroids is commonly assessed at 1 week of treatment using the Lille score. A score higher than 0.45 predicts a poor response and should trigger discontinuation of corticosteroids, particularly in those classified as null responders (Lille score > 0.56).

Typical biochemical derangements include elevated AST and, to a lesser extent, ALT

Adverse effects of steroids include sepsis, gastrointestinal bleeding, and steroid psychosis. Of note, patients who have evidence of hepatorenal syndrome or gastrointestinal bleeding tend to have a less favorable response to corticosteroids. Also, while infections were once considered a contraindication to steroid therapy, recent evidence suggests that steroid use might not be precluded in infected patients after appropriate antibiotic therapy. Infections occur in about a quarter of all alcoholic hepatitis patients treated with steroids, more frequently in null responders (42.5%) than in responders (11.1%), which supports corticosteroid discontinuance at 1 week in null responders.³²

Pentoxifylline

An oral phosphodiesterase inhibitor, pentoxifylline, also inhibits production of several cytokines, including tumor necrosis factor alpha. At a dose of 400 mg orally three times daily for 4 weeks, pentoxifylline has been used in treating severe alcoholic hepatitis (MDF score ≥ 32) and is recommended especially if corticosteroids are contraindicated, as with sepsis.²¹

An early double-blind clinical trial randomized patients with severe alcoholic hepatitis to receive either pentoxifylline 400 mg orally three times daily or placebo. Of the patients who received pentoxifylline, 24.5% died during the index hospitalization, compared with 46.1% of patients who received placebo. This survival benefit was mainly related to a markedly lower incidence of hepatorenal syndrome as the cause of death in the pentoxifylline group than in the placebo group (50% vs 91.7% of deaths).³⁷

In a small clinical trial in patients with severe alcoholic hepatitis, pentoxifylline recipients had a higher 3-month survival rate than prednisolone recipients (35.29% vs 14.71%, P = .04).³⁸ However, a larger trial showed no improvement in 6-month survival with the combination of prednisolone and pentoxifylline compared with prednisolone alone (69.9% vs 69.2%, P = .91).³⁹ Also, a meta-analysis of five randomized clinical trials found no survival benefit with pentoxifylline therapy.⁴⁰

Of note, in the unfortunate subgroup of patients who have a poor response to corticosteroids, no alternative treatment, including pentoxifylline, has been shown to be effective.⁴¹

Prednisone or pentoxifylline? Very recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial have been released.⁴² This is a large, multicenter, double-blinded clinical trial that aimed to provide a definitive answer to whether corticosteroids or pentoxifylline (or both) are beneficial in patients with alcoholic hepatitis. The study included 1,103 adult patients with severe alcoholic hepatitis (MDF score ≥ 32) who were randomized to monotherapy with prednisolone or pentoxifylline, combination therapy, or placebo. The primary end point was mortality at 28 days, and secondary end points included mortality at 90 days and at 1 year. Prednisolone reduced 28-day mortality by about 39%. In contrast, the 28-day mortality rate was similar in patients who received pentoxifylline and those who did not. Also, neither drug was significantly associated with a survival benefit beyond 28 days. The investigators concluded that pentoxifylline has no impact on disease progression and should not be used for the treatment of severe alcoholic hepatitis.⁴²

Other tumor necrosis factor alpha inhibitors not recommended

Two other tumor necrosis factor alpha inhibitors, infliximab and etanercept, have been tested in clinical trials in alcoholic hepatitis. Unfortunately, the results were not encouraging, with no major reduction in mortality.^43–45 In fact, these trials demonstrated a significantly increased risk of infections in the treatment groups. Therefore, these drugs are not recommended for treating alcoholic hepatitis.

A possible explanation is that tumor necrosis factor alpha plays an important role in liver regeneration, aiding in recovery from alcohol-induced liver injury, and inhibiting it can have deleterious consequences.

Other agents

A number of other agents have undergone clinical trials in alcoholic hepatitis.

N-acetylcysteine, an antioxidant that replenishes glutathione stores in hepatocytes, was evaluated in a randomized clinical trial in combination with prednisolone.⁴⁶ Although the 1-month mortality rate was significantly lower in the combination group than in the prednisolone-only group (8% vs 24%, P = .006), 3-month and 6-month mortality rates were not. Nonetheless, the rates of infection and hepatorenal syndrome were lower in the combination group. Therefore, corticosteroids and N-acetylcysteine may have synergistic effects, but the optimum duration of N-acetylcysteine therapy needs to be determined in further studies.

Vitamin E, silymarin, propylthiouracil, colchicine, and oxandrolone (an anabolic steroid) have also been studied, but with no convincing benefit.²¹

Role of liver transplantation

Liver transplantation for alcoholic liver disease has been a topic of great medical and social controversy. The view that alcoholic patients are responsible for their own illness led to caution when contemplating liver transplantation. Many countries require 6 months of abstinence from alcohol before placing a patient on the liver transplant list, posing a major obstacle to patients with alcoholic hepatitis, as almost all are active drinkers at the time of presentation and many will die within 6 months. Reasons for this 6-month rule include donor shortage and risk of recidivism.⁴⁷

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis

With regard to survival following alcoholic hepatitis, a study utilizing the United Network for Organ Sharing database matched patients with alcoholic hepatitis and alcoholic cirrhosis who underwent liver transplantation. Rates of 5-year graft survival were 75% in those with alcoholic hepatitis and 73% in those with alcoholic cirrhosis (P = .97), and rates of patient survival were 80% and 78% (P = .90), respectively. Proportional regression analysis adjusting for other variables showed no impact of the etiology of liver disease on graft or patient survival. The investigators concluded that liver transplantation could be considered in a select group of patients with alcoholic hepatitis who do not improve with medical therapy.⁴⁸

In a pivotal case-control prospective study,⁴⁹ 26 patients with Lille scores greater than 0.45 were listed for liver transplantation within a median of 13 days after nonresponse to medical therapy. The cumulative 6-month survival rate was higher in patients who received a liver transplant early than in those who did not (77% vs 23%, P < .001). This benefit was maintained through 2 years of follow-up (hazard ratio 6.08, P = .004). Of note, all these patients had supportive family members, no severe coexisting conditions, and a commitment to alcohol abstinence (although 3 patients resumed drinking after liver transplantation).⁴⁹

Although these studies support early liver transplantation in carefully selected patients with severe alcoholic hepatitis, the criteria for transplantation in this group need to be refined. Views on alcoholism also need to be reconciled, as strong evidence is emerging that implicates genetic and environmental influences on alcohol dependence.

Management algorithm

FIGURE 2 shows a suggested management algorithm for alcoholic hepatitis, adapted from the guidelines of the AASLD and European Association for the Study of the Liver.

NEW THERAPIES NEEDED

Novel therapies for severe alcoholic hepatitis are urgently needed to help combat this devastating condition. Advances in understanding its pathophysiology have uncovered several new therapeutic targets, and new agents are already being evaluated in clinical trials.

IMM 124-E, a hyperimmune bovine colostrum enriched with immunoglobulin G anti-
lipopolysaccharide, is going to be evaluated in combination with prednisolone in patients with severe alcoholic hepatitis.

Anakinra, an interleukin 1 receptor antagonist, has significant anti-inflammatory activity and is used to treat rheumatoid arthritis. A clinical trial to evaluate its role in alcoholic hepatitis has been designed in which patients with severe alcoholic hepatitis (defined as a MELD score ≥ 21) will be randomized to receive either methylprednisolone or a combination of anakinra, pentoxifylline, and zinc (a mineral that improves gut integrity).

Emricasan, an orally active caspase protease inhibitor, is another agent currently being tested in a phase 2 clinical trial in patients with severe alcoholic hepatitis. Since caspases induce apoptosis, inhibiting them should theoretically dampen alcohol-induced hepatocyte injury.

Interleukin 22, a hepatoprotective cytokine, shows promise as a treatment and will soon be evaluated in alcoholic hepatitis.

TAKE THE POST-TEST AND COMPLETE THE CME PROCESS

ALCOHOLIC HEPATITIS, a severe manifestation of alcoholic liver disease, is rising in incidence. Complete abstinence from alcohol remains the cornerstone of treatment, while other specific interventions aim to decrease short-term mortality rates.

Despite current treatments, about 25% of patients with severe alcoholic hepatitis eventually die of it. For those who survive hospitalization, measures need to be taken to prevent recidivism. Although liver transplantation seems to hold promise, early transplantation is still largely experimental in alcoholic hepatitis and will likely be available to only a small subset of patients, especially in view of ethical issues and the possible wider implications for transplant centers.

New treatments will largely depend on a better understanding of the disease’s pathophysiology, and future clinical trials should evaluate therapies that improve short-term as well as long-term outcomes.

ACUTE HEPATIC DECOMPENSATION IN A HEAVY DRINKER

Excessive alcohol consumption is very common worldwide, is a major risk factor for liver disease, and is a leading cause of preventable death. Alcoholic cirrhosis is the eighth most common cause of death in the United States and in 2010 was responsible for nearly half of cirrhosis-related deaths worldwide.¹

Alcoholic liver disease is a spectrum. Nearly all heavy drinkers (ie, those consuming 40 g or more of alcohol per day, TABLE 1) have fatty liver changes, 20% to 40% develop fibrosis, 10% to 20% progress to cirrhosis, and of those with cirrhosis, 1% to 2% are diagnosed with hepatocellular carcinoma every year.²

Within this spectrum, alcoholic hepatitis is a well-defined clinical syndrome characterized by acute hepatic decompensation that typically results from long-standing alcohol abuse. Binge drinkers may also be at risk for alcoholic hepatitis, but good data on the association between drinking patterns and the risk of alcoholic hepatitis are limited.

Alcoholic hepatitis varies in severity from mild to life-threatening.³ Although its exact incidence is unknown, its prevalence in alcoholics has been estimated at 20%.⁴ Nearly half of patients with alcoholic hepatitis have cirrhosis at the time of their acute presentation, and these patients generally have a poor prognosis, with a 28-day death rate as high as 50% in severe cases.^5,6 Moreover, although alcoholic hepatitis develops in only a subset of patients with alcoholic liver disease, hospitalizations for it are increasing in the United States.⁷

Women are at higher risk of developing alcoholic hepatitis, an observation attributed to the effect of estrogens on oxidative stress and inflammation, lower gastric alcohol dehydrogenase levels resulting in slower first-pass metabolism of alcohol, and higher body fat content causing a lower volume of distribution for alcohol than in men.⁸ The incidence of alcoholic hepatitis is also influenced by a number of demographic and genetic factors as well as nutritional status and coexistence of other liver diseases.⁹ Most patients diagnosed with alcoholic hepatitis are active drinkers, but it can develop even after significantly reducing or stopping alcohol consumption.

FATTY ACIDS, ENZYMES, CYTOKINES, INFLAMMATION

Alcohol consumption induces fatty acid synthesis and inhibits fatty acid oxidation, thereby promoting fat deposition in the liver.

The major enzymes involved in alcohol metabolism are cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase. CYP2E1 is inducible and is up-regulated when excess alcohol is ingested, while alcohol dehydrogen-
ase function is relatively stable. Oxidative degradation of alcohol by these enzymes generates reactive oxygen species and acetaldehyde, inducing liver injury.¹⁰ Interestingly, it has been proposed that variations in the genes for these enzymes influence alcohol consumption and dependency as well as alcohol-driven tissue damage.

In addition, alcohol disrupts the intestinal mucosal barrier, allowing lipopolysaccharides from gram-negative bacteria to travel to the liver via the portal vein. These lipopolysaccharides then bind to and activate sinusoidal Kupffer cells, leading to production of several cytokines such as tumor necrosis factor alpha, interleukin 1, and transforming growth factor beta. These cytokines promote hepatocyte inflammation, apoptosis, and necrosis (FIGURE 1).¹¹

Besides activating the innate immune system, the reactive oxygen species resulting from alcohol metabolism interact with cellular components, leading to production of protein adducts. These act as antigens that activate the adaptive immune response, followed by B- and T-lymphocyte infiltration, which in turn contribute to liver injury and inflammation.¹²

THE DIAGNOSIS IS MAINLY CLINICAL

The diagnosis of alcoholic hepatitis is mainly clinical. In its usual presentation, jaundice develops rapidly in a person with a known history of heavy alcohol use. Other symptoms and signs may include ascites, encephalopathy, and fever. On examination, the liver may be enlarged and tender, and a hepatic bruit has been reported.¹³

Other classic signs of liver disease such as parotid enlargement, Dupuytren contracture, dilated abdominal wall veins, and spider nevi can be present, but none is highly specific or sensitive for alcoholic hepatitis.

Elevated liver enzymes and other clues

Laboratory tests are important in evaluating potential alcoholic hepatitis, although no single laboratory marker can definitively establish alcohol as the cause of liver disease. To detect alcohol consumption, biochemical markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), mean corpuscular volume, carbohydrate-deficient transferrin, and, more commonly, gamma-glutamyl transpeptidase are used.

In the acute setting, typical biochemical derangements in alcoholic hepatitis include elevated AST (up to 2 to 6 times the upper limit of normal; usually less than 300 IU/L) and elevated ALT to a lesser extent,¹⁴ with an AST-to-ALT ratio greater than 2. Neutrophilia, anemia, hyperbilirubinemia, and coagulopathy with an elevated international normalized ratio are common.

Patients with alcoholic hepatitis are also prone to develop bacterial infections, and about 7% develop hepatorenal syndrome, itself an ominous sign.¹⁵

Imaging studies are valuable in excluding other causes of abnormal liver test results in patients who abuse alcohol, such as biliary obstruction, infiltrative liver diseases, and hepatocellular carcinoma.

Screen for alcohol intake

Women are at higher risk of developing alcoholic hepatitis

During the initial evaluation of suspected alcoholic hepatitis, one should screen for excessive drinking. In a US Centers for Disease Control and Prevention study, only one of six US adults, including binge drinkers, said they had ever discussed alcohol consumption with a health professional.¹⁶ Many patients with alcoholic liver disease in general and alcoholic hepatitis in particular deny alcohol abuse or underreport their intake.¹⁷

Screening tests such as the CAGE questionnaire and the Alcohol Use Disorders Identification Test can be used to assess alcohol dependence or abuse.^18,19 The CAGE questionnaire consists of four questions:

• Have you ever felt you should cut down on your drinking?
• Have people annoyed you by criticizing your drinking?
• Have you ever felt guilty about your drinking?
• Have you ever had a drink first thing in the morning (an eye-opener) to steady your nerves or to get rid of a hangover?

A yes answer to two or more questions is considered clinically significant.

Is liver biopsy always needed?

Although alcoholic hepatitis can be suspected on the basis of clinical and biochemical clues, liver biopsy remains the gold standard diagnostic tool. It confirms the clinical diagnosis of alcoholic hepatitis in about 85% of all patients and in up to 95% when significant hyperbilirubinemia is present.²⁰

However, whether a particular patient needs a biopsy is not always clear. The American Association for the Study of Liver Diseases (AASLD) recommends biopsy in patients who have a clinical diagnosis of severe alcoholic hepatitis for whom medical treatment is being considered and in those with an uncertain underlying diagnosis.

Findings on liver biopsy in alcoholic hepatitis include steatosis, hepatocyte ballooning, neutrophilic infiltration, Mallory bodies (which represent aggregated cytokeratin intermediate filaments and other proteins), and scarring with a typical perivenular distribution as opposed to the periportal fibrosis seen in chronic viral hepatitis. Some histologic findings, such as centrilobular necrosis, may overlap alcoholic hepatitis and nonalcoholic steatohepatitis.

In addition to confirming the diagnosis and staging the disease, liver biopsy has prognostic value. The severity of inflammation and cholestatic changes correlates with poor prognosis and may also predict response to corticosteroid treatment in severe cases of alcoholic hepatitis.²¹

However, the utility of liver biopsy in confirming the diagnosis and assessing the prognosis of alcoholic hepatitis is controversial for several reasons. Coagulopathy, thrombocytopenia, and ascites are all common in patients with alcoholic hepatitis, often making percutaneous liver biopsy contraindicated. Trans-
jugular liver biopsy is not universally available outside tertiary care centers.

The major enzymes involved in alcohol metabolism are CYP2E1 and ADH

Needed is a minimally invasive test for assessing this disease. Breath analysis might be such a test, offering a noninvasive means to study the composition of volatile organic compounds and elemental gases and an attractive method to evaluate health and disease in a patient-friendly manner. Our group devised a model based on breath levels of trimethylamine and pentane. When we tested it, we found that it distinguishes patients with alcoholic hepatitis from those with acute liver decompensation from causes other than alcohol and controls without liver disease with up to 90% sensitivity and 80% specificity.²²

ASSESSING THE SEVERITY OF ALCOHOLIC HEPATITIS

Several models have been developed to assess the severity of alcoholic hepatitis and guide treatment decisions (TABLE 2). 

The MDF (Maddrey Discriminant Function)⁶ system was the first scoring system developed and is still the most widely used. A score of 32 or higher indicates severe alcoholic hepatitis and has been used as the threshold for starting treatment with corticosteroids.⁶

The MDF has limitations. Patients with a score lower than 32 are considered not to have severe alcoholic hepatitis, but up to 17% of them still die. Also, since it uses the prothrombin time, its results can vary considerably among laboratories, depending on the sensitivity of the thromboplastin reagent used.

The MELD (Model for End-stage Liver Disease) score. Sheth et al²³ compared the MELD and the MDF scores in assessing the severity of alcoholic hepatitis. They found that the MELD performed as well as the MDF in predicting 30-day mortality. A MELD score of greater than 11 had a sensitivity in predicting 30-day mortality of 86% and a specificity of 81%, compared with 86% and 48%, respectively, for MDF scores greater than 32.

Another study found a MELD score of 21 to have the highest sensitivity and specificity in predicting mortality (an estimated 90-day death rate of 20%). Thus, a MELD score of 21 is an appropriate threshold for prompt consideration of specific therapies such as corticosteroids.²⁴

The MELD score has become increasingly important in patients with alcoholic hepatitis, as some of them may become candidates for liver transplantation (see below). Also, serial MELD scores in hospitalized patients have prognostic implications, since an increase of 2 or more points in the first week has been shown to predict in-hospital mortality.²⁵

The GAHS (Glasgow Alcoholic Hepatitis Score)²⁶ was shown to identify patients with alcoholic hepatitis who have an especially poor prognosis and need corticosteroid therapy. In those with a GAHS of 9 or higher, the 28-day survival rate was 78% with corticosteroid treatment and 52% without corticosteroid treatment; survival rates at 84 days were 59% and 38%, respectively.²⁶

The ABIC scoring system (Age, Serum Bilirubin, INR, and Serum Creatinine) stratifies patients by risk of death at 90 days²⁷:

• Score less than 6.71: low risk (100% survival)
• A score 6.71–8.99: intermediate risk (70% survival)
• A score 9.0 or higher: high risk (25% survival). 

Both the GAHS and ABIC score are limited by lack of external validation.

The Lille score.²⁸ While the above scores are used to identify patients at risk of death from alcoholic hepatitis and to decide on starting corticosteroids, the Lille score is designed to assess response to corticosteroids after 1 week of treatment. It is calculated based on five pretreatment variables and the change in serum bilirubin level at day 7 of corticosteroid therapy. Lille scores range from 0 to 1; a score higher than 0.45 is associated with a 75% mortality rate at 6 months and indicates a lack of response to corticosteroids and that these drugs should be discontinued.²⁸

MANAGEMENT

Supportive treatment

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis. Early management of alcohol abuse or dependence is, therefore, warranted in all patients with alcoholic hepatitis. Referral to addiction specialists, motivational therapies, and anticraving drugs such as baclofen can be utilized.

Treat alcohol withdrawal. Alcoholics who suddenly decrease or discontinue their alcohol use are at high risk of alcohol withdrawal syndrome. Within 24 hours after the last drink, patients can experience increases in their heart rate and blood pressure, along with irritability and hyperreflexia. Within the next few days, more dangerous complications including seizures and delirium tremens can arise.

Alcohol withdrawal symptoms should be treated with short-acting benzodiazepines or clomethiazole, keeping the risk of worsening encephalopathy in mind.²⁹ If present, complications of cirrhosis such as encephalopathy, ascites, and variceal bleeding should be managed.

Usual presentation: Rapid onset of jaundice in a person with a history of heavy alcohol use

Nutritional support is important. Protein-calorie malnutrition is common in alcoholics, as are deficiencies of vitamin A, vitamin D, thiamine, folate, pyridoxine, and zinc.³⁰ Although a randomized controlled trial comparing enteral nutrition (2,000 kcal/day) vs corticosteroids (prednisolone 40 mg/day) in patients with alcoholic hepatitis did not show any difference in the 28-day mortality rate, those who received nutritional support and survived the first month had a lower mortality rate than those treated with corticosteroids (8% vs 37%).³¹ A daily protein intake of 1.5 g per kilogram of body weight is therefore recommended, even in patients with hepatic encephalopathy.¹⁵

Combining enteral nutrition and corticosteroid treatment may have a synergistic effect but is yet to be investigated.

Screen for infection. Patients with alcoholic hepatitis should be screened for infection, as about 25% of those with severe alcoholic hepatitis have an infection at admission.³² Since many of these patients meet the criteria for systemic inflammatory response syndrome, infections can be particularly difficult to diagnose. Patients require close clinical monitoring as well as regular pancultures for early detection. Antibiotics are frequently started empirically even though we lack specific evidence-based guidelines on this practice.³³

Corticosteroids

Various studies have evaluated the role of corticosteroids in treating alcoholic hepatitis, differing considerably in sample populations, methods, and end points. Although the results of individual trials differ, meta-analyses indicate that corticosteroids have a moderate beneficial effect in patients with severe alcoholic hepatitis.

For example, Rambaldi et al³⁴ performed a meta-analysis that concluded the mortality rate was lower in alcoholic hepatitis patients with MDF scores of at least 32 or hepatic encephalopathy who were treated with corticosteroids than in controls (relative risk 0.37, 95% confidence interval 0.16–0.86).

Therefore, in the absence of contraindications, the AASLD recommends starting corticosteroids in patients with severe alcoholic hepatitis, defined as an MDF score of 32 or higher.²¹ The preferred agent is oral prednisolone 40 mg daily or parenteral methylprednisolone 32 mg daily for 4 weeks and then tapered over the next 2 to 4 weeks or abruptly discontinued. Because activation of prednisone is decreased in patients with liver disease, prednisolone (the active form) is preferred over prednisone (the inactive precursor).³⁵ In alcoholic hepatitis, the number needed to treat with corticosteroids to prevent one death has been calculated³⁶ at 5.

As mentioned, response to corticosteroids is commonly assessed at 1 week of treatment using the Lille score. A score higher than 0.45 predicts a poor response and should trigger discontinuation of corticosteroids, particularly in those classified as null responders (Lille score > 0.56).

Typical biochemical derangements include elevated AST and, to a lesser extent, ALT

Adverse effects of steroids include sepsis, gastrointestinal bleeding, and steroid psychosis. Of note, patients who have evidence of hepatorenal syndrome or gastrointestinal bleeding tend to have a less favorable response to corticosteroids. Also, while infections were once considered a contraindication to steroid therapy, recent evidence suggests that steroid use might not be precluded in infected patients after appropriate antibiotic therapy. Infections occur in about a quarter of all alcoholic hepatitis patients treated with steroids, more frequently in null responders (42.5%) than in responders (11.1%), which supports corticosteroid discontinuance at 1 week in null responders.³²

Pentoxifylline

An oral phosphodiesterase inhibitor, pentoxifylline, also inhibits production of several cytokines, including tumor necrosis factor alpha. At a dose of 400 mg orally three times daily for 4 weeks, pentoxifylline has been used in treating severe alcoholic hepatitis (MDF score ≥ 32) and is recommended especially if corticosteroids are contraindicated, as with sepsis.²¹

An early double-blind clinical trial randomized patients with severe alcoholic hepatitis to receive either pentoxifylline 400 mg orally three times daily or placebo. Of the patients who received pentoxifylline, 24.5% died during the index hospitalization, compared with 46.1% of patients who received placebo. This survival benefit was mainly related to a markedly lower incidence of hepatorenal syndrome as the cause of death in the pentoxifylline group than in the placebo group (50% vs 91.7% of deaths).³⁷

In a small clinical trial in patients with severe alcoholic hepatitis, pentoxifylline recipients had a higher 3-month survival rate than prednisolone recipients (35.29% vs 14.71%, P = .04).³⁸ However, a larger trial showed no improvement in 6-month survival with the combination of prednisolone and pentoxifylline compared with prednisolone alone (69.9% vs 69.2%, P = .91).³⁹ Also, a meta-analysis of five randomized clinical trials found no survival benefit with pentoxifylline therapy.⁴⁰

Of note, in the unfortunate subgroup of patients who have a poor response to corticosteroids, no alternative treatment, including pentoxifylline, has been shown to be effective.⁴¹

Prednisone or pentoxifylline? Very recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial have been released.⁴² This is a large, multicenter, double-blinded clinical trial that aimed to provide a definitive answer to whether corticosteroids or pentoxifylline (or both) are beneficial in patients with alcoholic hepatitis. The study included 1,103 adult patients with severe alcoholic hepatitis (MDF score ≥ 32) who were randomized to monotherapy with prednisolone or pentoxifylline, combination therapy, or placebo. The primary end point was mortality at 28 days, and secondary end points included mortality at 90 days and at 1 year. Prednisolone reduced 28-day mortality by about 39%. In contrast, the 28-day mortality rate was similar in patients who received pentoxifylline and those who did not. Also, neither drug was significantly associated with a survival benefit beyond 28 days. The investigators concluded that pentoxifylline has no impact on disease progression and should not be used for the treatment of severe alcoholic hepatitis.⁴²

Other tumor necrosis factor alpha inhibitors not recommended

Two other tumor necrosis factor alpha inhibitors, infliximab and etanercept, have been tested in clinical trials in alcoholic hepatitis. Unfortunately, the results were not encouraging, with no major reduction in mortality.^43–45 In fact, these trials demonstrated a significantly increased risk of infections in the treatment groups. Therefore, these drugs are not recommended for treating alcoholic hepatitis.

A possible explanation is that tumor necrosis factor alpha plays an important role in liver regeneration, aiding in recovery from alcohol-induced liver injury, and inhibiting it can have deleterious consequences.

Other agents

A number of other agents have undergone clinical trials in alcoholic hepatitis.

N-acetylcysteine, an antioxidant that replenishes glutathione stores in hepatocytes, was evaluated in a randomized clinical trial in combination with prednisolone.⁴⁶ Although the 1-month mortality rate was significantly lower in the combination group than in the prednisolone-only group (8% vs 24%, P = .006), 3-month and 6-month mortality rates were not. Nonetheless, the rates of infection and hepatorenal syndrome were lower in the combination group. Therefore, corticosteroids and N-acetylcysteine may have synergistic effects, but the optimum duration of N-acetylcysteine therapy needs to be determined in further studies.

Vitamin E, silymarin, propylthiouracil, colchicine, and oxandrolone (an anabolic steroid) have also been studied, but with no convincing benefit.²¹

Role of liver transplantation

Liver transplantation for alcoholic liver disease has been a topic of great medical and social controversy. The view that alcoholic patients are responsible for their own illness led to caution when contemplating liver transplantation. Many countries require 6 months of abstinence from alcohol before placing a patient on the liver transplant list, posing a major obstacle to patients with alcoholic hepatitis, as almost all are active drinkers at the time of presentation and many will die within 6 months. Reasons for this 6-month rule include donor shortage and risk of recidivism.⁴⁷

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis

With regard to survival following alcoholic hepatitis, a study utilizing the United Network for Organ Sharing database matched patients with alcoholic hepatitis and alcoholic cirrhosis who underwent liver transplantation. Rates of 5-year graft survival were 75% in those with alcoholic hepatitis and 73% in those with alcoholic cirrhosis (P = .97), and rates of patient survival were 80% and 78% (P = .90), respectively. Proportional regression analysis adjusting for other variables showed no impact of the etiology of liver disease on graft or patient survival. The investigators concluded that liver transplantation could be considered in a select group of patients with alcoholic hepatitis who do not improve with medical therapy.⁴⁸

In a pivotal case-control prospective study,⁴⁹ 26 patients with Lille scores greater than 0.45 were listed for liver transplantation within a median of 13 days after nonresponse to medical therapy. The cumulative 6-month survival rate was higher in patients who received a liver transplant early than in those who did not (77% vs 23%, P < .001). This benefit was maintained through 2 years of follow-up (hazard ratio 6.08, P = .004). Of note, all these patients had supportive family members, no severe coexisting conditions, and a commitment to alcohol abstinence (although 3 patients resumed drinking after liver transplantation).⁴⁹

Although these studies support early liver transplantation in carefully selected patients with severe alcoholic hepatitis, the criteria for transplantation in this group need to be refined. Views on alcoholism also need to be reconciled, as strong evidence is emerging that implicates genetic and environmental influences on alcohol dependence.

Management algorithm

FIGURE 2 shows a suggested management algorithm for alcoholic hepatitis, adapted from the guidelines of the AASLD and European Association for the Study of the Liver.

NEW THERAPIES NEEDED

Novel therapies for severe alcoholic hepatitis are urgently needed to help combat this devastating condition. Advances in understanding its pathophysiology have uncovered several new therapeutic targets, and new agents are already being evaluated in clinical trials.

IMM 124-E, a hyperimmune bovine colostrum enriched with immunoglobulin G anti-
lipopolysaccharide, is going to be evaluated in combination with prednisolone in patients with severe alcoholic hepatitis.

Anakinra, an interleukin 1 receptor antagonist, has significant anti-inflammatory activity and is used to treat rheumatoid arthritis. A clinical trial to evaluate its role in alcoholic hepatitis has been designed in which patients with severe alcoholic hepatitis (defined as a MELD score ≥ 21) will be randomized to receive either methylprednisolone or a combination of anakinra, pentoxifylline, and zinc (a mineral that improves gut integrity).

Emricasan, an orally active caspase protease inhibitor, is another agent currently being tested in a phase 2 clinical trial in patients with severe alcoholic hepatitis. Since caspases induce apoptosis, inhibiting them should theoretically dampen alcohol-induced hepatocyte injury.

Interleukin 22, a hepatoprotective cytokine, shows promise as a treatment and will soon be evaluated in alcoholic hepatitis.

TAKE THE POST-TEST AND COMPLETE THE CME PROCESS

ALCOHOLIC HEPATITIS, a severe manifestation of alcoholic liver disease, is rising in incidence. Complete abstinence from alcohol remains the cornerstone of treatment, while other specific interventions aim to decrease short-term mortality rates.

Despite current treatments, about 25% of patients with severe alcoholic hepatitis eventually die of it. For those who survive hospitalization, measures need to be taken to prevent recidivism. Although liver transplantation seems to hold promise, early transplantation is still largely experimental in alcoholic hepatitis and will likely be available to only a small subset of patients, especially in view of ethical issues and the possible wider implications for transplant centers.

New treatments will largely depend on a better understanding of the disease’s pathophysiology, and future clinical trials should evaluate therapies that improve short-term as well as long-term outcomes.

ACUTE HEPATIC DECOMPENSATION IN A HEAVY DRINKER

Excessive alcohol consumption is very common worldwide, is a major risk factor for liver disease, and is a leading cause of preventable death. Alcoholic cirrhosis is the eighth most common cause of death in the United States and in 2010 was responsible for nearly half of cirrhosis-related deaths worldwide.¹

Alcoholic liver disease is a spectrum. Nearly all heavy drinkers (ie, those consuming 40 g or more of alcohol per day, TABLE 1) have fatty liver changes, 20% to 40% develop fibrosis, 10% to 20% progress to cirrhosis, and of those with cirrhosis, 1% to 2% are diagnosed with hepatocellular carcinoma every year.²

Within this spectrum, alcoholic hepatitis is a well-defined clinical syndrome characterized by acute hepatic decompensation that typically results from long-standing alcohol abuse. Binge drinkers may also be at risk for alcoholic hepatitis, but good data on the association between drinking patterns and the risk of alcoholic hepatitis are limited.

Alcoholic hepatitis varies in severity from mild to life-threatening.³ Although its exact incidence is unknown, its prevalence in alcoholics has been estimated at 20%.⁴ Nearly half of patients with alcoholic hepatitis have cirrhosis at the time of their acute presentation, and these patients generally have a poor prognosis, with a 28-day death rate as high as 50% in severe cases.^5,6 Moreover, although alcoholic hepatitis develops in only a subset of patients with alcoholic liver disease, hospitalizations for it are increasing in the United States.⁷

Women are at higher risk of developing alcoholic hepatitis, an observation attributed to the effect of estrogens on oxidative stress and inflammation, lower gastric alcohol dehydrogenase levels resulting in slower first-pass metabolism of alcohol, and higher body fat content causing a lower volume of distribution for alcohol than in men.⁸ The incidence of alcoholic hepatitis is also influenced by a number of demographic and genetic factors as well as nutritional status and coexistence of other liver diseases.⁹ Most patients diagnosed with alcoholic hepatitis are active drinkers, but it can develop even after significantly reducing or stopping alcohol consumption.

FATTY ACIDS, ENZYMES, CYTOKINES, INFLAMMATION

Alcohol consumption induces fatty acid synthesis and inhibits fatty acid oxidation, thereby promoting fat deposition in the liver.

The major enzymes involved in alcohol metabolism are cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase. CYP2E1 is inducible and is up-regulated when excess alcohol is ingested, while alcohol dehydrogen-
ase function is relatively stable. Oxidative degradation of alcohol by these enzymes generates reactive oxygen species and acetaldehyde, inducing liver injury.¹⁰ Interestingly, it has been proposed that variations in the genes for these enzymes influence alcohol consumption and dependency as well as alcohol-driven tissue damage.

In addition, alcohol disrupts the intestinal mucosal barrier, allowing lipopolysaccharides from gram-negative bacteria to travel to the liver via the portal vein. These lipopolysaccharides then bind to and activate sinusoidal Kupffer cells, leading to production of several cytokines such as tumor necrosis factor alpha, interleukin 1, and transforming growth factor beta. These cytokines promote hepatocyte inflammation, apoptosis, and necrosis (FIGURE 1).¹¹

Besides activating the innate immune system, the reactive oxygen species resulting from alcohol metabolism interact with cellular components, leading to production of protein adducts. These act as antigens that activate the adaptive immune response, followed by B- and T-lymphocyte infiltration, which in turn contribute to liver injury and inflammation.¹²

THE DIAGNOSIS IS MAINLY CLINICAL

The diagnosis of alcoholic hepatitis is mainly clinical. In its usual presentation, jaundice develops rapidly in a person with a known history of heavy alcohol use. Other symptoms and signs may include ascites, encephalopathy, and fever. On examination, the liver may be enlarged and tender, and a hepatic bruit has been reported.¹³

Other classic signs of liver disease such as parotid enlargement, Dupuytren contracture, dilated abdominal wall veins, and spider nevi can be present, but none is highly specific or sensitive for alcoholic hepatitis.

Elevated liver enzymes and other clues

Laboratory tests are important in evaluating potential alcoholic hepatitis, although no single laboratory marker can definitively establish alcohol as the cause of liver disease. To detect alcohol consumption, biochemical markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), mean corpuscular volume, carbohydrate-deficient transferrin, and, more commonly, gamma-glutamyl transpeptidase are used.

In the acute setting, typical biochemical derangements in alcoholic hepatitis include elevated AST (up to 2 to 6 times the upper limit of normal; usually less than 300 IU/L) and elevated ALT to a lesser extent,¹⁴ with an AST-to-ALT ratio greater than 2. Neutrophilia, anemia, hyperbilirubinemia, and coagulopathy with an elevated international normalized ratio are common.

Patients with alcoholic hepatitis are also prone to develop bacterial infections, and about 7% develop hepatorenal syndrome, itself an ominous sign.¹⁵

Imaging studies are valuable in excluding other causes of abnormal liver test results in patients who abuse alcohol, such as biliary obstruction, infiltrative liver diseases, and hepatocellular carcinoma.

Screen for alcohol intake

Women are at higher risk of developing alcoholic hepatitis

During the initial evaluation of suspected alcoholic hepatitis, one should screen for excessive drinking. In a US Centers for Disease Control and Prevention study, only one of six US adults, including binge drinkers, said they had ever discussed alcohol consumption with a health professional.¹⁶ Many patients with alcoholic liver disease in general and alcoholic hepatitis in particular deny alcohol abuse or underreport their intake.¹⁷

Screening tests such as the CAGE questionnaire and the Alcohol Use Disorders Identification Test can be used to assess alcohol dependence or abuse.^18,19 The CAGE questionnaire consists of four questions:

• Have you ever felt you should cut down on your drinking?
• Have people annoyed you by criticizing your drinking?
• Have you ever felt guilty about your drinking?
• Have you ever had a drink first thing in the morning (an eye-opener) to steady your nerves or to get rid of a hangover?

A yes answer to two or more questions is considered clinically significant.

Is liver biopsy always needed?

Although alcoholic hepatitis can be suspected on the basis of clinical and biochemical clues, liver biopsy remains the gold standard diagnostic tool. It confirms the clinical diagnosis of alcoholic hepatitis in about 85% of all patients and in up to 95% when significant hyperbilirubinemia is present.²⁰

However, whether a particular patient needs a biopsy is not always clear. The American Association for the Study of Liver Diseases (AASLD) recommends biopsy in patients who have a clinical diagnosis of severe alcoholic hepatitis for whom medical treatment is being considered and in those with an uncertain underlying diagnosis.

Findings on liver biopsy in alcoholic hepatitis include steatosis, hepatocyte ballooning, neutrophilic infiltration, Mallory bodies (which represent aggregated cytokeratin intermediate filaments and other proteins), and scarring with a typical perivenular distribution as opposed to the periportal fibrosis seen in chronic viral hepatitis. Some histologic findings, such as centrilobular necrosis, may overlap alcoholic hepatitis and nonalcoholic steatohepatitis.

In addition to confirming the diagnosis and staging the disease, liver biopsy has prognostic value. The severity of inflammation and cholestatic changes correlates with poor prognosis and may also predict response to corticosteroid treatment in severe cases of alcoholic hepatitis.²¹

However, the utility of liver biopsy in confirming the diagnosis and assessing the prognosis of alcoholic hepatitis is controversial for several reasons. Coagulopathy, thrombocytopenia, and ascites are all common in patients with alcoholic hepatitis, often making percutaneous liver biopsy contraindicated. Trans-
jugular liver biopsy is not universally available outside tertiary care centers.

The major enzymes involved in alcohol metabolism are CYP2E1 and ADH

Needed is a minimally invasive test for assessing this disease. Breath analysis might be such a test, offering a noninvasive means to study the composition of volatile organic compounds and elemental gases and an attractive method to evaluate health and disease in a patient-friendly manner. Our group devised a model based on breath levels of trimethylamine and pentane. When we tested it, we found that it distinguishes patients with alcoholic hepatitis from those with acute liver decompensation from causes other than alcohol and controls without liver disease with up to 90% sensitivity and 80% specificity.²²

ASSESSING THE SEVERITY OF ALCOHOLIC HEPATITIS

Several models have been developed to assess the severity of alcoholic hepatitis and guide treatment decisions (TABLE 2). 

The MDF (Maddrey Discriminant Function)⁶ system was the first scoring system developed and is still the most widely used. A score of 32 or higher indicates severe alcoholic hepatitis and has been used as the threshold for starting treatment with corticosteroids.⁶

The MDF has limitations. Patients with a score lower than 32 are considered not to have severe alcoholic hepatitis, but up to 17% of them still die. Also, since it uses the prothrombin time, its results can vary considerably among laboratories, depending on the sensitivity of the thromboplastin reagent used.

The MELD (Model for End-stage Liver Disease) score. Sheth et al²³ compared the MELD and the MDF scores in assessing the severity of alcoholic hepatitis. They found that the MELD performed as well as the MDF in predicting 30-day mortality. A MELD score of greater than 11 had a sensitivity in predicting 30-day mortality of 86% and a specificity of 81%, compared with 86% and 48%, respectively, for MDF scores greater than 32.

Another study found a MELD score of 21 to have the highest sensitivity and specificity in predicting mortality (an estimated 90-day death rate of 20%). Thus, a MELD score of 21 is an appropriate threshold for prompt consideration of specific therapies such as corticosteroids.²⁴

The MELD score has become increasingly important in patients with alcoholic hepatitis, as some of them may become candidates for liver transplantation (see below). Also, serial MELD scores in hospitalized patients have prognostic implications, since an increase of 2 or more points in the first week has been shown to predict in-hospital mortality.²⁵

The GAHS (Glasgow Alcoholic Hepatitis Score)²⁶ was shown to identify patients with alcoholic hepatitis who have an especially poor prognosis and need corticosteroid therapy. In those with a GAHS of 9 or higher, the 28-day survival rate was 78% with corticosteroid treatment and 52% without corticosteroid treatment; survival rates at 84 days were 59% and 38%, respectively.²⁶

The ABIC scoring system (Age, Serum Bilirubin, INR, and Serum Creatinine) stratifies patients by risk of death at 90 days²⁷:

• Score less than 6.71: low risk (100% survival)
• A score 6.71–8.99: intermediate risk (70% survival)
• A score 9.0 or higher: high risk (25% survival). 

Both the GAHS and ABIC score are limited by lack of external validation.

The Lille score.²⁸ While the above scores are used to identify patients at risk of death from alcoholic hepatitis and to decide on starting corticosteroids, the Lille score is designed to assess response to corticosteroids after 1 week of treatment. It is calculated based on five pretreatment variables and the change in serum bilirubin level at day 7 of corticosteroid therapy. Lille scores range from 0 to 1; a score higher than 0.45 is associated with a 75% mortality rate at 6 months and indicates a lack of response to corticosteroids and that these drugs should be discontinued.²⁸

MANAGEMENT

Supportive treatment

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis. Early management of alcohol abuse or dependence is, therefore, warranted in all patients with alcoholic hepatitis. Referral to addiction specialists, motivational therapies, and anticraving drugs such as baclofen can be utilized.

Treat alcohol withdrawal. Alcoholics who suddenly decrease or discontinue their alcohol use are at high risk of alcohol withdrawal syndrome. Within 24 hours after the last drink, patients can experience increases in their heart rate and blood pressure, along with irritability and hyperreflexia. Within the next few days, more dangerous complications including seizures and delirium tremens can arise.

Alcohol withdrawal symptoms should be treated with short-acting benzodiazepines or clomethiazole, keeping the risk of worsening encephalopathy in mind.²⁹ If present, complications of cirrhosis such as encephalopathy, ascites, and variceal bleeding should be managed.

Usual presentation: Rapid onset of jaundice in a person with a history of heavy alcohol use

Nutritional support is important. Protein-calorie malnutrition is common in alcoholics, as are deficiencies of vitamin A, vitamin D, thiamine, folate, pyridoxine, and zinc.³⁰ Although a randomized controlled trial comparing enteral nutrition (2,000 kcal/day) vs corticosteroids (prednisolone 40 mg/day) in patients with alcoholic hepatitis did not show any difference in the 28-day mortality rate, those who received nutritional support and survived the first month had a lower mortality rate than those treated with corticosteroids (8% vs 37%).³¹ A daily protein intake of 1.5 g per kilogram of body weight is therefore recommended, even in patients with hepatic encephalopathy.¹⁵

Combining enteral nutrition and corticosteroid treatment may have a synergistic effect but is yet to be investigated.

Screen for infection. Patients with alcoholic hepatitis should be screened for infection, as about 25% of those with severe alcoholic hepatitis have an infection at admission.³² Since many of these patients meet the criteria for systemic inflammatory response syndrome, infections can be particularly difficult to diagnose. Patients require close clinical monitoring as well as regular pancultures for early detection. Antibiotics are frequently started empirically even though we lack specific evidence-based guidelines on this practice.³³

Corticosteroids

Various studies have evaluated the role of corticosteroids in treating alcoholic hepatitis, differing considerably in sample populations, methods, and end points. Although the results of individual trials differ, meta-analyses indicate that corticosteroids have a moderate beneficial effect in patients with severe alcoholic hepatitis.

For example, Rambaldi et al³⁴ performed a meta-analysis that concluded the mortality rate was lower in alcoholic hepatitis patients with MDF scores of at least 32 or hepatic encephalopathy who were treated with corticosteroids than in controls (relative risk 0.37, 95% confidence interval 0.16–0.86).

Therefore, in the absence of contraindications, the AASLD recommends starting corticosteroids in patients with severe alcoholic hepatitis, defined as an MDF score of 32 or higher.²¹ The preferred agent is oral prednisolone 40 mg daily or parenteral methylprednisolone 32 mg daily for 4 weeks and then tapered over the next 2 to 4 weeks or abruptly discontinued. Because activation of prednisone is decreased in patients with liver disease, prednisolone (the active form) is preferred over prednisone (the inactive precursor).³⁵ In alcoholic hepatitis, the number needed to treat with corticosteroids to prevent one death has been calculated³⁶ at 5.

As mentioned, response to corticosteroids is commonly assessed at 1 week of treatment using the Lille score. A score higher than 0.45 predicts a poor response and should trigger discontinuation of corticosteroids, particularly in those classified as null responders (Lille score > 0.56).

Typical biochemical derangements include elevated AST and, to a lesser extent, ALT

Adverse effects of steroids include sepsis, gastrointestinal bleeding, and steroid psychosis. Of note, patients who have evidence of hepatorenal syndrome or gastrointestinal bleeding tend to have a less favorable response to corticosteroids. Also, while infections were once considered a contraindication to steroid therapy, recent evidence suggests that steroid use might not be precluded in infected patients after appropriate antibiotic therapy. Infections occur in about a quarter of all alcoholic hepatitis patients treated with steroids, more frequently in null responders (42.5%) than in responders (11.1%), which supports corticosteroid discontinuance at 1 week in null responders.³²

Pentoxifylline

An oral phosphodiesterase inhibitor, pentoxifylline, also inhibits production of several cytokines, including tumor necrosis factor alpha. At a dose of 400 mg orally three times daily for 4 weeks, pentoxifylline has been used in treating severe alcoholic hepatitis (MDF score ≥ 32) and is recommended especially if corticosteroids are contraindicated, as with sepsis.²¹

An early double-blind clinical trial randomized patients with severe alcoholic hepatitis to receive either pentoxifylline 400 mg orally three times daily or placebo. Of the patients who received pentoxifylline, 24.5% died during the index hospitalization, compared with 46.1% of patients who received placebo. This survival benefit was mainly related to a markedly lower incidence of hepatorenal syndrome as the cause of death in the pentoxifylline group than in the placebo group (50% vs 91.7% of deaths).³⁷

In a small clinical trial in patients with severe alcoholic hepatitis, pentoxifylline recipients had a higher 3-month survival rate than prednisolone recipients (35.29% vs 14.71%, P = .04).³⁸ However, a larger trial showed no improvement in 6-month survival with the combination of prednisolone and pentoxifylline compared with prednisolone alone (69.9% vs 69.2%, P = .91).³⁹ Also, a meta-analysis of five randomized clinical trials found no survival benefit with pentoxifylline therapy.⁴⁰

Of note, in the unfortunate subgroup of patients who have a poor response to corticosteroids, no alternative treatment, including pentoxifylline, has been shown to be effective.⁴¹

Prednisone or pentoxifylline? Very recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial have been released.⁴² This is a large, multicenter, double-blinded clinical trial that aimed to provide a definitive answer to whether corticosteroids or pentoxifylline (or both) are beneficial in patients with alcoholic hepatitis. The study included 1,103 adult patients with severe alcoholic hepatitis (MDF score ≥ 32) who were randomized to monotherapy with prednisolone or pentoxifylline, combination therapy, or placebo. The primary end point was mortality at 28 days, and secondary end points included mortality at 90 days and at 1 year. Prednisolone reduced 28-day mortality by about 39%. In contrast, the 28-day mortality rate was similar in patients who received pentoxifylline and those who did not. Also, neither drug was significantly associated with a survival benefit beyond 28 days. The investigators concluded that pentoxifylline has no impact on disease progression and should not be used for the treatment of severe alcoholic hepatitis.⁴²

Other tumor necrosis factor alpha inhibitors not recommended

Two other tumor necrosis factor alpha inhibitors, infliximab and etanercept, have been tested in clinical trials in alcoholic hepatitis. Unfortunately, the results were not encouraging, with no major reduction in mortality.^43–45 In fact, these trials demonstrated a significantly increased risk of infections in the treatment groups. Therefore, these drugs are not recommended for treating alcoholic hepatitis.

A possible explanation is that tumor necrosis factor alpha plays an important role in liver regeneration, aiding in recovery from alcohol-induced liver injury, and inhibiting it can have deleterious consequences.

Other agents

A number of other agents have undergone clinical trials in alcoholic hepatitis.

N-acetylcysteine, an antioxidant that replenishes glutathione stores in hepatocytes, was evaluated in a randomized clinical trial in combination with prednisolone.⁴⁶ Although the 1-month mortality rate was significantly lower in the combination group than in the prednisolone-only group (8% vs 24%, P = .006), 3-month and 6-month mortality rates were not. Nonetheless, the rates of infection and hepatorenal syndrome were lower in the combination group. Therefore, corticosteroids and N-acetylcysteine may have synergistic effects, but the optimum duration of N-acetylcysteine therapy needs to be determined in further studies.

Vitamin E, silymarin, propylthiouracil, colchicine, and oxandrolone (an anabolic steroid) have also been studied, but with no convincing benefit.²¹

Role of liver transplantation

Liver transplantation for alcoholic liver disease has been a topic of great medical and social controversy. The view that alcoholic patients are responsible for their own illness led to caution when contemplating liver transplantation. Many countries require 6 months of abstinence from alcohol before placing a patient on the liver transplant list, posing a major obstacle to patients with alcoholic hepatitis, as almost all are active drinkers at the time of presentation and many will die within 6 months. Reasons for this 6-month rule include donor shortage and risk of recidivism.⁴⁷

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis

With regard to survival following alcoholic hepatitis, a study utilizing the United Network for Organ Sharing database matched patients with alcoholic hepatitis and alcoholic cirrhosis who underwent liver transplantation. Rates of 5-year graft survival were 75% in those with alcoholic hepatitis and 73% in those with alcoholic cirrhosis (P = .97), and rates of patient survival were 80% and 78% (P = .90), respectively. Proportional regression analysis adjusting for other variables showed no impact of the etiology of liver disease on graft or patient survival. The investigators concluded that liver transplantation could be considered in a select group of patients with alcoholic hepatitis who do not improve with medical therapy.⁴⁸

In a pivotal case-control prospective study,⁴⁹ 26 patients with Lille scores greater than 0.45 were listed for liver transplantation within a median of 13 days after nonresponse to medical therapy. The cumulative 6-month survival rate was higher in patients who received a liver transplant early than in those who did not (77% vs 23%, P < .001). This benefit was maintained through 2 years of follow-up (hazard ratio 6.08, P = .004). Of note, all these patients had supportive family members, no severe coexisting conditions, and a commitment to alcohol abstinence (although 3 patients resumed drinking after liver transplantation).⁴⁹

Although these studies support early liver transplantation in carefully selected patients with severe alcoholic hepatitis, the criteria for transplantation in this group need to be refined. Views on alcoholism also need to be reconciled, as strong evidence is emerging that implicates genetic and environmental influences on alcohol dependence.

Management algorithm

FIGURE 2 shows a suggested management algorithm for alcoholic hepatitis, adapted from the guidelines of the AASLD and European Association for the Study of the Liver.

NEW THERAPIES NEEDED

Novel therapies for severe alcoholic hepatitis are urgently needed to help combat this devastating condition. Advances in understanding its pathophysiology have uncovered several new therapeutic targets, and new agents are already being evaluated in clinical trials.

IMM 124-E, a hyperimmune bovine colostrum enriched with immunoglobulin G anti-
lipopolysaccharide, is going to be evaluated in combination with prednisolone in patients with severe alcoholic hepatitis.

Anakinra, an interleukin 1 receptor antagonist, has significant anti-inflammatory activity and is used to treat rheumatoid arthritis. A clinical trial to evaluate its role in alcoholic hepatitis has been designed in which patients with severe alcoholic hepatitis (defined as a MELD score ≥ 21) will be randomized to receive either methylprednisolone or a combination of anakinra, pentoxifylline, and zinc (a mineral that improves gut integrity).

Emricasan, an orally active caspase protease inhibitor, is another agent currently being tested in a phase 2 clinical trial in patients with severe alcoholic hepatitis. Since caspases induce apoptosis, inhibiting them should theoretically dampen alcohol-induced hepatocyte injury.

Interleukin 22, a hepatoprotective cytokine, shows promise as a treatment and will soon be evaluated in alcoholic hepatitis.

TAKE THE POST-TEST AND COMPLETE THE CME PROCESS

THE IMMUNOSUPPRESSED STATE of liver transplant recipients makes them vulnerable to infections after surgery.¹ These infections are directly correlated with the net state of immunosuppression. Higher levels of immunosuppression mean a higher risk of infection, with rates of infection typically highest in the early posttransplant period.

Common infections during this period include operative and perioperative nosocomial bacterial and fungal infections, reactivation of latent infections, and invasive fungal infections such as candidiasis, aspergillosis, and pneumocystosis. Donor-derived infections also must be considered. As time passes and the level of immunosuppression is reduced, liver recipients are less prone to infection.¹

The risk of infection can be minimized by appropriate antimicrobial prophylaxis, strategies for safe living after transplant,² vaccination,³ careful balancing of immunosuppressive therapy,⁴ and thoughtful donor selection.⁵ Drug-drug interactions are common and must be carefully considered to minimize the risk.

This review highlights common infectious complications encountered after liver transplant.

INTRA-ABDOMINAL INFECTIONS

Intra-abdominal infections are common in the early postoperative period.^6,7

Risk factors include:

• Pretransplant ascites
• Posttransplant dialysis
• Wound infection
• Reoperation⁸
• Hepatic artery thrombosis
• Roux-en-Y choledochojejunostomy anastomosis.⁹

Signs that may indicate intra-abdominal infection include fever, abdominal pain, leukocytosis, and elevated liver enzymes. But because of their immunosuppressed state, transplant recipients may not manifest fever as readily as the general population. They should be evaluated for cholangitis, peritonitis, biloma, and intra-abdominal abscess.

Organisms. Intra-abdominal infections are often polymicrobial. Enterococci, Staphylococcus aureus, gram-negative species including Pseudomonas, Klebsiella, and Acinetobacter, and Candida species are the most common pathogens. Strains are often resistant to multiple drugs, especially in patients who received antibiotics in the weeks before transplant.^8,10

Liver transplant recipients are also particularly susceptible to Clostridium difficile-associated colitis as a result of immunosuppression and frequent use of antibiotics perioperatively and postoperatively.¹¹ The spectrum of C difficile infection ranges from mild diarrhea to life-threatening colitis, and the course in liver transplant patients tends to be more complicated than in immunocompetent patients.¹²

Diagnosis. Intra-abdominal infections should be looked for and treated promptly, as they are associated with a higher mortality rate, a greater risk of graft loss, and a higher incidence of retransplant.^6,10 Abdominal ultrasonography or computed tomography (CT) can confirm the presence of fluid collections.

Treatment. Infected collections can be treated with percutaneous or surgical drainage and antimicrobial therapy. In the case of biliary tract complications, retransplant or surgical correction of biliary leakage or stenosis decreases the risk of death.⁶

Suspicion should be high for C difficile-associated colitis in cases of posttransplant diarrhea. C difficile toxin stool assays help confirm the diagnosis.¹² Oral metronidazole is recommended in mild to moderate C difficile infection, with oral vancomycin and intravenous metronidazole reserved for severe cases. Colectomy may be necessary in patients with toxic megacolon.

CYTOMEGALOVIRUS INFECTION

Cytomegalovirus is an important opportunistic pathogen in liver transplant recipients.¹³ It causes a range of manifestations, from infection (viremia with or without symptoms) to cytomegalovirus syndrome (fever, malaise, and cell-line cytopenias) to tissue-invasive disease with end-organ disease.¹⁴ Without preventive measures and treatment, cytomegalovirus disease can increase the risk of morbidity, allograft loss and death.^15,16

Risk factors for cytomegalovirus infection (Table 1) include:

• Discordant serostatus of the donor and recipient (the risk is highest in seronegative recipients of organs from seropositive donors)
• Higher levels of immunosuppression, especially when antilymphocyte antibodies are used
• Treatment of graft rejection
• Coinfection with other human herpesviruses, such as Epstein-Barr virus.^4,17

Preventing cytomegalovirus infection

The strategy to prevent cytomegalovirus infection depends on the serologic status of the donor and recipient and may include antiviral prophylaxis or preemptive treatment (Table 2).¹⁸

Prophylaxis involves giving antiviral drugs during the early high-risk period, with the goal of preventing the development of cytomegalovirus viremia. The alternative preemptive strategy emphasizes serial testing for cytomegalovirus viremia, with the goal of intervening with antiviral medications while viremia is at a low level, thus avoiding potential progression to cytomegalovirus disease. Both strategies have pros and cons that should be considered by each transplant center when setting institutional policy.

A prophylactic approach seems very effective at preventing both infection and disease from cytomegalovirus and has been shown to reduce graft rejection and the risk of death.¹⁸ It is preferred in cytomegalovirus-negative recipients when the donor was cytomegalovirus-positive—a high-risk situation.¹⁹ However, these patients are also at higher risk of late-onset cytomegalovirus disease. Higher cost and potential drug toxicity, mainly neutropenia from ganciclovir-based regimens, are additional considerations.

Preemptive treatment, in contrast, reserves drug treatment for patients who are actually infected with cytomegalovirus, thus resulting in fewer adverse drug events and lower cost; but it requires regular monitoring. Preemptive methods, by definition, cannot prevent infection, and with this strategy tissue-invasive disease not associated with viremia does occasionally occur.²⁰ As such, patients with a clinical presentation that suggests cytomegalovirus but have negative results on blood testing should be considered for tissue biopsy with culture and immunohistochemical stain.

The most commonly used regimens for antiviral prophylaxis and treatment in liver transplant recipients are intravenous ganciclovir and oral valganciclovir.²¹ Although valganciclovir is the most commonly used agent in this setting because of ease of administration, it has not been approved by the US Food and Drug Administration in liver transplant patients, as it was associated with higher rates of cytomegalovirus tissue-invasive disease.^22–24 Additionally, drug-resistant cytomegalovirus strains have been associated with valganciclovir prophylaxis in cytomegalovirus-negative recipients of solid organs from cytomegalovirus-positive donors.²⁵

Prophylaxis typically consists of therapy for 3 months from the time of transplant. In higher-risk patients (donor-positive, recipient-negative), longer courses of prophylaxis have been extrapolated from data in kidney transplant recipients.²⁶ Extension or reinstitution of prophylaxis should also be considered in liver transplant patients receiving treatment for rejection with antilymphocyte therapy.

Routine screening for cytomegalovirus is not recommended while patients are receiving prophylaxis. High-risk patients who are not receiving prophylaxis should be monitored with nucleic acid or pp65 antigenemia testing as part of the preemptive strategy protocol.

Treatment of cytomegalovirus disease

Although no specific threshold has been established, treatment is generally indicated if a patient has a consistent clinical syndrome, evidence of tissue injury, and persistent or increasing viremia.

Treatment involves giving antiviral drugs and also reducing the level of immunosuppression, if possible, until symptoms and viremia have resolved.

The choice of antiviral therapy depends on the severity of disease. Intravenous ganciclovir (5 mg/kg twice daily adjusted for renal impairment) or oral valganciclovir (900 mg twice daily, also renally dose-adjusted when necessary) can be used for mild to moderate disease if no significant gastrointestinal involvement is reported. Intravenous ganciclovir is preferred for patients with more severe disease or gastrointestinal involvement. The minimum duration of treatment is 2 weeks and may need to be prolonged until both symptoms and viremia completely resolve.¹⁸

Drug resistance can occur and should be considered in patients who have a history of prolonged ganciclovir or valganciclovir exposure who do not clinically improve or have persistent or rising viremia. In such cases, genotype assays are helpful, and initiation of alternative therapy should be considered. Mutations conferring resistance to ganciclovir are often associated with cross-resistance to cidofovir. Cidofovir can therefore be considered only when genotype assays demonstrate specific mutations conferring an isolated resistance to ganciclovir.²⁷ The addition of foscarnet to the ganciclovir regimen or substitution of foscarnet for ganciclovir are accepted approaches.

Although cytomegalovirus hyperimmunoglobulin has been used in prophylaxis and invasive disease treatment, its role in the management of ganciclovir-resistant cytomegalovirus infections remains controversial.²⁸

EPSTEIN-BARR VIRUS POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE

Epstein-Barr virus-associated posttransplant lymphoproliferative disease is a spectrum of disorders ranging from an infectious mononucleosis syndrome to aggressive malignancy with the potential for death and significant morbidity after liver transplant.²⁹ The timeline of risk varies, but the disease is most common in the first year after transplant.

Risk factors for this disease (Table 1) are:

• Primary Epstein-Barr virus infection
• Cytomegalovirus donor-recipient mismatch
• Cytomegalovirus disease
• Higher levels of immunosuppression, especially with antilymphocyte antibodies.³⁰

The likelihood of Epstein-Barr virus playing a contributing role is lower in later-onset posttransplant lymphoproliferative disease. Patients who are older at the time of transplant, who receive highly immunogenic allografts including a liver as a component of a multivisceral transplant, and who receive increased immunosuppression to treat rejection are at even greater risk of late posttransplant lymphoproliferative disease.³¹ This is in contrast to early posttransplant lymphoproliferative disease, which is seen more commonly in children as a result of primary Epstein-Barr virus infection.

Recognition and diagnosis. Heightened suspicion is required when considering posttransplant lymphoproliferative disease, and careful evaluation of consistent symptoms and allograft dysfunction are required.

Clinically, posttransplant lymphoproliferative disease should be suspected if a liver transplant recipient develops unexplained fever, weight loss, lymphadenopathy, or cell-line cytopenias.^30,32 Other signs and symptoms may be related to the organ involved and may include evidence of hepatitis, pneumonitis, and gastrointestinal disease.³¹

Adjunctive diagnostic testing includes donor and recipient serology to characterize overall risk before transplantation and quantification of Epstein-Barr viral load, but confirmation relies on tissue histopathology.

Treatment focuses on reducing immunosuppression.^30,32 Adding antiviral agents does not seem to improve outcome in all cases.³³ Depending on clinical response and histologic classification, additional therapies such as anti-CD20 humanized chimeric monoclonal antibodies, surgery, radiation, and conventional chemotherapy may be required.³⁴

Preventive approaches remain controversial. Chemoprophylaxis with an antiviral such as ganciclovir is occasionally used but has not been shown to consistently decrease rates of posttransplant lymphoproliferative disease. These agents may act in an indirect manner, leading to decreased rates of cytomegalovirus infection, a major cofactor for posttransplant lymphoproliferative disease.²⁴

Although oral valganciclovir is used more than intravenous ganciclovir, it is not approved for liver transplant patients

Passive immunoprophylaxis with immunoglobulin targeting cytomegalovirus has shown to decrease rates of non-Hodgkin lymphoma from posttransplant lymphoproliferative disease in renal transplant recipients in the first year after transplant,³⁵ but data are lacking regarding its use in liver transplant recipients. Monitoring of the viral load and subsequent reduction of immunosuppression remain the most efficient measures to date.³⁶

FUNGAL INFECTIONS

Candida species account for more than half of fungal infections in liver transplant recipients.³⁷ However, a change has been noted in the past 20 years, with a decrease in Candida infections accompanied by an increase in Aspergillus infections.³⁸ Endemic mycoses such as coccidioidomycosis, blastomycosis, and histoplasmosis should be considered with the appropriate epidemiologic history or if disease develops early after transplant and the donor came from a highly endemic region.³⁹Cryptococcus may also be encountered.

Diagnosis. One of the most challenging aspects of fungal infection in liver transplant recipients is timely diagnosis. Heightened suspicion and early biopsy for pathological and microbiological confirmation are necessary. Although available noninvasive diagnostic tools often lack specificity, early detection of fungal markers may be of great use in guiding further diagnostic workup or empiric treatment in the critically ill.

Noninvasive tests include galactomannan, cryptococcal antigen, histoplasma antigen, (1-3)-beta-D-glucan assay and various antibody tests. Galactomannan testing has been widely used to aid in the diagnosis of invasive aspergillosis. Similarly, the (1-3)-beta-D-glucan assay is a non–culture-based tool for diagnosing and monitoring the treatment of invasive fungal infections. However, a definite diagnosis cannot be made on the basis of a positive test alone.⁴⁰ The complementary diagnostic characteristics of combining noninvasive assays have yet to be fully elucidated.⁴¹ Cultures and tissue histopathology are also used when possible.

Treatment is based on targeted specific antifungal drug therapy and reduction of immunosuppressive therapy, when possible. The choice of antifungal agent varies with the pathogen, the site of involvement, and the severity of the disease. A focus on potential drug interactions, their management, and therapeutic drug monitoring when using antifungal medications is essential in the posttransplant period. Combination therapy can be considered in some situations to enhance synergy. The following sections discuss in greater detail Candida species, Aspergillus species, and Pneumocystis jirovecii infections.

Candida infections

Candidiasis after liver transplant is typically nosocomial, especially when diagnosed during the first 3 months (Table 3).³⁷

Risk factors for invasive candidiasis include perioperative colonization, prolonged operative time, retransplant, greater transfusion requirements, and postoperative renal failure.^37,42,43 Invasive candidiasis is of concern for its effects on morbidity, mortality, and cost of care.^43–46

Organisms. The frequency of implicated species, in particular those with a natural resistance to fluconazole, differs in various reports.^37,45,46Candida albicans remains the most commonly isolated pathogen; however, non-albicans species including those resistant to fluconazole have been reported more frequently and include Candida glabrata and Candida krusei.^47,48

Signs and diagnosis. Invasive candidiasis in liver transplant recipients generally manifests itself in catheter-related blood stream infections, urinary tract infections, or intra-abdominal infections. Diagnosis can be made by isolating Candida from blood cultures, recovering organisms in culture of a normally sterile site, or finding direct microscopic evidence of the fungus on tissue specimens.⁴⁹

Disseminated candidiasis refers to the involvement of distant anatomic sites. Clinical manifestations may cause vision changes, abdominal pain or skin nodules with findings of candidemia, hepatosplenic abscesses, or retinal exudates on funduscopy.⁴⁹

Treatment of invasive candidiasis in liver recipients often involves antifungal therapy and reduction of immunosuppression. Broad-spectrum antifungals are initially advocated in an empirical approach to cover fluconazole-resistant strains of the non-albicans subgroups.⁵⁰ Depending on antifungal susceptibility, treatment can later be adjusted.

Fluconazole remains the agent of choice in most C albicans infections.⁴⁷ However, attention should be paid to the possibility of resistance in patients who have received fluconazole prophylaxis within the past 30 days. Additional agents used in treatment may include echinocandins, amphotericin, and additional azoles.

Antifungal prophylaxis is recommended in high-risk liver transplant patients, although its optimal duration remains undetermined.⁴⁴ Antifungal prophylaxis has been associated with decreased incidence of both superficial and invasive candidiasis.⁵¹

Aspergillus infection

Aspergillus, the second most common fungal pathogen, has become a more common concern in liver transplant recipients. Aspergillus fumigatus is the most frequently encountered species.^38,52

Risk factors. These infections typically occur in the first year, during intense immunosuppression. Retransplant, renal failure, and fulminant hepatic failure are major risk factors.⁵² In the presence of risk factors and a suggestive clinical setting, invasive aspergillosis should be considered and the diagnosis pursued.

Diagnosis is suggested by positive findings on CT accompanied by lower respiratory tract symptoms, focal lesions on neuroimaging, or demonstration of the fungus on cultures.⁴⁹ However, Aspergillus is rarely grown in blood culture. The galactomannan antigen is a noninvasive test that can provide supporting evidence for the diagnosis.^41,52 False-positive results do occur in the setting of certain antibiotics and cross-reacting fungi.⁵³

Treatment consists of antifungal therapy and immunosuppression reduction.⁵²

Candida accounts for more than half of fungal infections in liver transplant recipients, but Aspergillus is gaining

Voriconazole is the first-line agent for invasive aspergillosis. Monitoring for potential drug-drug interactions and side effects is required.^54,55 Amphotericin B is considered a second-line choice due to toxicity and lack of an oral formulation. In refractory cases, combined antifungal therapy could be considered.⁵² The duration of treatment is generally a minimum of 12 weeks.

Prophylaxis. Specific prophylaxis against invasive aspergillosis is not currently recommended; however, some authors suggest a prophylactic approach using echinocandins or liposomal amphotericin B in high-risk patients.^51,52 Aspergillosis is associated with a considerable increase in mortality in liver transplant recipients, which highlights the importance of timely management.^52,56

Pneumocystis jirovecii

P jirovecii remains a common opportunistic pathogen in people with impaired immunity, including transplant and human immunodeficiency virus patients.

Prophylaxis. Widespread adoption of antimicrobial prophylaxis by transplant centers has decreased the rates of P jirovecii infection in liver transplant recipients.^57,58 Commonly used prophylactic regimens after liver transplantation include a single-strength trimeth­oprim-sulfamethoxazole tablet daily or a double-strength tablet three times per week for a minimum of 6 to 12 months after transplant. Atovaquone and dapsone can be used as alternatives in cases of intolerance to tri­methoprim-sulfamethoxazole (Table 2).

Inhaled pentamidine is clearly inferior and should be used only when the other medications are contraindicated.⁵⁹

Signs and diagnosis. P jirovecii pneumonia is characterized by fever, cough, dyspnea, and chest pain. Insidious hypoxemia, abnormal chest examination, and bilateral interstitial pneumonia on chest radiography are common.

CT may be more sensitive than chest radiography.⁵⁷ Findings suggestive of P jirovecii pneumonia on chest CT are extensive bilateral and symmetrical ground-glass attenuations. Other less-characteristic findings include upper lobar parenchymal opacities and spontaneous pneumothorax.^57,60

The serum (1,3)-beta-D-glucan assay derived from major cell-wall components of P jiro­vecii might be helpful. Studies report a sensitivity for P jirovecii pneumonia as high as 96% and a negative predictive value of 99.8%.^61,62

Definitive diagnosis requires identification of the pathogen. Routine expectorated sputum sampling is generally associated with a poor diagnostic yield. Bronchoscopy and bronchoalveolar lavage with silver or fluorescent antibody staining of samples, polymerase chain reaction testing, or both significantly improves diagnosis. Transbronchial or open lung biopsy are often unnecessary.⁵⁷

Treatment. Trimethoprim-sulfamethoxazole is the first-line agent for treating P jirovecii pneumonia.⁵⁷ The minimum duration of treatment is 14 days, with extended courses for severe infection.

Intravenous pentamidine or clindamycin plus primaquine are alternatives for patients who cannot tolerate trimethoprim-sulfamethoxazole. The major concern with intravenous pentamidine is renal dysfunction. Hypoglycemia or hyperglycemia, neutropenia, thrombocytopenia, nausea, dysgeusia, and pancreatitis may also occur.⁶³

Atovaquone might also be beneficial in mild to moderate P jirovecii pneumonia. The main side effects include skin rashes, gastrointestinal intolerance, and elevation of transaminases.⁶⁴

A corticosteroid (40–60 mg of prednisone or its equivalent) may be beneficial in conjunction with antimicrobial therapy in patients with significant hypoxia (partial pressure of arterial oxygen < 70 mm Hg on room air) in decreasing the risk of respiratory failure and need for intubation.

With appropriate and timely antimicrobial prophylaxis, cases of P jirovecii pneumonia should continue to decrease.

TUBERCULOSIS

Development of tuberculosis after transplantation is a catastrophic complication, with mortality rates of up to 30%.⁶⁵ Most cases of posttransplant tuberculosis represent reactivation of latent disease.⁶⁶ Screening with tuberculin skin tests or interferon-gamma-release assays is recommended in all liver transplant candidates. Chest radiography before transplant is necessary when assessing a positive screening test.⁶⁷

The optimal management of latent tuberculosis in these cases remains controversial. Patients at high risk or those with positive screening results on chest radiography warrant treatment for latent tuberculosis infection with isoniazid unless contraindicated.^67,68

The ideal time to initiate prophylactic isoniazid therapy is unclear. Some authors suggest delaying it, as it might be associated with poor tolerance and hepatotoxicity.⁶⁹ Others have found that early isoniazid use was not associated with negative outcomes.⁷⁰

Risk factors for symptomatic tuberculosis after liver transplant include previous infection with tuberculosis, intensified immunosuppression (especially anti-T-lymphocyte therapies), diabetes mellitus, and other co-infections (Table 1).⁷¹

The increased incidence of atypical presentations in recent years makes the diagnosis of active tuberculosis among liver transplant recipients challenging. Sputum smears can be negative due to low mycobacterial burdens, and tuberculin skin testing and interferon-gamma-release assays may be falsely negative due to immunosuppression.⁶⁷

Treatment of active tuberculosis consists initially of a four-drug regimen using isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months. Adjustments are made in accordance with culture and sensitivity results. Treatment can then be tapered to two drugs (isoniazid and rifampin) for a minimum of 4 additional months. Prolonged treatment may be required in instances of extrapulmonary or disseminated disease.^65,72

Tuberculosis treatment can be complicated by hepatotoxicity in liver transplant recipients because of direct drug effects and drug-drug interactions with immunosuppressive agents. Close monitoring for rejection and hepatotoxicity is therefore imperative while liver transplant recipients are receiving antituberculosis therapy. Drug-drug interactions may also be responsible for marked reductions in immunosuppression levels, especially with regimens containing rifampin.⁷¹ Substitution of rifabutin for rifampin reduces the effect of drug interactions.⁶⁶

VIRAL HEPATITIS

Hepatitis B virus

Hepatitis B virus-related end-stage liver disease and hepatocellular carcinoma are common indications for liver transplant in Asia. It is less common in the United States and Europe, accounting for less than 10% of all liver transplant cases. Prognosis is favorable in recipients undergoing liver transplant for hepatitis B virus, with excellent survival rates. Prevention of reinfection is crucial in these patients.

Treatment with combination antiviral agents and hepatitis B immunoglobulin (HBIG) is effective.⁷³ Lamivudine was the first nucleoside analogue found to be effective against hepatitis B virus. Its low cost and relative safety are strong arguments in favor of its continued use in liver transplant recipients.⁷⁴ In patients without evidence of hepatitis B viral replication at the time of transplant, monotherapy with lamivudine has led to low recurrence rates, and adefovir can be added to control resistant viral strains.⁷⁵

Widespread adoption of prophylaxis has decreased the rate of P jirovecii infection in liver transplant recipients

The frequent emergence of resistance with lamivudine favors newer agents such as entecavir or tenofovir. These nucleoside and nucleotide analogues have a higher barrier to resistance, and thus resistance to them is rare. They are also more efficient, potentially allowing use of an HBIG-sparing protocol.⁷⁶ However, they are associated with a higher risk of nephrotoxicity and require dose adjustments in renal insufficiency. Data directly comparing entecavir and tenofovir are scarce.

Prophylaxis. Most studies support an individualized approach for prevention of hepatitis B virus reinfection. High-risk patients, ie, those positive for HBe antigen or with high viral loads (> 100,000 copies/mL) are generally treated with both HBIG and antiviral agents.⁷⁷ Low-risk patients are those with a negative HBe antigen, low hepatitis B virus DNA levels, hepatitis B virus-related acute liver failure, and cirrhosis resulting from coinfection with both hepatitis B and hepatitis D virus.⁷⁵ In low-risk patients, discontinuation of HBIG after 1 to 2 years of treatment is appropriate, and long-term prophylaxis with antiviral agents alone is an option. However, levels of hepatitis B DNA should be monitored closely.^78,79

Hepatitis C virus

Recurrence of hepatitis C virus infection is the rule among patients who are viremic at the time of liver transplant.^80,81 Most of these patients will show histologic evidence of recurrent hepatitis within the first year after liver transplant. It is often difficult to distinguish between the histopathological appearance of a recurrent hepatitis C virus infection and acute cellular rejection.

Progression to fibrosis and subsequently cirrhosis and decompensation is highly variable in hepatitis C virus-infected liver transplant recipients. Diabetes, insulin resistance, and possibly hepatitis steatosis have been associated with a rapid progression to advanced fibrosis. The contribution of immunosuppression to the progression of hepatitis C virus remains an area of active study. Some studies point to antilymphocyte immunosuppressive agents as a potential cause.⁸² Liver biopsy is a useful tool in this situation. It allows monitoring of disease severity and progression and may distinguish recurrent hepatitis C virus disease from other causes of liver enzyme elevation.

The major concern with the recurrence of hepatitis C virus infection after liver transplant is allograft loss. Rates of patient and graft survival are reduced in infected patients compared with hepatitis C virus-negative patients.^83,84 Prophylactic antiviral therapy has no current role in the management of hepatitis C virus disease. Those manifesting moderate to severe necroinflammation or mild to moderate fibrosis indicative of progressive disease should be treated.^81,85

Sustained viral clearance with antiviral agents confers a graft survival benefit.

The combination of peg-interferon and weight-based ribavirin has been the standard of treatment but may be associated with increased rates of rejection.^86,87 The sustained virologic response rates for hepatitis C virus range from 60% in genotypes 4, 5, and 6 after 48 weeks of treatment to 60% to 80% in genotypes 2 and 3 after 24 weeks, but only about 30% in genotype 1.⁸⁸

The major concern with hepatitis C recurrence after liver transplant is allograft loss

Treatment with the newer agents, especially protease inhibitors, in genotype 1 (peg-interferon, ribavirin, and either telaprevir or boceprevir) has been evaluated. Success rates reaching 70% have been achieved.⁸⁹ Adverse effects can be a major setback. Serious complications include severe anemia, renal dysfunction, increased risk of infection, and death.

Triple therapy should be carefully considered in liver transplant patients with genotype 1 hepatitis C virus.⁹⁰ Significant drug-drug interactions are reported between hepatitis C virus protease inhibitors and immunosuppression regimens. Additional new oral direct- acting antivirals have been investigated. They bring promising advances in hepatitis C virus treatment and pave the way for interferon-free regimens with pangenotypic activity.

IMMUNIZATION

Immunization can decrease the risk of infectious complications in liver transplant recipients, as well as in close contacts and healthcare professionals.³

Influenza. Pretransplant influenza vaccine and posttransplant annual influenza vaccines are necessary.

Pneumococcal immunization should additionally be provided prior to transplant and repeated every 3 to 5 years thereafter.^3,91

A number of other vaccinations should also be completed before transplant, including the hepatitis A and B vaccines and the tetanus/diphtheria/acellular pertussis vaccines. However, these vaccinations have not been shown to be detrimental to patients after transplant.⁹¹

Varicella and zoster vaccines should be given before liver transplant—zoster in patients over age 60, and varicella in patients with no immunity. Live vaccines, including varicella and zoster vaccines, are contraindicated after liver transplant.³

Human papillomavirus. The bivalent human papillomavirus vaccine can be given before transplant in females ages 9 to 26; the quadrivalent vaccine is beneficial in those ages 9 to 26 and in women under age 45.^3,91

IMMUNOSUPPRESSION CARRIES RISK OF INFECTION

Most liver transplant patients require prolonged immunosuppressive therapy. This comes with an increased risk of new or recurrent infections, potentially causing death and significant morbidity.

Evaluation of existing risk factors, appropriate prophylaxis and immunization, timely diagnosis, and treatment of such infections are therefore essential steps for the successful management of liver transplant recipients.

*Dr. Taege has disclosed teaching, speaking, and membership on advisory committee or review panels for Gilead, and independent contracting (including contracted research) for Pfizer.

TAKE THE POST-TEST AND COMPLETE THE CME PROCESS

THE IMMUNOSUPPRESSED STATE of liver transplant recipients makes them vulnerable to infections after surgery.¹ These infections are directly correlated with the net state of immunosuppression. Higher levels of immunosuppression mean a higher risk of infection, with rates of infection typically highest in the early posttransplant period.

Common infections during this period include operative and perioperative nosocomial bacterial and fungal infections, reactivation of latent infections, and invasive fungal infections such as candidiasis, aspergillosis, and pneumocystosis. Donor-derived infections also must be considered. As time passes and the level of immunosuppression is reduced, liver recipients are less prone to infection.¹

The risk of infection can be minimized by appropriate antimicrobial prophylaxis, strategies for safe living after transplant,² vaccination,³ careful balancing of immunosuppressive therapy,⁴ and thoughtful donor selection.⁵ Drug-drug interactions are common and must be carefully considered to minimize the risk.

This review highlights common infectious complications encountered after liver transplant.

INTRA-ABDOMINAL INFECTIONS

Intra-abdominal infections are common in the early postoperative period.^6,7

Risk factors include:

• Pretransplant ascites
• Posttransplant dialysis
• Wound infection
• Reoperation⁸
• Hepatic artery thrombosis
• Roux-en-Y choledochojejunostomy anastomosis.⁹

Signs that may indicate intra-abdominal infection include fever, abdominal pain, leukocytosis, and elevated liver enzymes. But because of their immunosuppressed state, transplant recipients may not manifest fever as readily as the general population. They should be evaluated for cholangitis, peritonitis, biloma, and intra-abdominal abscess.

Organisms. Intra-abdominal infections are often polymicrobial. Enterococci, Staphylococcus aureus, gram-negative species including Pseudomonas, Klebsiella, and Acinetobacter, and Candida species are the most common pathogens. Strains are often resistant to multiple drugs, especially in patients who received antibiotics in the weeks before transplant.^8,10

Liver transplant recipients are also particularly susceptible to Clostridium difficile-associated colitis as a result of immunosuppression and frequent use of antibiotics perioperatively and postoperatively.¹¹ The spectrum of C difficile infection ranges from mild diarrhea to life-threatening colitis, and the course in liver transplant patients tends to be more complicated than in immunocompetent patients.¹²

Diagnosis. Intra-abdominal infections should be looked for and treated promptly, as they are associated with a higher mortality rate, a greater risk of graft loss, and a higher incidence of retransplant.^6,10 Abdominal ultrasonography or computed tomography (CT) can confirm the presence of fluid collections.

Treatment. Infected collections can be treated with percutaneous or surgical drainage and antimicrobial therapy. In the case of biliary tract complications, retransplant or surgical correction of biliary leakage or stenosis decreases the risk of death.⁶

Suspicion should be high for C difficile-associated colitis in cases of posttransplant diarrhea. C difficile toxin stool assays help confirm the diagnosis.¹² Oral metronidazole is recommended in mild to moderate C difficile infection, with oral vancomycin and intravenous metronidazole reserved for severe cases. Colectomy may be necessary in patients with toxic megacolon.

CYTOMEGALOVIRUS INFECTION

Cytomegalovirus is an important opportunistic pathogen in liver transplant recipients.¹³ It causes a range of manifestations, from infection (viremia with or without symptoms) to cytomegalovirus syndrome (fever, malaise, and cell-line cytopenias) to tissue-invasive disease with end-organ disease.¹⁴ Without preventive measures and treatment, cytomegalovirus disease can increase the risk of morbidity, allograft loss and death.^15,16

Risk factors for cytomegalovirus infection (Table 1) include:

• Discordant serostatus of the donor and recipient (the risk is highest in seronegative recipients of organs from seropositive donors)
• Higher levels of immunosuppression, especially when antilymphocyte antibodies are used
• Treatment of graft rejection
• Coinfection with other human herpesviruses, such as Epstein-Barr virus.^4,17

Preventing cytomegalovirus infection

The strategy to prevent cytomegalovirus infection depends on the serologic status of the donor and recipient and may include antiviral prophylaxis or preemptive treatment (Table 2).¹⁸

Prophylaxis involves giving antiviral drugs during the early high-risk period, with the goal of preventing the development of cytomegalovirus viremia. The alternative preemptive strategy emphasizes serial testing for cytomegalovirus viremia, with the goal of intervening with antiviral medications while viremia is at a low level, thus avoiding potential progression to cytomegalovirus disease. Both strategies have pros and cons that should be considered by each transplant center when setting institutional policy.

A prophylactic approach seems very effective at preventing both infection and disease from cytomegalovirus and has been shown to reduce graft rejection and the risk of death.¹⁸ It is preferred in cytomegalovirus-negative recipients when the donor was cytomegalovirus-positive—a high-risk situation.¹⁹ However, these patients are also at higher risk of late-onset cytomegalovirus disease. Higher cost and potential drug toxicity, mainly neutropenia from ganciclovir-based regimens, are additional considerations.

Preemptive treatment, in contrast, reserves drug treatment for patients who are actually infected with cytomegalovirus, thus resulting in fewer adverse drug events and lower cost; but it requires regular monitoring. Preemptive methods, by definition, cannot prevent infection, and with this strategy tissue-invasive disease not associated with viremia does occasionally occur.²⁰ As such, patients with a clinical presentation that suggests cytomegalovirus but have negative results on blood testing should be considered for tissue biopsy with culture and immunohistochemical stain.

The most commonly used regimens for antiviral prophylaxis and treatment in liver transplant recipients are intravenous ganciclovir and oral valganciclovir.²¹ Although valganciclovir is the most commonly used agent in this setting because of ease of administration, it has not been approved by the US Food and Drug Administration in liver transplant patients, as it was associated with higher rates of cytomegalovirus tissue-invasive disease.^22–24 Additionally, drug-resistant cytomegalovirus strains have been associated with valganciclovir prophylaxis in cytomegalovirus-negative recipients of solid organs from cytomegalovirus-positive donors.²⁵

Prophylaxis typically consists of therapy for 3 months from the time of transplant. In higher-risk patients (donor-positive, recipient-negative), longer courses of prophylaxis have been extrapolated from data in kidney transplant recipients.²⁶ Extension or reinstitution of prophylaxis should also be considered in liver transplant patients receiving treatment for rejection with antilymphocyte therapy.

Routine screening for cytomegalovirus is not recommended while patients are receiving prophylaxis. High-risk patients who are not receiving prophylaxis should be monitored with nucleic acid or pp65 antigenemia testing as part of the preemptive strategy protocol.

Treatment of cytomegalovirus disease

Although no specific threshold has been established, treatment is generally indicated if a patient has a consistent clinical syndrome, evidence of tissue injury, and persistent or increasing viremia.

Treatment involves giving antiviral drugs and also reducing the level of immunosuppression, if possible, until symptoms and viremia have resolved.

The choice of antiviral therapy depends on the severity of disease. Intravenous ganciclovir (5 mg/kg twice daily adjusted for renal impairment) or oral valganciclovir (900 mg twice daily, also renally dose-adjusted when necessary) can be used for mild to moderate disease if no significant gastrointestinal involvement is reported. Intravenous ganciclovir is preferred for patients with more severe disease or gastrointestinal involvement. The minimum duration of treatment is 2 weeks and may need to be prolonged until both symptoms and viremia completely resolve.¹⁸

Drug resistance can occur and should be considered in patients who have a history of prolonged ganciclovir or valganciclovir exposure who do not clinically improve or have persistent or rising viremia. In such cases, genotype assays are helpful, and initiation of alternative therapy should be considered. Mutations conferring resistance to ganciclovir are often associated with cross-resistance to cidofovir. Cidofovir can therefore be considered only when genotype assays demonstrate specific mutations conferring an isolated resistance to ganciclovir.²⁷ The addition of foscarnet to the ganciclovir regimen or substitution of foscarnet for ganciclovir are accepted approaches.

Although cytomegalovirus hyperimmunoglobulin has been used in prophylaxis and invasive disease treatment, its role in the management of ganciclovir-resistant cytomegalovirus infections remains controversial.²⁸

EPSTEIN-BARR VIRUS POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE

Epstein-Barr virus-associated posttransplant lymphoproliferative disease is a spectrum of disorders ranging from an infectious mononucleosis syndrome to aggressive malignancy with the potential for death and significant morbidity after liver transplant.²⁹ The timeline of risk varies, but the disease is most common in the first year after transplant.

Risk factors for this disease (Table 1) are:

• Primary Epstein-Barr virus infection
• Cytomegalovirus donor-recipient mismatch
• Cytomegalovirus disease
• Higher levels of immunosuppression, especially with antilymphocyte antibodies.³⁰

The likelihood of Epstein-Barr virus playing a contributing role is lower in later-onset posttransplant lymphoproliferative disease. Patients who are older at the time of transplant, who receive highly immunogenic allografts including a liver as a component of a multivisceral transplant, and who receive increased immunosuppression to treat rejection are at even greater risk of late posttransplant lymphoproliferative disease.³¹ This is in contrast to early posttransplant lymphoproliferative disease, which is seen more commonly in children as a result of primary Epstein-Barr virus infection.

Recognition and diagnosis. Heightened suspicion is required when considering posttransplant lymphoproliferative disease, and careful evaluation of consistent symptoms and allograft dysfunction are required.

Clinically, posttransplant lymphoproliferative disease should be suspected if a liver transplant recipient develops unexplained fever, weight loss, lymphadenopathy, or cell-line cytopenias.^30,32 Other signs and symptoms may be related to the organ involved and may include evidence of hepatitis, pneumonitis, and gastrointestinal disease.³¹

Adjunctive diagnostic testing includes donor and recipient serology to characterize overall risk before transplantation and quantification of Epstein-Barr viral load, but confirmation relies on tissue histopathology.

Treatment focuses on reducing immunosuppression.^30,32 Adding antiviral agents does not seem to improve outcome in all cases.³³ Depending on clinical response and histologic classification, additional therapies such as anti-CD20 humanized chimeric monoclonal antibodies, surgery, radiation, and conventional chemotherapy may be required.³⁴

Preventive approaches remain controversial. Chemoprophylaxis with an antiviral such as ganciclovir is occasionally used but has not been shown to consistently decrease rates of posttransplant lymphoproliferative disease. These agents may act in an indirect manner, leading to decreased rates of cytomegalovirus infection, a major cofactor for posttransplant lymphoproliferative disease.²⁴

Although oral valganciclovir is used more than intravenous ganciclovir, it is not approved for liver transplant patients

Passive immunoprophylaxis with immunoglobulin targeting cytomegalovirus has shown to decrease rates of non-Hodgkin lymphoma from posttransplant lymphoproliferative disease in renal transplant recipients in the first year after transplant,³⁵ but data are lacking regarding its use in liver transplant recipients. Monitoring of the viral load and subsequent reduction of immunosuppression remain the most efficient measures to date.³⁶

FUNGAL INFECTIONS

Candida species account for more than half of fungal infections in liver transplant recipients.³⁷ However, a change has been noted in the past 20 years, with a decrease in Candida infections accompanied by an increase in Aspergillus infections.³⁸ Endemic mycoses such as coccidioidomycosis, blastomycosis, and histoplasmosis should be considered with the appropriate epidemiologic history or if disease develops early after transplant and the donor came from a highly endemic region.³⁹Cryptococcus may also be encountered.

Diagnosis. One of the most challenging aspects of fungal infection in liver transplant recipients is timely diagnosis. Heightened suspicion and early biopsy for pathological and microbiological confirmation are necessary. Although available noninvasive diagnostic tools often lack specificity, early detection of fungal markers may be of great use in guiding further diagnostic workup or empiric treatment in the critically ill.

Noninvasive tests include galactomannan, cryptococcal antigen, histoplasma antigen, (1-3)-beta-D-glucan assay and various antibody tests. Galactomannan testing has been widely used to aid in the diagnosis of invasive aspergillosis. Similarly, the (1-3)-beta-D-glucan assay is a non–culture-based tool for diagnosing and monitoring the treatment of invasive fungal infections. However, a definite diagnosis cannot be made on the basis of a positive test alone.⁴⁰ The complementary diagnostic characteristics of combining noninvasive assays have yet to be fully elucidated.⁴¹ Cultures and tissue histopathology are also used when possible.

Treatment is based on targeted specific antifungal drug therapy and reduction of immunosuppressive therapy, when possible. The choice of antifungal agent varies with the pathogen, the site of involvement, and the severity of the disease. A focus on potential drug interactions, their management, and therapeutic drug monitoring when using antifungal medications is essential in the posttransplant period. Combination therapy can be considered in some situations to enhance synergy. The following sections discuss in greater detail Candida species, Aspergillus species, and Pneumocystis jirovecii infections.

Candida infections

Candidiasis after liver transplant is typically nosocomial, especially when diagnosed during the first 3 months (Table 3).³⁷

Risk factors for invasive candidiasis include perioperative colonization, prolonged operative time, retransplant, greater transfusion requirements, and postoperative renal failure.^37,42,43 Invasive candidiasis is of concern for its effects on morbidity, mortality, and cost of care.^43–46

Organisms. The frequency of implicated species, in particular those with a natural resistance to fluconazole, differs in various reports.^37,45,46Candida albicans remains the most commonly isolated pathogen; however, non-albicans species including those resistant to fluconazole have been reported more frequently and include Candida glabrata and Candida krusei.^47,48

Signs and diagnosis. Invasive candidiasis in liver transplant recipients generally manifests itself in catheter-related blood stream infections, urinary tract infections, or intra-abdominal infections. Diagnosis can be made by isolating Candida from blood cultures, recovering organisms in culture of a normally sterile site, or finding direct microscopic evidence of the fungus on tissue specimens.⁴⁹

Disseminated candidiasis refers to the involvement of distant anatomic sites. Clinical manifestations may cause vision changes, abdominal pain or skin nodules with findings of candidemia, hepatosplenic abscesses, or retinal exudates on funduscopy.⁴⁹

Treatment of invasive candidiasis in liver recipients often involves antifungal therapy and reduction of immunosuppression. Broad-spectrum antifungals are initially advocated in an empirical approach to cover fluconazole-resistant strains of the non-albicans subgroups.⁵⁰ Depending on antifungal susceptibility, treatment can later be adjusted.

Fluconazole remains the agent of choice in most C albicans infections.⁴⁷ However, attention should be paid to the possibility of resistance in patients who have received fluconazole prophylaxis within the past 30 days. Additional agents used in treatment may include echinocandins, amphotericin, and additional azoles.

Antifungal prophylaxis is recommended in high-risk liver transplant patients, although its optimal duration remains undetermined.⁴⁴ Antifungal prophylaxis has been associated with decreased incidence of both superficial and invasive candidiasis.⁵¹

Aspergillus infection

Aspergillus, the second most common fungal pathogen, has become a more common concern in liver transplant recipients. Aspergillus fumigatus is the most frequently encountered species.^38,52

Risk factors. These infections typically occur in the first year, during intense immunosuppression. Retransplant, renal failure, and fulminant hepatic failure are major risk factors.⁵² In the presence of risk factors and a suggestive clinical setting, invasive aspergillosis should be considered and the diagnosis pursued.

Diagnosis is suggested by positive findings on CT accompanied by lower respiratory tract symptoms, focal lesions on neuroimaging, or demonstration of the fungus on cultures.⁴⁹ However, Aspergillus is rarely grown in blood culture. The galactomannan antigen is a noninvasive test that can provide supporting evidence for the diagnosis.^41,52 False-positive results do occur in the setting of certain antibiotics and cross-reacting fungi.⁵³

Treatment consists of antifungal therapy and immunosuppression reduction.⁵²

Candida accounts for more than half of fungal infections in liver transplant recipients, but Aspergillus is gaining

Voriconazole is the first-line agent for invasive aspergillosis. Monitoring for potential drug-drug interactions and side effects is required.^54,55 Amphotericin B is considered a second-line choice due to toxicity and lack of an oral formulation. In refractory cases, combined antifungal therapy could be considered.⁵² The duration of treatment is generally a minimum of 12 weeks.

Prophylaxis. Specific prophylaxis against invasive aspergillosis is not currently recommended; however, some authors suggest a prophylactic approach using echinocandins or liposomal amphotericin B in high-risk patients.^51,52 Aspergillosis is associated with a considerable increase in mortality in liver transplant recipients, which highlights the importance of timely management.^52,56

Pneumocystis jirovecii

P jirovecii remains a common opportunistic pathogen in people with impaired immunity, including transplant and human immunodeficiency virus patients.

Prophylaxis. Widespread adoption of antimicrobial prophylaxis by transplant centers has decreased the rates of P jirovecii infection in liver transplant recipients.^57,58 Commonly used prophylactic regimens after liver transplantation include a single-strength trimeth­oprim-sulfamethoxazole tablet daily or a double-strength tablet three times per week for a minimum of 6 to 12 months after transplant. Atovaquone and dapsone can be used as alternatives in cases of intolerance to tri­methoprim-sulfamethoxazole (Table 2).

Inhaled pentamidine is clearly inferior and should be used only when the other medications are contraindicated.⁵⁹

Signs and diagnosis. P jirovecii pneumonia is characterized by fever, cough, dyspnea, and chest pain. Insidious hypoxemia, abnormal chest examination, and bilateral interstitial pneumonia on chest radiography are common.

CT may be more sensitive than chest radiography.⁵⁷ Findings suggestive of P jirovecii pneumonia on chest CT are extensive bilateral and symmetrical ground-glass attenuations. Other less-characteristic findings include upper lobar parenchymal opacities and spontaneous pneumothorax.^57,60

The serum (1,3)-beta-D-glucan assay derived from major cell-wall components of P jiro­vecii might be helpful. Studies report a sensitivity for P jirovecii pneumonia as high as 96% and a negative predictive value of 99.8%.^61,62

Definitive diagnosis requires identification of the pathogen. Routine expectorated sputum sampling is generally associated with a poor diagnostic yield. Bronchoscopy and bronchoalveolar lavage with silver or fluorescent antibody staining of samples, polymerase chain reaction testing, or both significantly improves diagnosis. Transbronchial or open lung biopsy are often unnecessary.⁵⁷

Treatment. Trimethoprim-sulfamethoxazole is the first-line agent for treating P jirovecii pneumonia.⁵⁷ The minimum duration of treatment is 14 days, with extended courses for severe infection.

Intravenous pentamidine or clindamycin plus primaquine are alternatives for patients who cannot tolerate trimethoprim-sulfamethoxazole. The major concern with intravenous pentamidine is renal dysfunction. Hypoglycemia or hyperglycemia, neutropenia, thrombocytopenia, nausea, dysgeusia, and pancreatitis may also occur.⁶³

Atovaquone might also be beneficial in mild to moderate P jirovecii pneumonia. The main side effects include skin rashes, gastrointestinal intolerance, and elevation of transaminases.⁶⁴

A corticosteroid (40–60 mg of prednisone or its equivalent) may be beneficial in conjunction with antimicrobial therapy in patients with significant hypoxia (partial pressure of arterial oxygen < 70 mm Hg on room air) in decreasing the risk of respiratory failure and need for intubation.

With appropriate and timely antimicrobial prophylaxis, cases of P jirovecii pneumonia should continue to decrease.

TUBERCULOSIS

Development of tuberculosis after transplantation is a catastrophic complication, with mortality rates of up to 30%.⁶⁵ Most cases of posttransplant tuberculosis represent reactivation of latent disease.⁶⁶ Screening with tuberculin skin tests or interferon-gamma-release assays is recommended in all liver transplant candidates. Chest radiography before transplant is necessary when assessing a positive screening test.⁶⁷

The optimal management of latent tuberculosis in these cases remains controversial. Patients at high risk or those with positive screening results on chest radiography warrant treatment for latent tuberculosis infection with isoniazid unless contraindicated.^67,68

The ideal time to initiate prophylactic isoniazid therapy is unclear. Some authors suggest delaying it, as it might be associated with poor tolerance and hepatotoxicity.⁶⁹ Others have found that early isoniazid use was not associated with negative outcomes.⁷⁰

Risk factors for symptomatic tuberculosis after liver transplant include previous infection with tuberculosis, intensified immunosuppression (especially anti-T-lymphocyte therapies), diabetes mellitus, and other co-infections (Table 1).⁷¹

The increased incidence of atypical presentations in recent years makes the diagnosis of active tuberculosis among liver transplant recipients challenging. Sputum smears can be negative due to low mycobacterial burdens, and tuberculin skin testing and interferon-gamma-release assays may be falsely negative due to immunosuppression.⁶⁷

Treatment of active tuberculosis consists initially of a four-drug regimen using isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months. Adjustments are made in accordance with culture and sensitivity results. Treatment can then be tapered to two drugs (isoniazid and rifampin) for a minimum of 4 additional months. Prolonged treatment may be required in instances of extrapulmonary or disseminated disease.^65,72

Tuberculosis treatment can be complicated by hepatotoxicity in liver transplant recipients because of direct drug effects and drug-drug interactions with immunosuppressive agents. Close monitoring for rejection and hepatotoxicity is therefore imperative while liver transplant recipients are receiving antituberculosis therapy. Drug-drug interactions may also be responsible for marked reductions in immunosuppression levels, especially with regimens containing rifampin.⁷¹ Substitution of rifabutin for rifampin reduces the effect of drug interactions.⁶⁶

VIRAL HEPATITIS

Hepatitis B virus

Hepatitis B virus-related end-stage liver disease and hepatocellular carcinoma are common indications for liver transplant in Asia. It is less common in the United States and Europe, accounting for less than 10% of all liver transplant cases. Prognosis is favorable in recipients undergoing liver transplant for hepatitis B virus, with excellent survival rates. Prevention of reinfection is crucial in these patients.

Treatment with combination antiviral agents and hepatitis B immunoglobulin (HBIG) is effective.⁷³ Lamivudine was the first nucleoside analogue found to be effective against hepatitis B virus. Its low cost and relative safety are strong arguments in favor of its continued use in liver transplant recipients.⁷⁴ In patients without evidence of hepatitis B viral replication at the time of transplant, monotherapy with lamivudine has led to low recurrence rates, and adefovir can be added to control resistant viral strains.⁷⁵

Widespread adoption of prophylaxis has decreased the rate of P jirovecii infection in liver transplant recipients

The frequent emergence of resistance with lamivudine favors newer agents such as entecavir or tenofovir. These nucleoside and nucleotide analogues have a higher barrier to resistance, and thus resistance to them is rare. They are also more efficient, potentially allowing use of an HBIG-sparing protocol.⁷⁶ However, they are associated with a higher risk of nephrotoxicity and require dose adjustments in renal insufficiency. Data directly comparing entecavir and tenofovir are scarce.

Prophylaxis. Most studies support an individualized approach for prevention of hepatitis B virus reinfection. High-risk patients, ie, those positive for HBe antigen or with high viral loads (> 100,000 copies/mL) are generally treated with both HBIG and antiviral agents.⁷⁷ Low-risk patients are those with a negative HBe antigen, low hepatitis B virus DNA levels, hepatitis B virus-related acute liver failure, and cirrhosis resulting from coinfection with both hepatitis B and hepatitis D virus.⁷⁵ In low-risk patients, discontinuation of HBIG after 1 to 2 years of treatment is appropriate, and long-term prophylaxis with antiviral agents alone is an option. However, levels of hepatitis B DNA should be monitored closely.^78,79

Hepatitis C virus

Recurrence of hepatitis C virus infection is the rule among patients who are viremic at the time of liver transplant.^80,81 Most of these patients will show histologic evidence of recurrent hepatitis within the first year after liver transplant. It is often difficult to distinguish between the histopathological appearance of a recurrent hepatitis C virus infection and acute cellular rejection.

Progression to fibrosis and subsequently cirrhosis and decompensation is highly variable in hepatitis C virus-infected liver transplant recipients. Diabetes, insulin resistance, and possibly hepatitis steatosis have been associated with a rapid progression to advanced fibrosis. The contribution of immunosuppression to the progression of hepatitis C virus remains an area of active study. Some studies point to antilymphocyte immunosuppressive agents as a potential cause.⁸² Liver biopsy is a useful tool in this situation. It allows monitoring of disease severity and progression and may distinguish recurrent hepatitis C virus disease from other causes of liver enzyme elevation.

The major concern with the recurrence of hepatitis C virus infection after liver transplant is allograft loss. Rates of patient and graft survival are reduced in infected patients compared with hepatitis C virus-negative patients.^83,84 Prophylactic antiviral therapy has no current role in the management of hepatitis C virus disease. Those manifesting moderate to severe necroinflammation or mild to moderate fibrosis indicative of progressive disease should be treated.^81,85

Sustained viral clearance with antiviral agents confers a graft survival benefit.

The combination of peg-interferon and weight-based ribavirin has been the standard of treatment but may be associated with increased rates of rejection.^86,87 The sustained virologic response rates for hepatitis C virus range from 60% in genotypes 4, 5, and 6 after 48 weeks of treatment to 60% to 80% in genotypes 2 and 3 after 24 weeks, but only about 30% in genotype 1.⁸⁸

The major concern with hepatitis C recurrence after liver transplant is allograft loss

Treatment with the newer agents, especially protease inhibitors, in genotype 1 (peg-interferon, ribavirin, and either telaprevir or boceprevir) has been evaluated. Success rates reaching 70% have been achieved.⁸⁹ Adverse effects can be a major setback. Serious complications include severe anemia, renal dysfunction, increased risk of infection, and death.

Triple therapy should be carefully considered in liver transplant patients with genotype 1 hepatitis C virus.⁹⁰ Significant drug-drug interactions are reported between hepatitis C virus protease inhibitors and immunosuppression regimens. Additional new oral direct- acting antivirals have been investigated. They bring promising advances in hepatitis C virus treatment and pave the way for interferon-free regimens with pangenotypic activity.

IMMUNIZATION

Immunization can decrease the risk of infectious complications in liver transplant recipients, as well as in close contacts and healthcare professionals.³

Influenza. Pretransplant influenza vaccine and posttransplant annual influenza vaccines are necessary.

Pneumococcal immunization should additionally be provided prior to transplant and repeated every 3 to 5 years thereafter.^3,91

A number of other vaccinations should also be completed before transplant, including the hepatitis A and B vaccines and the tetanus/diphtheria/acellular pertussis vaccines. However, these vaccinations have not been shown to be detrimental to patients after transplant.⁹¹

Varicella and zoster vaccines should be given before liver transplant—zoster in patients over age 60, and varicella in patients with no immunity. Live vaccines, including varicella and zoster vaccines, are contraindicated after liver transplant.³

Human papillomavirus. The bivalent human papillomavirus vaccine can be given before transplant in females ages 9 to 26; the quadrivalent vaccine is beneficial in those ages 9 to 26 and in women under age 45.^3,91

IMMUNOSUPPRESSION CARRIES RISK OF INFECTION

Most liver transplant patients require prolonged immunosuppressive therapy. This comes with an increased risk of new or recurrent infections, potentially causing death and significant morbidity.

Evaluation of existing risk factors, appropriate prophylaxis and immunization, timely diagnosis, and treatment of such infections are therefore essential steps for the successful management of liver transplant recipients.

*Dr. Taege has disclosed teaching, speaking, and membership on advisory committee or review panels for Gilead, and independent contracting (including contracted research) for Pfizer.

TAKE THE POST-TEST AND COMPLETE THE CME PROCESS

THE IMMUNOSUPPRESSED STATE of liver transplant recipients makes them vulnerable to infections after surgery.¹ These infections are directly correlated with the net state of immunosuppression. Higher levels of immunosuppression mean a higher risk of infection, with rates of infection typically highest in the early posttransplant period.

Common infections during this period include operative and perioperative nosocomial bacterial and fungal infections, reactivation of latent infections, and invasive fungal infections such as candidiasis, aspergillosis, and pneumocystosis. Donor-derived infections also must be considered. As time passes and the level of immunosuppression is reduced, liver recipients are less prone to infection.¹

The risk of infection can be minimized by appropriate antimicrobial prophylaxis, strategies for safe living after transplant,² vaccination,³ careful balancing of immunosuppressive therapy,⁴ and thoughtful donor selection.⁵ Drug-drug interactions are common and must be carefully considered to minimize the risk.

This review highlights common infectious complications encountered after liver transplant.

INTRA-ABDOMINAL INFECTIONS

Intra-abdominal infections are common in the early postoperative period.^6,7

Risk factors include:

• Pretransplant ascites
• Posttransplant dialysis
• Wound infection
• Reoperation⁸
• Hepatic artery thrombosis
• Roux-en-Y choledochojejunostomy anastomosis.⁹

Signs that may indicate intra-abdominal infection include fever, abdominal pain, leukocytosis, and elevated liver enzymes. But because of their immunosuppressed state, transplant recipients may not manifest fever as readily as the general population. They should be evaluated for cholangitis, peritonitis, biloma, and intra-abdominal abscess.

Organisms. Intra-abdominal infections are often polymicrobial. Enterococci, Staphylococcus aureus, gram-negative species including Pseudomonas, Klebsiella, and Acinetobacter, and Candida species are the most common pathogens. Strains are often resistant to multiple drugs, especially in patients who received antibiotics in the weeks before transplant.^8,10

Liver transplant recipients are also particularly susceptible to Clostridium difficile-associated colitis as a result of immunosuppression and frequent use of antibiotics perioperatively and postoperatively.¹¹ The spectrum of C difficile infection ranges from mild diarrhea to life-threatening colitis, and the course in liver transplant patients tends to be more complicated than in immunocompetent patients.¹²

Diagnosis. Intra-abdominal infections should be looked for and treated promptly, as they are associated with a higher mortality rate, a greater risk of graft loss, and a higher incidence of retransplant.^6,10 Abdominal ultrasonography or computed tomography (CT) can confirm the presence of fluid collections.

Treatment. Infected collections can be treated with percutaneous or surgical drainage and antimicrobial therapy. In the case of biliary tract complications, retransplant or surgical correction of biliary leakage or stenosis decreases the risk of death.⁶

Suspicion should be high for C difficile-associated colitis in cases of posttransplant diarrhea. C difficile toxin stool assays help confirm the diagnosis.¹² Oral metronidazole is recommended in mild to moderate C difficile infection, with oral vancomycin and intravenous metronidazole reserved for severe cases. Colectomy may be necessary in patients with toxic megacolon.

CYTOMEGALOVIRUS INFECTION

Cytomegalovirus is an important opportunistic pathogen in liver transplant recipients.¹³ It causes a range of manifestations, from infection (viremia with or without symptoms) to cytomegalovirus syndrome (fever, malaise, and cell-line cytopenias) to tissue-invasive disease with end-organ disease.¹⁴ Without preventive measures and treatment, cytomegalovirus disease can increase the risk of morbidity, allograft loss and death.^15,16

Risk factors for cytomegalovirus infection (Table 1) include:

• Discordant serostatus of the donor and recipient (the risk is highest in seronegative recipients of organs from seropositive donors)
• Higher levels of immunosuppression, especially when antilymphocyte antibodies are used
• Treatment of graft rejection
• Coinfection with other human herpesviruses, such as Epstein-Barr virus.^4,17

Preventing cytomegalovirus infection

The strategy to prevent cytomegalovirus infection depends on the serologic status of the donor and recipient and may include antiviral prophylaxis or preemptive treatment (Table 2).¹⁸

Prophylaxis involves giving antiviral drugs during the early high-risk period, with the goal of preventing the development of cytomegalovirus viremia. The alternative preemptive strategy emphasizes serial testing for cytomegalovirus viremia, with the goal of intervening with antiviral medications while viremia is at a low level, thus avoiding potential progression to cytomegalovirus disease. Both strategies have pros and cons that should be considered by each transplant center when setting institutional policy.

A prophylactic approach seems very effective at preventing both infection and disease from cytomegalovirus and has been shown to reduce graft rejection and the risk of death.¹⁸ It is preferred in cytomegalovirus-negative recipients when the donor was cytomegalovirus-positive—a high-risk situation.¹⁹ However, these patients are also at higher risk of late-onset cytomegalovirus disease. Higher cost and potential drug toxicity, mainly neutropenia from ganciclovir-based regimens, are additional considerations.

Preemptive treatment, in contrast, reserves drug treatment for patients who are actually infected with cytomegalovirus, thus resulting in fewer adverse drug events and lower cost; but it requires regular monitoring. Preemptive methods, by definition, cannot prevent infection, and with this strategy tissue-invasive disease not associated with viremia does occasionally occur.²⁰ As such, patients with a clinical presentation that suggests cytomegalovirus but have negative results on blood testing should be considered for tissue biopsy with culture and immunohistochemical stain.

The most commonly used regimens for antiviral prophylaxis and treatment in liver transplant recipients are intravenous ganciclovir and oral valganciclovir.²¹ Although valganciclovir is the most commonly used agent in this setting because of ease of administration, it has not been approved by the US Food and Drug Administration in liver transplant patients, as it was associated with higher rates of cytomegalovirus tissue-invasive disease.^22–24 Additionally, drug-resistant cytomegalovirus strains have been associated with valganciclovir prophylaxis in cytomegalovirus-negative recipients of solid organs from cytomegalovirus-positive donors.²⁵

Prophylaxis typically consists of therapy for 3 months from the time of transplant. In higher-risk patients (donor-positive, recipient-negative), longer courses of prophylaxis have been extrapolated from data in kidney transplant recipients.²⁶ Extension or reinstitution of prophylaxis should also be considered in liver transplant patients receiving treatment for rejection with antilymphocyte therapy.

Routine screening for cytomegalovirus is not recommended while patients are receiving prophylaxis. High-risk patients who are not receiving prophylaxis should be monitored with nucleic acid or pp65 antigenemia testing as part of the preemptive strategy protocol.

Treatment of cytomegalovirus disease

Although no specific threshold has been established, treatment is generally indicated if a patient has a consistent clinical syndrome, evidence of tissue injury, and persistent or increasing viremia.

Treatment involves giving antiviral drugs and also reducing the level of immunosuppression, if possible, until symptoms and viremia have resolved.

The choice of antiviral therapy depends on the severity of disease. Intravenous ganciclovir (5 mg/kg twice daily adjusted for renal impairment) or oral valganciclovir (900 mg twice daily, also renally dose-adjusted when necessary) can be used for mild to moderate disease if no significant gastrointestinal involvement is reported. Intravenous ganciclovir is preferred for patients with more severe disease or gastrointestinal involvement. The minimum duration of treatment is 2 weeks and may need to be prolonged until both symptoms and viremia completely resolve.¹⁸

Drug resistance can occur and should be considered in patients who have a history of prolonged ganciclovir or valganciclovir exposure who do not clinically improve or have persistent or rising viremia. In such cases, genotype assays are helpful, and initiation of alternative therapy should be considered. Mutations conferring resistance to ganciclovir are often associated with cross-resistance to cidofovir. Cidofovir can therefore be considered only when genotype assays demonstrate specific mutations conferring an isolated resistance to ganciclovir.²⁷ The addition of foscarnet to the ganciclovir regimen or substitution of foscarnet for ganciclovir are accepted approaches.

Although cytomegalovirus hyperimmunoglobulin has been used in prophylaxis and invasive disease treatment, its role in the management of ganciclovir-resistant cytomegalovirus infections remains controversial.²⁸

EPSTEIN-BARR VIRUS POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE

Epstein-Barr virus-associated posttransplant lymphoproliferative disease is a spectrum of disorders ranging from an infectious mononucleosis syndrome to aggressive malignancy with the potential for death and significant morbidity after liver transplant.²⁹ The timeline of risk varies, but the disease is most common in the first year after transplant.

Risk factors for this disease (Table 1) are:

• Primary Epstein-Barr virus infection
• Cytomegalovirus donor-recipient mismatch
• Cytomegalovirus disease
• Higher levels of immunosuppression, especially with antilymphocyte antibodies.³⁰

The likelihood of Epstein-Barr virus playing a contributing role is lower in later-onset posttransplant lymphoproliferative disease. Patients who are older at the time of transplant, who receive highly immunogenic allografts including a liver as a component of a multivisceral transplant, and who receive increased immunosuppression to treat rejection are at even greater risk of late posttransplant lymphoproliferative disease.³¹ This is in contrast to early posttransplant lymphoproliferative disease, which is seen more commonly in children as a result of primary Epstein-Barr virus infection.

Recognition and diagnosis. Heightened suspicion is required when considering posttransplant lymphoproliferative disease, and careful evaluation of consistent symptoms and allograft dysfunction are required.

Clinically, posttransplant lymphoproliferative disease should be suspected if a liver transplant recipient develops unexplained fever, weight loss, lymphadenopathy, or cell-line cytopenias.^30,32 Other signs and symptoms may be related to the organ involved and may include evidence of hepatitis, pneumonitis, and gastrointestinal disease.³¹

Adjunctive diagnostic testing includes donor and recipient serology to characterize overall risk before transplantation and quantification of Epstein-Barr viral load, but confirmation relies on tissue histopathology.

Treatment focuses on reducing immunosuppression.^30,32 Adding antiviral agents does not seem to improve outcome in all cases.³³ Depending on clinical response and histologic classification, additional therapies such as anti-CD20 humanized chimeric monoclonal antibodies, surgery, radiation, and conventional chemotherapy may be required.³⁴

Preventive approaches remain controversial. Chemoprophylaxis with an antiviral such as ganciclovir is occasionally used but has not been shown to consistently decrease rates of posttransplant lymphoproliferative disease. These agents may act in an indirect manner, leading to decreased rates of cytomegalovirus infection, a major cofactor for posttransplant lymphoproliferative disease.²⁴

Although oral valganciclovir is used more than intravenous ganciclovir, it is not approved for liver transplant patients

Passive immunoprophylaxis with immunoglobulin targeting cytomegalovirus has shown to decrease rates of non-Hodgkin lymphoma from posttransplant lymphoproliferative disease in renal transplant recipients in the first year after transplant,³⁵ but data are lacking regarding its use in liver transplant recipients. Monitoring of the viral load and subsequent reduction of immunosuppression remain the most efficient measures to date.³⁶

FUNGAL INFECTIONS

Candida species account for more than half of fungal infections in liver transplant recipients.³⁷ However, a change has been noted in the past 20 years, with a decrease in Candida infections accompanied by an increase in Aspergillus infections.³⁸ Endemic mycoses such as coccidioidomycosis, blastomycosis, and histoplasmosis should be considered with the appropriate epidemiologic history or if disease develops early after transplant and the donor came from a highly endemic region.³⁹Cryptococcus may also be encountered.

Diagnosis. One of the most challenging aspects of fungal infection in liver transplant recipients is timely diagnosis. Heightened suspicion and early biopsy for pathological and microbiological confirmation are necessary. Although available noninvasive diagnostic tools often lack specificity, early detection of fungal markers may be of great use in guiding further diagnostic workup or empiric treatment in the critically ill.

Noninvasive tests include galactomannan, cryptococcal antigen, histoplasma antigen, (1-3)-beta-D-glucan assay and various antibody tests. Galactomannan testing has been widely used to aid in the diagnosis of invasive aspergillosis. Similarly, the (1-3)-beta-D-glucan assay is a non–culture-based tool for diagnosing and monitoring the treatment of invasive fungal infections. However, a definite diagnosis cannot be made on the basis of a positive test alone.⁴⁰ The complementary diagnostic characteristics of combining noninvasive assays have yet to be fully elucidated.⁴¹ Cultures and tissue histopathology are also used when possible.

Treatment is based on targeted specific antifungal drug therapy and reduction of immunosuppressive therapy, when possible. The choice of antifungal agent varies with the pathogen, the site of involvement, and the severity of the disease. A focus on potential drug interactions, their management, and therapeutic drug monitoring when using antifungal medications is essential in the posttransplant period. Combination therapy can be considered in some situations to enhance synergy. The following sections discuss in greater detail Candida species, Aspergillus species, and Pneumocystis jirovecii infections.

Candida infections

Candidiasis after liver transplant is typically nosocomial, especially when diagnosed during the first 3 months (Table 3).³⁷

Risk factors for invasive candidiasis include perioperative colonization, prolonged operative time, retransplant, greater transfusion requirements, and postoperative renal failure.^37,42,43 Invasive candidiasis is of concern for its effects on morbidity, mortality, and cost of care.^43–46

Organisms. The frequency of implicated species, in particular those with a natural resistance to fluconazole, differs in various reports.^37,45,46Candida albicans remains the most commonly isolated pathogen; however, non-albicans species including those resistant to fluconazole have been reported more frequently and include Candida glabrata and Candida krusei.^47,48

Signs and diagnosis. Invasive candidiasis in liver transplant recipients generally manifests itself in catheter-related blood stream infections, urinary tract infections, or intra-abdominal infections. Diagnosis can be made by isolating Candida from blood cultures, recovering organisms in culture of a normally sterile site, or finding direct microscopic evidence of the fungus on tissue specimens.⁴⁹

Disseminated candidiasis refers to the involvement of distant anatomic sites. Clinical manifestations may cause vision changes, abdominal pain or skin nodules with findings of candidemia, hepatosplenic abscesses, or retinal exudates on funduscopy.⁴⁹

Treatment of invasive candidiasis in liver recipients often involves antifungal therapy and reduction of immunosuppression. Broad-spectrum antifungals are initially advocated in an empirical approach to cover fluconazole-resistant strains of the non-albicans subgroups.⁵⁰ Depending on antifungal susceptibility, treatment can later be adjusted.

Fluconazole remains the agent of choice in most C albicans infections.⁴⁷ However, attention should be paid to the possibility of resistance in patients who have received fluconazole prophylaxis within the past 30 days. Additional agents used in treatment may include echinocandins, amphotericin, and additional azoles.

Antifungal prophylaxis is recommended in high-risk liver transplant patients, although its optimal duration remains undetermined.⁴⁴ Antifungal prophylaxis has been associated with decreased incidence of both superficial and invasive candidiasis.⁵¹

Aspergillus infection

Aspergillus, the second most common fungal pathogen, has become a more common concern in liver transplant recipients. Aspergillus fumigatus is the most frequently encountered species.^38,52

Risk factors. These infections typically occur in the first year, during intense immunosuppression. Retransplant, renal failure, and fulminant hepatic failure are major risk factors.⁵² In the presence of risk factors and a suggestive clinical setting, invasive aspergillosis should be considered and the diagnosis pursued.

Diagnosis is suggested by positive findings on CT accompanied by lower respiratory tract symptoms, focal lesions on neuroimaging, or demonstration of the fungus on cultures.⁴⁹ However, Aspergillus is rarely grown in blood culture. The galactomannan antigen is a noninvasive test that can provide supporting evidence for the diagnosis.^41,52 False-positive results do occur in the setting of certain antibiotics and cross-reacting fungi.⁵³

Treatment consists of antifungal therapy and immunosuppression reduction.⁵²

Candida accounts for more than half of fungal infections in liver transplant recipients, but Aspergillus is gaining

Voriconazole is the first-line agent for invasive aspergillosis. Monitoring for potential drug-drug interactions and side effects is required.^54,55 Amphotericin B is considered a second-line choice due to toxicity and lack of an oral formulation. In refractory cases, combined antifungal therapy could be considered.⁵² The duration of treatment is generally a minimum of 12 weeks.

Prophylaxis. Specific prophylaxis against invasive aspergillosis is not currently recommended; however, some authors suggest a prophylactic approach using echinocandins or liposomal amphotericin B in high-risk patients.^51,52 Aspergillosis is associated with a considerable increase in mortality in liver transplant recipients, which highlights the importance of timely management.^52,56

Pneumocystis jirovecii

P jirovecii remains a common opportunistic pathogen in people with impaired immunity, including transplant and human immunodeficiency virus patients.

Prophylaxis. Widespread adoption of antimicrobial prophylaxis by transplant centers has decreased the rates of P jirovecii infection in liver transplant recipients.^57,58 Commonly used prophylactic regimens after liver transplantation include a single-strength trimeth­oprim-sulfamethoxazole tablet daily or a double-strength tablet three times per week for a minimum of 6 to 12 months after transplant. Atovaquone and dapsone can be used as alternatives in cases of intolerance to tri­methoprim-sulfamethoxazole (Table 2).

Inhaled pentamidine is clearly inferior and should be used only when the other medications are contraindicated.⁵⁹

Signs and diagnosis. P jirovecii pneumonia is characterized by fever, cough, dyspnea, and chest pain. Insidious hypoxemia, abnormal chest examination, and bilateral interstitial pneumonia on chest radiography are common.

CT may be more sensitive than chest radiography.⁵⁷ Findings suggestive of P jirovecii pneumonia on chest CT are extensive bilateral and symmetrical ground-glass attenuations. Other less-characteristic findings include upper lobar parenchymal opacities and spontaneous pneumothorax.^57,60

The serum (1,3)-beta-D-glucan assay derived from major cell-wall components of P jiro­vecii might be helpful. Studies report a sensitivity for P jirovecii pneumonia as high as 96% and a negative predictive value of 99.8%.^61,62

Definitive diagnosis requires identification of the pathogen. Routine expectorated sputum sampling is generally associated with a poor diagnostic yield. Bronchoscopy and bronchoalveolar lavage with silver or fluorescent antibody staining of samples, polymerase chain reaction testing, or both significantly improves diagnosis. Transbronchial or open lung biopsy are often unnecessary.⁵⁷

Treatment. Trimethoprim-sulfamethoxazole is the first-line agent for treating P jirovecii pneumonia.⁵⁷ The minimum duration of treatment is 14 days, with extended courses for severe infection.

Intravenous pentamidine or clindamycin plus primaquine are alternatives for patients who cannot tolerate trimethoprim-sulfamethoxazole. The major concern with intravenous pentamidine is renal dysfunction. Hypoglycemia or hyperglycemia, neutropenia, thrombocytopenia, nausea, dysgeusia, and pancreatitis may also occur.⁶³

Atovaquone might also be beneficial in mild to moderate P jirovecii pneumonia. The main side effects include skin rashes, gastrointestinal intolerance, and elevation of transaminases.⁶⁴

A corticosteroid (40–60 mg of prednisone or its equivalent) may be beneficial in conjunction with antimicrobial therapy in patients with significant hypoxia (partial pressure of arterial oxygen < 70 mm Hg on room air) in decreasing the risk of respiratory failure and need for intubation.

With appropriate and timely antimicrobial prophylaxis, cases of P jirovecii pneumonia should continue to decrease.

TUBERCULOSIS

Development of tuberculosis after transplantation is a catastrophic complication, with mortality rates of up to 30%.⁶⁵ Most cases of posttransplant tuberculosis represent reactivation of latent disease.⁶⁶ Screening with tuberculin skin tests or interferon-gamma-release assays is recommended in all liver transplant candidates. Chest radiography before transplant is necessary when assessing a positive screening test.⁶⁷

The optimal management of latent tuberculosis in these cases remains controversial. Patients at high risk or those with positive screening results on chest radiography warrant treatment for latent tuberculosis infection with isoniazid unless contraindicated.^67,68

The ideal time to initiate prophylactic isoniazid therapy is unclear. Some authors suggest delaying it, as it might be associated with poor tolerance and hepatotoxicity.⁶⁹ Others have found that early isoniazid use was not associated with negative outcomes.⁷⁰

Risk factors for symptomatic tuberculosis after liver transplant include previous infection with tuberculosis, intensified immunosuppression (especially anti-T-lymphocyte therapies), diabetes mellitus, and other co-infections (Table 1).⁷¹

The increased incidence of atypical presentations in recent years makes the diagnosis of active tuberculosis among liver transplant recipients challenging. Sputum smears can be negative due to low mycobacterial burdens, and tuberculin skin testing and interferon-gamma-release assays may be falsely negative due to immunosuppression.⁶⁷

Treatment of active tuberculosis consists initially of a four-drug regimen using isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months. Adjustments are made in accordance with culture and sensitivity results. Treatment can then be tapered to two drugs (isoniazid and rifampin) for a minimum of 4 additional months. Prolonged treatment may be required in instances of extrapulmonary or disseminated disease.^65,72

Tuberculosis treatment can be complicated by hepatotoxicity in liver transplant recipients because of direct drug effects and drug-drug interactions with immunosuppressive agents. Close monitoring for rejection and hepatotoxicity is therefore imperative while liver transplant recipients are receiving antituberculosis therapy. Drug-drug interactions may also be responsible for marked reductions in immunosuppression levels, especially with regimens containing rifampin.⁷¹ Substitution of rifabutin for rifampin reduces the effect of drug interactions.⁶⁶

VIRAL HEPATITIS

Hepatitis B virus

Hepatitis B virus-related end-stage liver disease and hepatocellular carcinoma are common indications for liver transplant in Asia. It is less common in the United States and Europe, accounting for less than 10% of all liver transplant cases. Prognosis is favorable in recipients undergoing liver transplant for hepatitis B virus, with excellent survival rates. Prevention of reinfection is crucial in these patients.

Treatment with combination antiviral agents and hepatitis B immunoglobulin (HBIG) is effective.⁷³ Lamivudine was the first nucleoside analogue found to be effective against hepatitis B virus. Its low cost and relative safety are strong arguments in favor of its continued use in liver transplant recipients.⁷⁴ In patients without evidence of hepatitis B viral replication at the time of transplant, monotherapy with lamivudine has led to low recurrence rates, and adefovir can be added to control resistant viral strains.⁷⁵

Widespread adoption of prophylaxis has decreased the rate of P jirovecii infection in liver transplant recipients

The frequent emergence of resistance with lamivudine favors newer agents such as entecavir or tenofovir. These nucleoside and nucleotide analogues have a higher barrier to resistance, and thus resistance to them is rare. They are also more efficient, potentially allowing use of an HBIG-sparing protocol.⁷⁶ However, they are associated with a higher risk of nephrotoxicity and require dose adjustments in renal insufficiency. Data directly comparing entecavir and tenofovir are scarce.

Prophylaxis. Most studies support an individualized approach for prevention of hepatitis B virus reinfection. High-risk patients, ie, those positive for HBe antigen or with high viral loads (> 100,000 copies/mL) are generally treated with both HBIG and antiviral agents.⁷⁷ Low-risk patients are those with a negative HBe antigen, low hepatitis B virus DNA levels, hepatitis B virus-related acute liver failure, and cirrhosis resulting from coinfection with both hepatitis B and hepatitis D virus.⁷⁵ In low-risk patients, discontinuation of HBIG after 1 to 2 years of treatment is appropriate, and long-term prophylaxis with antiviral agents alone is an option. However, levels of hepatitis B DNA should be monitored closely.^78,79

Hepatitis C virus

Recurrence of hepatitis C virus infection is the rule among patients who are viremic at the time of liver transplant.^80,81 Most of these patients will show histologic evidence of recurrent hepatitis within the first year after liver transplant. It is often difficult to distinguish between the histopathological appearance of a recurrent hepatitis C virus infection and acute cellular rejection.

Progression to fibrosis and subsequently cirrhosis and decompensation is highly variable in hepatitis C virus-infected liver transplant recipients. Diabetes, insulin resistance, and possibly hepatitis steatosis have been associated with a rapid progression to advanced fibrosis. The contribution of immunosuppression to the progression of hepatitis C virus remains an area of active study. Some studies point to antilymphocyte immunosuppressive agents as a potential cause.⁸² Liver biopsy is a useful tool in this situation. It allows monitoring of disease severity and progression and may distinguish recurrent hepatitis C virus disease from other causes of liver enzyme elevation.

The major concern with the recurrence of hepatitis C virus infection after liver transplant is allograft loss. Rates of patient and graft survival are reduced in infected patients compared with hepatitis C virus-negative patients.^83,84 Prophylactic antiviral therapy has no current role in the management of hepatitis C virus disease. Those manifesting moderate to severe necroinflammation or mild to moderate fibrosis indicative of progressive disease should be treated.^81,85

Sustained viral clearance with antiviral agents confers a graft survival benefit.

The combination of peg-interferon and weight-based ribavirin has been the standard of treatment but may be associated with increased rates of rejection.^86,87 The sustained virologic response rates for hepatitis C virus range from 60% in genotypes 4, 5, and 6 after 48 weeks of treatment to 60% to 80% in genotypes 2 and 3 after 24 weeks, but only about 30% in genotype 1.⁸⁸

The major concern with hepatitis C recurrence after liver transplant is allograft loss

Treatment with the newer agents, especially protease inhibitors, in genotype 1 (peg-interferon, ribavirin, and either telaprevir or boceprevir) has been evaluated. Success rates reaching 70% have been achieved.⁸⁹ Adverse effects can be a major setback. Serious complications include severe anemia, renal dysfunction, increased risk of infection, and death.

Triple therapy should be carefully considered in liver transplant patients with genotype 1 hepatitis C virus.⁹⁰ Significant drug-drug interactions are reported between hepatitis C virus protease inhibitors and immunosuppression regimens. Additional new oral direct- acting antivirals have been investigated. They bring promising advances in hepatitis C virus treatment and pave the way for interferon-free regimens with pangenotypic activity.

IMMUNIZATION

Immunization can decrease the risk of infectious complications in liver transplant recipients, as well as in close contacts and healthcare professionals.³

Influenza. Pretransplant influenza vaccine and posttransplant annual influenza vaccines are necessary.

Pneumococcal immunization should additionally be provided prior to transplant and repeated every 3 to 5 years thereafter.^3,91

A number of other vaccinations should also be completed before transplant, including the hepatitis A and B vaccines and the tetanus/diphtheria/acellular pertussis vaccines. However, these vaccinations have not been shown to be detrimental to patients after transplant.⁹¹

Varicella and zoster vaccines should be given before liver transplant—zoster in patients over age 60, and varicella in patients with no immunity. Live vaccines, including varicella and zoster vaccines, are contraindicated after liver transplant.³

Human papillomavirus. The bivalent human papillomavirus vaccine can be given before transplant in females ages 9 to 26; the quadrivalent vaccine is beneficial in those ages 9 to 26 and in women under age 45.^3,91

IMMUNOSUPPRESSION CARRIES RISK OF INFECTION

Most liver transplant patients require prolonged immunosuppressive therapy. This comes with an increased risk of new or recurrent infections, potentially causing death and significant morbidity.

Evaluation of existing risk factors, appropriate prophylaxis and immunization, timely diagnosis, and treatment of such infections are therefore essential steps for the successful management of liver transplant recipients.

*Dr. Taege has disclosed teaching, speaking, and membership on advisory committee or review panels for Gilead, and independent contracting (including contracted research) for Pfizer.

TAKE THE POST-TEST AND COMPLETE THE CME PROCESS

This is the second installment of a five-part monthly series that will discuss the pathologic, genomic, and clinical factors that contribute to the racial survival disparity in breast cancer. The series, which is adapted from an article that originally appeared in CA: A Cancer Journal for Clinicians¹, a journal of the American Cancer Society, will also review exciting and innovative interventions to close this survival gap. This month’s column reviews tumor biology and genomics—the first element in the perfect storm.

Hormone receptor status and human epidermal growth factor receptor 2 (HER2)/neu

Breast cancer is not a single disease, and breast cancer subtype classifications are used in the clinical setting to determine prognosis and guide management. These different molecular subtypes are based on tumor markers, which include the presence or absence of three proteins: estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. Hormone receptor status is a main factor in planning breast cancer treatment. Hormone receptor–positive breast tumors benefit from hormone therapies, such as selective ER modulators (for example, tamoxifen) and aromatase inhibitors (for example, anastrozole). Thus, these tumors have a more favorable disease-specific survival than do hormone receptor–negative tumors.²

African American women are more likely to present with hormone receptor-negative tumors. In an analysis of the California Cancer Registry, which has collected patient ER and PR status since 1990, whites had a higher proportion of tumors that were ER positive or PR positive (or both) and HER2 negative (72% vs. 53%).³ DeSantis et al.⁴ reported similar results for this tumor type, with 76% of non-Hispanic whites having hormone receptor–positive, HER2-negative tumors vs. 62% of non-Hispanic blacks. Even with stratification by tumor stage, African Americans continue to have a significantly higher proportion of hormone receptor–negative tumors than do whites for localized and advanced disease.⁵

Although hormone receptor status varies significantly by race, HER2 status does not show the same divergence. HER2 overexpression is present in approximately 20% of invasive breast cancers. HER2-positive, hormone receptor–negative tumors demonstrate more-aggressive features and worse breast cancer–specific survival than do hormone receptor–positive and HER2-negative tumors,² although survival has vastly improved with new HER2-targeted therapies such as trastuzumab and pertuzumab. Unlike hormone receptor status, there was no association between race and HER2-positive/ER-negative tumors in the Carolina Breast Cancer Study.²

Triple-negative breast cancer (TNBC)

TNBC is the subtype of breast cancer with the worst prognosis. TNBC gets its name because its tumor cells lack the markers for ER, PR, and HER2 overexpression. Thus, TNBC tumors are estrogen receptor negative (ER), progesterone receptor negative (PR), and HER2/neu negative (HER2). While other subtypes of breast cancer have benefited from drug development regarding hormonal therapies and HER2-targeted treatments, TNBC has not experienced the same pharmacologic breakthroughs.

As such, even after analyses control for the stage at diagnosis, women with this subtype have poorer survival than those with other breast cancers.⁶ African American women have a higher incidence of TNBC than white women.⁷ DeSantis et al.⁴ reported that 22% of breast cancers were triple negative in non-Hispanic black patients vs. only 11% in non-Hispanic white patients. The Carolina Breast Cancer Study found that 26% of African American women had TNBC, whereas 16% of non-African American women did.² This subtype was most common among younger, premenopausal African American women (39% of diagnosed cancer subtypes). When TNBC patients were excluded from analysis in the Carolina Breast Cancer Study, breast cancer–specific survival remained significantly worse among premenopausal African American women, suggesting that although tumor biology in part explains the poor outcomes, the survival disparity story is more complex.

Germline mutations: BRCA1 and BRCA2 Mutations

In addition to tumor biology, cancer genomics has become increasingly important in determining cancer prognosis and guiding treatment. Approximately 5%-10% of breast cancer cases present in individuals with inherited mutations in autosomal dominant, highly penetrant breast cancer susceptibility genes.⁸ Accounting for 80%-90% of families containing multiple cases of breast and ovarian cancer, BRCA1 and BRCA2 germline mutations are the most common of the breast cancer susceptibility genes.⁹ These patients often are younger and have a higher-grade tumor that is hormone receptor negative, which also often matches the profile of the African American breast cancer patient.¹⁰

Despite similarities between BRCA1-associated breast cancers and breast cancer in African Americans, genetic abnormalities in African American breast cancer patients remain underresearched. Nanda et al.¹¹ found that BRCA1 and BRCA2 mutations occur with appreciable frequency in high-risk families of African ancestry, with 28% testing positive for a deleterious mutation in one of these genes. This frequency was at a lower rate than that found in non-Hispanic, non-Jewish whites, who had a rate of 46%, because African Americans had a higher rate of polymorphisms or variants of unknown significance (44% vs. 12%). This large percentage of variants of unknown significance indicates that more analysis is needed to understand the clinical implications of these genetic variations. In another study from the Northern California site of the Breast Cancer Family Registry, the BRCA1 mutation prevalence was 16.7% in African American cases diagnosed under the age of 35 years vs. 7.2% in non-Hispanic, non-Ashkenazi Jewish whites in the same age category.¹² High frequencies of mutations in BRCA1 and BRCA2 have also been reported in breast cancer patients of African ancestry from Nigeria and the Bahamas.¹³, ¹⁴

These results in African American patients highlight the need for further study of breast cancer genomics in minority populations. However, Armstrong et al.¹⁵ illuminated the existence of racial/ethnic disparities in patterns of referral to cancer risk clinics. In their study, African American women with a family history of breast or ovarian cancer were significantly less likely to undergo genetic counseling for BRCA1/2 testing than were white women with this family history. The results of this study were noteworthy for the magnitude of the disparity, with white women having almost five times greater odds of undergoing this clinically important evaluation. More than two decades after BRCA1 and BRCA2 genes were identified, larger studies are still needed in diverse populations to derive true estimates of the burden of mutations in both genes in underserved and understudied populations.

Although these differences in tumor biology and genomics tell part of the mortality disparity story, there is more to be told. In a study of African American and white patients in South Carolina, Adams et al.¹⁶ determined survival rates by ethnicity that were adjusted for disease stage and other prognostic characteristics. After they controlled for age, stage, ER, and HER2 expression as well as insurance status, African American women still had a twofold excess risk of death from breast cancer. Thus, in addition to differences in the innate characteristics of the breast tumors, racial differences in patterns of care for women with breast cancer must be considered in unraveling the observed disparity in mortality. The third installment of this series will discuss the second element of the perfect storm – patterns of care.

Other installments of this column can be found in the Related Content box.

 1. Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015;65(3):221-238.

 2. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295(21):2492-502.

 3. Kurian AW, Fish K, Shema SJ, Clarke CA. Lifetime risks of specific breast cancer subtypes among women in four racial/ethnic groups. Breast Cancer Res. 2010;12(6):R99.

 4. DeSantis CE, Fedewa SA, Goding Sauer A, Kramer JL, Smith RA, Jemal A. Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J Clin. 2015 Oct 29. doi: 10.3322/caac.21320. [Epub ahead of print]

 5. Setiawan VW, Monroe KR, Wilkens LR, Kolonel LN, Pike MC, Henderson BE. Breast cancer risk factors defined by estrogen and progesterone receptor status: the multiethnic cohort study. Am J Epidemiol. 2009;169(10):1251-9.

 6. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer. 2007;109(9):1721-8.

 7. Ray M, Polite BN. Triple-negative breast cancers: a view from 10,000 feet. Cancer J. 2010;16(1):17-22.

 8. Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer. 1996;77(11):2318-24.

 9. Easton DF, Bishop DT, Ford D, Crockford GP. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1993;52(4):678-701.

 10. Polite BN, Olopade OI. Breast cancer and race: a rising tide does not lift all boats equally. Perspect Biol Med. 2005;48(1 Suppl):S166-75.

 11. Nanda R, Schumm LP, Cummings S, et al. Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. JAMA. 2005;294(15):1925-33.

 12. John EM, Miron A, Gong G, et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA. 2007;298(24):2869-76.

 13. Fackenthal JD, Zhang J, Zhang B, et al. High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients. Int J Cancer. 2012;131(5):1114-23.

 14. Donenberg T, Lunn J, Curling D, et al. A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas. Breast Cancer Res Treat. 2011;125(2):591-6.

 15. Armstrong K, Micco E, Carney A, Stopfer J, Putt M. Racial differences in the use of BRCA1/2 testing among women with a family history of breast or ovarian cancer. JAMA. 2005;293(14):1729-36.

 16. Adams SA, Butler WM, Fulton J, et al. Racial disparities in breast cancer mortality in a multi-ethnic cohort in the Southeast. Cancer. 2012;118(10):2693-9.

Bobby Daly, MD, MBA, is the chief fellow in the section of hematology/oncology at the University of Chicago Medicine. His clinical focus is breast and thoracic oncology, and his research focus is health services. Specifically, Dr. Daly researches disparities in oncology care delivery, oncology health care utilization, aggressive end-of-life oncology care, and oncology payment models. He received his MD and MBA from Harvard Medical School and Harvard Business School, both in Boston, and a BA in Economics and History from Stanford (Calif.) University. He was the recipient of the Dean’s Award at Harvard Medical and Business Schools.

Olufunmilayo Olopade, MD, FACP, OON, is the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, and director, Center for Global Health at the University of Chicago. She is adopting emerging high throughput genomic and informatics strategies to identify genetic and nongenetic risk factors for breast cancer in order to implement precision health care in diverse populations. This innovative approach has the potential to improve the quality of care and reduce costs while saving more lives.

Disclosures: Dr. Olopade serves on the Medical Advisory Board for CancerIQ. Dr. Daly serves as a director of Quadrant Holdings Corporation and receives compensation from this entity. Frontline Medical Communications is a subsidiary of Quadrant Holdings Corporation.

Published in conjunction with Susan G. Komen®.

This is the second installment of a five-part monthly series that will discuss the pathologic, genomic, and clinical factors that contribute to the racial survival disparity in breast cancer. The series, which is adapted from an article that originally appeared in CA: A Cancer Journal for Clinicians¹, a journal of the American Cancer Society, will also review exciting and innovative interventions to close this survival gap. This month’s column reviews tumor biology and genomics—the first element in the perfect storm.

Hormone receptor status and human epidermal growth factor receptor 2 (HER2)/neu

Breast cancer is not a single disease, and breast cancer subtype classifications are used in the clinical setting to determine prognosis and guide management. These different molecular subtypes are based on tumor markers, which include the presence or absence of three proteins: estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. Hormone receptor status is a main factor in planning breast cancer treatment. Hormone receptor–positive breast tumors benefit from hormone therapies, such as selective ER modulators (for example, tamoxifen) and aromatase inhibitors (for example, anastrozole). Thus, these tumors have a more favorable disease-specific survival than do hormone receptor–negative tumors.²

African American women are more likely to present with hormone receptor-negative tumors. In an analysis of the California Cancer Registry, which has collected patient ER and PR status since 1990, whites had a higher proportion of tumors that were ER positive or PR positive (or both) and HER2 negative (72% vs. 53%).³ DeSantis et al.⁴ reported similar results for this tumor type, with 76% of non-Hispanic whites having hormone receptor–positive, HER2-negative tumors vs. 62% of non-Hispanic blacks. Even with stratification by tumor stage, African Americans continue to have a significantly higher proportion of hormone receptor–negative tumors than do whites for localized and advanced disease.⁵

Although hormone receptor status varies significantly by race, HER2 status does not show the same divergence. HER2 overexpression is present in approximately 20% of invasive breast cancers. HER2-positive, hormone receptor–negative tumors demonstrate more-aggressive features and worse breast cancer–specific survival than do hormone receptor–positive and HER2-negative tumors,² although survival has vastly improved with new HER2-targeted therapies such as trastuzumab and pertuzumab. Unlike hormone receptor status, there was no association between race and HER2-positive/ER-negative tumors in the Carolina Breast Cancer Study.²

Triple-negative breast cancer (TNBC)

TNBC is the subtype of breast cancer with the worst prognosis. TNBC gets its name because its tumor cells lack the markers for ER, PR, and HER2 overexpression. Thus, TNBC tumors are estrogen receptor negative (ER), progesterone receptor negative (PR), and HER2/neu negative (HER2). While other subtypes of breast cancer have benefited from drug development regarding hormonal therapies and HER2-targeted treatments, TNBC has not experienced the same pharmacologic breakthroughs.

As such, even after analyses control for the stage at diagnosis, women with this subtype have poorer survival than those with other breast cancers.⁶ African American women have a higher incidence of TNBC than white women.⁷ DeSantis et al.⁴ reported that 22% of breast cancers were triple negative in non-Hispanic black patients vs. only 11% in non-Hispanic white patients. The Carolina Breast Cancer Study found that 26% of African American women had TNBC, whereas 16% of non-African American women did.² This subtype was most common among younger, premenopausal African American women (39% of diagnosed cancer subtypes). When TNBC patients were excluded from analysis in the Carolina Breast Cancer Study, breast cancer–specific survival remained significantly worse among premenopausal African American women, suggesting that although tumor biology in part explains the poor outcomes, the survival disparity story is more complex.

Germline mutations: BRCA1 and BRCA2 Mutations

In addition to tumor biology, cancer genomics has become increasingly important in determining cancer prognosis and guiding treatment. Approximately 5%-10% of breast cancer cases present in individuals with inherited mutations in autosomal dominant, highly penetrant breast cancer susceptibility genes.⁸ Accounting for 80%-90% of families containing multiple cases of breast and ovarian cancer, BRCA1 and BRCA2 germline mutations are the most common of the breast cancer susceptibility genes.⁹ These patients often are younger and have a higher-grade tumor that is hormone receptor negative, which also often matches the profile of the African American breast cancer patient.¹⁰

Despite similarities between BRCA1-associated breast cancers and breast cancer in African Americans, genetic abnormalities in African American breast cancer patients remain underresearched. Nanda et al.¹¹ found that BRCA1 and BRCA2 mutations occur with appreciable frequency in high-risk families of African ancestry, with 28% testing positive for a deleterious mutation in one of these genes. This frequency was at a lower rate than that found in non-Hispanic, non-Jewish whites, who had a rate of 46%, because African Americans had a higher rate of polymorphisms or variants of unknown significance (44% vs. 12%). This large percentage of variants of unknown significance indicates that more analysis is needed to understand the clinical implications of these genetic variations. In another study from the Northern California site of the Breast Cancer Family Registry, the BRCA1 mutation prevalence was 16.7% in African American cases diagnosed under the age of 35 years vs. 7.2% in non-Hispanic, non-Ashkenazi Jewish whites in the same age category.¹² High frequencies of mutations in BRCA1 and BRCA2 have also been reported in breast cancer patients of African ancestry from Nigeria and the Bahamas.¹³, ¹⁴

These results in African American patients highlight the need for further study of breast cancer genomics in minority populations. However, Armstrong et al.¹⁵ illuminated the existence of racial/ethnic disparities in patterns of referral to cancer risk clinics. In their study, African American women with a family history of breast or ovarian cancer were significantly less likely to undergo genetic counseling for BRCA1/2 testing than were white women with this family history. The results of this study were noteworthy for the magnitude of the disparity, with white women having almost five times greater odds of undergoing this clinically important evaluation. More than two decades after BRCA1 and BRCA2 genes were identified, larger studies are still needed in diverse populations to derive true estimates of the burden of mutations in both genes in underserved and understudied populations.

Although these differences in tumor biology and genomics tell part of the mortality disparity story, there is more to be told. In a study of African American and white patients in South Carolina, Adams et al.¹⁶ determined survival rates by ethnicity that were adjusted for disease stage and other prognostic characteristics. After they controlled for age, stage, ER, and HER2 expression as well as insurance status, African American women still had a twofold excess risk of death from breast cancer. Thus, in addition to differences in the innate characteristics of the breast tumors, racial differences in patterns of care for women with breast cancer must be considered in unraveling the observed disparity in mortality. The third installment of this series will discuss the second element of the perfect storm – patterns of care.

Other installments of this column can be found in the Related Content box.

 1. Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015;65(3):221-238.

 2. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295(21):2492-502.

 3. Kurian AW, Fish K, Shema SJ, Clarke CA. Lifetime risks of specific breast cancer subtypes among women in four racial/ethnic groups. Breast Cancer Res. 2010;12(6):R99.

 4. DeSantis CE, Fedewa SA, Goding Sauer A, Kramer JL, Smith RA, Jemal A. Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J Clin. 2015 Oct 29. doi: 10.3322/caac.21320. [Epub ahead of print]

 5. Setiawan VW, Monroe KR, Wilkens LR, Kolonel LN, Pike MC, Henderson BE. Breast cancer risk factors defined by estrogen and progesterone receptor status: the multiethnic cohort study. Am J Epidemiol. 2009;169(10):1251-9.

 6. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer. 2007;109(9):1721-8.

 7. Ray M, Polite BN. Triple-negative breast cancers: a view from 10,000 feet. Cancer J. 2010;16(1):17-22.

 8. Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer. 1996;77(11):2318-24.