INTRODUCTION — The management of patients with liver disease has changed dramatically in the last 25 years, leading to improved outcomes and survival. Prevention of liver disease has also improved. As an example, hepatitis A and B vaccines have reduced the incidence of acute viral hepatitis . Furthermore, hepatitis B vaccines have resulted in a decline in the sequelae of chronic hepatitis B virus infection, and, despite the absence of a specific hepatitis D vaccine, a marked decrease in hepatitis D infections in the United States. Although not yet Food and Drug Administration (FDA) approved, a hepatitis E vaccine may become available in the future . Despite these advances, chronic liver disease from multiple etiologies continues to be a prevalent health problem in the United States.
In one sense, patients with chronic liver disease are no different from the general population. Both groups require appropriate immunizations in order to maintain their general health status. However, for some individuals with chronic liver disease due to the bloodborne pathogens, shared risk factors may result in dual infections with hepatitis B and C or exposure to hepatitis A. Data suggest that the prevalence of hepatitis A infection is higher in patients with chronic liver disease than in the general population . Furthermore, in patients with chronic liver disease or in recipients of liver transplants, the superimposition of another acute disease (hepatitis virus superinfection, influenza, and pneumococcal infection) may result in higher morbidity and mortality than in individuals without pre-existing liver disease.
The impact of hepatitis viruses, pneumococcal disease, and influenza infection in the patient with chronic liver disease will be discussed here. Efficacy of preventive vaccines will also be discussed. For further information regarding general safety and efficacy issues related to these vaccines, please see appropriate topics. (See "Hepatitis A virus infection: Treatment and prevention" and "Hepatitis B virus immunization in adults" and "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults" and "Meningococcal vaccination in children and adults".)
IMPACT OF VACCINE-PREVENTABLE INFECTIONS — Studies of the impact of vaccine-preventable infections (hepatitis A and B, influenza, and pneumococcal disease) in chronic liver disease have been largely restricted to patients with chronic hepatitis B and C, alcohol-associated liver disease, compensated and decompensated cirrhosis, and liver transplant recipients.
Data on the impact of acute viral hepatitis A and B, influenza, and pneumococcal infection on other liver diseases are sparse. Fatty liver and nonalcohol-associated steatohepatitis, hereditary hemochromatosis, primary biliary cholangitis, autoimmune hepatitis, primary sclerosing cholangitis, alpha-1 antitrypsin deficiency, Wilson disease, and granulomatous liver disease have received little attention. In one study of 225 patients with autoimmune liver diseases, all achieved seroconversion following hepatitis A vaccination while 76 percent developed seroprotective levels of surface antibodies (anti-HBs) following hepatitis B vaccine . Both immunosuppressive therapy and advanced liver disease were common in nonresponders . Other systemic disorders that may involve the liver (eg, celiac disease and cystic fibrosis) also have not been extensively studied. Nonetheless, hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccinations have been recommended by one European group for individuals with cystic fibrosis, either at the time of diagnosis of cystic fibrosis or when liver involvement is recognized .
Acute viral hepatitis, regardless of etiology, may have deleterious consequences when occurring as a superinfection in patients with pre-existing chronic viral hepatitis or the HBV carrier state. This phenomenon was demonstrated decades ago when acute hepatitis D (hepatitis D virus [HDV] or delta) superinfection of patients with chronic hepatitis B was shown to result in severe and progressive disease . In a subsequent study of acute hepatitis in Taiwan, acute liver failure was observed in only 3.2 percent of 157 patients with acute viral hepatitis of varying etiologies . In contrast, acute liver failure was seen in 20.3 percent of 177 acute hepatitis patients among hepatitis B surface antigen (HBsAg) carriers. This increased risk was independent of the etiology of the acute hepatitis.
Acute hepatitis A — Anecdotal evidence that acute HAV superinfection could be a clinically important entity received modest attention until the publication of a longitudinal study in 1998 . Both the course and outcome of acute hepatitis A superinfection in 17 (3.9 percent) of 432 patients with pre-existing chronic hepatitis C virus (HCV) who were monitored for 86 months were described. In 10 of the 17 patients the course of acute HAV infection was uncomplicated and all recovered. In contrast, seven patients developed acute hepatic failure after superinfection with HAV, and six of these died. Severe hepatocyte necrosis with lymphocytic and plasma cell infiltration of the liver was evident in all patients. Outcome was probably unrelated to chronic hepatitis C disease severity, since none of the fatal cases had cirrhosis. Since HCV replication was reduced during infection with HAV, suggesting viral interference, it seemed unlikely that HCV per se was directly responsible for the severity of HAV superinfection. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis".)
Although the study was initially controversial due to the high fatality rate [9-11], subsequent studies have confirmed these observations in diverse regions. For example, in Thailand, 100 patients with acute hepatitis A without underlying chronic liver disease recovered fully, whereas 11 of 20 of patients with acute hepatitis A superimposed on the HBsAg carrier state and 4 of 12 patients with chronic hepatitis B or C developed fulminant or submassive liver necrosis . The average age of the patients who died was significantly older than those who survived severe hepatitis (59 versus 40 years of age). These observations confirm the notion that HBsAg carriers, in whom liver disease is often mild, also are an increased risk of severe disease when superinfected.
Acute hepatitis B — Anecdotal reports of acute hepatitis B superinfection of patients with chronic hepatitis C resulting in acute liver failure have supported the notion that superinfection may be devastating . In a study of 21 patients with chronic HCV infection who developed acute hepatitis B, 28.6 percent had severe disease (encephalopathy, ascites, or hypoprothrombinemia) . In contrast, among 20 patients with acute hepatitis B in the absence of HCV infection, none had evidence of severe disease. (See "Hepatitis B virus: Clinical manifestations and natural history".)
Acute hepatitis C — Acute hepatitis C superimposed on chronic hepatitis B also appears to be a clinically severe infection. Furthermore, patients who develop chronic hepatitis C may have a worse long-term prognosis due to an increased risk of cirrhosis and hepatocellular carcinoma . (See "Clinical manifestations and natural history of chronic hepatitis C virus infection".)
Pneumococcal disease — In addition to individuals over 65 years of age, pneumococcal infections may be more prevalent and may elicit more severe disease and life-threatening complications in those with underlying medical conditions, regardless of age. In patients with chronic liver disease, and particularly in liver disease as a consequence of alcohol use disorder, the incidence of pneumococcal disease is increased [16-18]. Patients with alcohol use disorder also are likely to have an increased risk of dying from pneumococcal disease, including pneumonia, meningitis, and septicemia.
Some of these observations may be related to defective antibody formation, poor functioning of polymorphonuclear cells, malnutrition, and general debilitation [19,20]. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia".)
Influenza — Limited anecdotal reports indicate that influenza virus infection has been associated with hepatic decompensation in patients with advanced chronic liver disease and in recipients of liver transplants [21,22].
VACCINES IN CHRONIC LIVER DISEASE
Hepatitis A vaccine — The Advisory Committee on Immunization Practices (ACIP) has recommended the immunization of all patients with chronic liver disease against hepatitis A . (See "Hepatitis A virus infection: Treatment and prevention".)
Immunogenicity — In a large US multicenter evaluation of the immunogenicity of the two-dose inactivated hepatitis A vaccine in 475 adult patients with compensated chronic liver disease and 188 healthy control subjects, 95 percent of the liver disease patients seroconverted versus 98 percent of controls . However, postvaccination titers of hepatitis A virus (HAV) antibodies were lower in the patients with liver disease than in controls. A similar reduction in anti-HAV titers was seen in 65 patients with hepatitis B virus (HBV) from Hong Kong when compared to 28 healthy controls . Whether this will have any impact on the duration of immunity remains uncertain. Hepatitis A vaccine has been demonstrated to be effective in children with chronic liver disease as well, although the titers of protective antibody were significantly lower in those with chronic liver disease [26,27].
The immunogenicity of the hepatitis A vaccine in patients with more advanced liver disease or decompensated disease is reduced. In three separate studies of patients with hepatic decompensation, seroconversion rates varied from 49 percent to 66 percent [28-30]. In liver transplant recipients, immunogenicity of the hepatitis A vaccine is also compromised  and antibody titers may wane over time [32,33].
The ACIP does not recommend routine postimmunization testing of vaccination titers. The efficacy of repeat HAV immunization has not been studied.
Safety — The inactivated hepatitis A vaccines are well tolerated with minimal side effects. No special precautions or monitoring are necessary following vaccination of patients with chronic liver disease. No serious adverse events have been identified in recipients of hepatitis A vaccine and because the vaccine is inactivated there are no concerns about immunizing immunocompromised individuals other than the possibility of a reduced immune response.
Hepatitis B vaccine — The ACIP recommends that all patients with chronic liver disease be immunized with the hepatitis B vaccine [23,34,35]. This includes those with elevated alanine or aspartate aminotransferase levels greater than twice the upper limits of normal. However, available data indicate that hepatitis B vaccination has been delivered to only 30 percent of patients with chronic liver disease in the United States. According to 2014 and 2015 National Health Interview Survey data, adherence is also an issue, with less than 30 percent of patients with chronic liver disease completing the hepatitis B vaccine series . Among those who are vaccinated, response rates in patients with cirrhosis are suboptimal (38 to 53 percent), with variation depending on the vaccine regimen [37,38].
A hepatitis B vaccine that uses a novel adjuvant (Heplisav-B) was approved for use in the United States in 2017, but clinical trials evaluating this vaccine did not include patients with chronic liver disease. Although small studies suggest increased response rates compared with conventional hepatitis B vaccines in patients with chronic liver disease  (see 'Immunogenicity' below), data are insufficient to recommend this vaccine for routine use in such patients. However, in patients with cirrhosis, Heplislav-B may be a reasonable alternative for either initial or second course of vaccination. A more detailed discussion of the different vaccine formulations is presented in a separate topic review. (See "Hepatitis B virus immunization in adults".)
Testing for postimmunization antibody titers is not routinely recommended; exceptions include patients at increased risk for recurrent exposure. This includes healthcare workers, patients on chronic hemodialysis, and other individuals (such as people who inject drugs, men who have sex with men, and sexual partners of HBV carriers). However, some experts also test for postimmunization antibody titers in patients with chronic liver diseases, due to the risk of severe infection in this subgroup. If the patient has not achieved seroconversion, repeat immunization with the same, an alternate, or high-dose HBV immunization schedule may be considered.
Immunogenicity — Available information suggests that the immunogenicity of the hepatitis B vaccine may vary depending upon the underlying condition. As an example, in one study the response to vaccination was unimpaired in patients with fatty liver , but was reduced in patients with cirrhosis. In this study, recombinant hepatitis B vaccine was given at 0, 1, and 2 months, and seroconversion rates measured three months after the first dose were 94 percent in the 16 patients with fatty liver versus 39 percent in the 13 patients with cirrhosis .
In patients with hepatitis C, immunogenicity appears to be reduced. In a prospective study of 85 patients with chronic hepatitis C and 46 healthy adults, nonresponse to the three-dose regimen of the recombinant hepatitis B vaccine was reported in 45 percent of patients with hepatitis C and 2 percent in the control group . No difference in vaccine response was found when patients with cirrhosis were compared to those without cirrhosis. Earlier studies [42-44] showed that response rates in patients with hepatitis C varied between 69 to 100 percent.
Impaired immunogenicity has also been described in patients with alcohol-associated liver disease [45-47], liver transplant recipients, and in those awaiting liver transplantation [48-50]. However, age may be an important determinant of response. In one report, a success rate of 90 percent was observed among 19 Korean pediatric patients after liver transplantation .
Studies have evaluated different strategies to enhance immunogenicity. In a retrospective study of 278 patients undergoing evaluation for liver transplantation, patients received four doses of a recombinant vaccine using a double dose of the vaccine (40 mcg at zero, one, two, and six months) . Multivariate analysis demonstrated that lower Model for End-Stage Liver Disease (MELD) score, absence of diabetes, and isolated hepatitis B core antibody (anti-HBc) status were associated with higher rates of response. In the same study, 57 nonresponders were given a second identical series, and the overall response rate was 40 percent.
Another study evaluated the use of Heplisav-B. In a retrospective study of 166 patients with chronic liver disease, including 56 with cirrhosis (mean MELD score 10), a two-dose regimen of Heplisav-B was almost three times more likely to achieve immunity (adjusted odds ratio 2.74, 95% CI 1.31-5.71, p = 0.01) than a three-dose regimen of Engerix-B. A seroprotective level of anti-HBs occurred more frequently in patients with cirrhosis who were given Heplisav-B compared with Engerix-B (45 versus 26 percent), but the differences were not statistically significant .
Other studies evaluating strategies to improve the immunogenicity of hepatitis B vaccine in this patient population include:
●A randomized trial in 110 patients with alcohol use disorder was conducted to assess whether the use of high-dose versus standard-dose hepatitis B vaccine would be more effective . Patients were randomly assigned to 20 micrograms at baseline, one, and six months versus 40 micrograms at baseline, one, two, and six months. Seroconversion rates were improved in the high-dose arm (75 versus 46 percent).
●Accelerated high-dose regimens have also been studied in transplant candidates and in transplant recipients without a control group [49,50]; although overall seroconversion rates were low in both studies, there was some suggestion that the patients with a double dose of vaccine had modest improvement in seroconversion rates.
●The use of anti-HBs immunoglobulins to enhance the immunogenicity of the three-dose hepatitis B vaccine schedule in patients with alcohol use disorder was unsuccessful in one small study of 25 patients .
Safety — The safety of the initial plasma-derived and the recombinant hepatitis B vaccines has been well documented in patients with chronic liver disease. Adverse events do not differ from those seen in healthy individuals.
Immunogenicity — The 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for use in adults with chronic liver disease [23,53]. Large studies of the immunogenicity of pneumococcal vaccine in patients with chronic liver disease are not available and the spectrum of liver disease evaluated has been narrow [54,55]. In one small study of 15 patients with alcohol-related cirrhosis, antibody titers after pneumococcal immunization were comparable to healthy volunteers . A detailed discussion on pneumococcal vaccination is found elsewhere. (See "Pneumococcal vaccination in adults".)
Safety — No specific safety issues have been described.
●In a controlled prospective study from Korea, 198 patients with cirrhosis were vaccinated with a trivalent influenza vaccine and 113 were unvaccinated . Immunization was associated with decreased rates of influenza-like illness and complications and viral culture positivity .
●The immune response to an adjuvanted trivalent influenza vaccine was studied in 20 Italian patients with cirrhosis due to chronic hepatitis B or C and eight age-matched healthy controls . Seroconversion or a fourfold or greater rise in antibody titers to each antigen occurred in 75 to 85 percent of patients and 100 percent of controls, suggesting a mild impairment of immunogenicity in these patients with cirrhosis.
●Two studies of the effectiveness of influenza vaccine in transplant recipients demonstrated conflicting results [58,60]. In a subsequent study of 51 liver transplant recipients, antibody responses developed in 14 percent of patients vaccinated within four months of transplantation and in 67 percent immunized between month 4 and 12, suggesting that efficacy may improve further out from the time of transplant . Whether a two-dose vaccination strategy would improve responsiveness has been suggested  but has not been adequately studied.
Safety — The inactivated vaccines are generally well tolerated, with reactions seen in fewer than 5 percent of cases. There are no data about special safety concerns in patients with liver disease. Inactivated vaccine is recommended for use in patients with hepatic dysfunction by the ACIP .
There are no specific data on the use of intranasal live-attenuated vaccine in patients with liver disease.
Routine immunizations — The ACIP publishes vaccination schedules for measles, mumps, and rubella; diphtheria and tetanus and acellular pertussis; and zoster and other vaccines in persons with chronic medical conditions (figure 1) .
There are no specific data on the use of these vaccines in patients with chronic liver disease. However, a retrospective study demonstrated that herpes zoster vaccine was associated with a significantly reduced risk of herpes zoster disease by more than 50 percent . This vaccine benefit was also seen among persons with chronic medical conditions, including liver disease. Herpes zoster immunization is recommended in persons over the age of 60.
Meningococcal and Haemophilus influenzae vaccines — Patients with advanced liver disease who may be undergoing splenectomy for other medical conditions (eg, idiopathic thrombocytopenia) should be considered for meningococcal and Haemophilus influenzae vaccines. (See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations'.)
COVID-19 vaccine — All patients with chronic liver disease should receive one of the available COVID-19 vaccines, unless contraindicated for other reasons (eg, hypersensitivity to the vaccine or its components). Chronic liver disease is a risk factor for adverse outcome with COVID-19 infection. COVID-19 vaccination for patients with chronic liver disease and details regarding vaccine administration are discussed separately. (See "COVID-19: Issues related to liver disease in adults", section on 'COVID-19 vaccination' and "COVID-19: Vaccines".)
MISSED OPPORTUNITIES FOR VACCINATION — Many missed opportunities for vaccine administration occur despite widespread recognition of the importance of immunizations in disease prevention . As a consequence, immunization appears to be underutilized in patients with chronic liver disease. As an example, during the period between January and December 2014, the National Health Interview Survey (NHIS) reported that hepatitis B virus (HBV) vaccine coverage in adults with chronic liver disease was 27.4 percent .
Another example is hepatitis A vaccine. The US Department of Veterans Affairs has recommended the hepatitis A vaccine for susceptible patients with chronic liver disease. A retrospective study was undertaken between 2000 and 2002 in two Veterans Affairs medical centers in New York to assess the frequency of testing for susceptibility to hepatitis A virus (HAV) and administration of the hepatitis A vaccine to patients with chronic hepatitis C with the following results :
●Despite multiple visits to their primary care practitioners or to the Gastroenterology Clinic, only 54 percent of the 1193 chronic hepatitis C patients identified had been tested for anti-HAV.
●Older patients and those with psychiatric disorders were less likely to be tested, while those with a history of an STI or those seen in the Gastroenterology Clinic were more likely to be tested.
●Slightly more than half the tested patients were immune and did not require HAV vaccination. Among the susceptible, only 27 percent received at least one dose of the hepatitis A vaccine.
The clinical importance of this study in these two centers takes on added significance with the observation that on follow-up, 3 of the 1193 chronic hepatitis C patients in this study developed acute hepatitis A and one of these died of acute liver failure. All three patients were susceptible to HAV and none had received the hepatitis A vaccine.
In a separate retrospective cohort study of chronic hepatitis C patients receiving care at a large Veterans Administration Medical Center between 2002 and 2005, only 8 percent had documented receipt of hepatitis vaccines. Of those patients who had not been vaccinated, half had not been tested for susceptibility nor had negative serologies .
Variations in coverage rates between primary care and specialist centers, such as gastroenterology and hepatology practices, involved in the care of patients with chronic liver disease are receiving attention. In a retrospective analysis of vaccine coverage in almost 700 patients with chronic liver disease seen by 22 primary care offices (337 patients) and 15 gastroenterologists or hepatologists (356 patients), chronic hepatitis C was the most common diagnosis, followed by nonalcohol-associated liver disease, alcohol-associated liver disease, and chronic hepatitis B . The study was notable for the following results:
●Patients seen in primary care offices were more likely to receive seasonal influenza and pneumococcal vaccine than the patients who frequented specialty offices.
●Of patients who were susceptible to HAV and HBV, patients were much more likely to receive hepatitis A or B vaccines if they were seen in specialist offices.
Better communication between primary care personnel and specialists, with explicit understanding of which office will assume responsibility for immunization and accurate record keeping of immunization history may reduce vaccine underutilization in patients with chronic liver disease and improve health outcomes. Electronic medical record prompts may increase immunization utilization.
LIVER TRANSPLANT CANDIDATES — Immunization in liver transplant candidates is discussed separately. (See "Immunizations in solid organ transplant candidates and recipients".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immunizations in adults" and "Society guideline links: Hepatitis B vaccination".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Vaccines for adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Acute viral hepatitis in patients with chronic liver disease and in liver transplant recipients can lead to significant morbidity and mortality. (See 'Impact of vaccine-preventable infections' above.)
●We recommend vaccination of all patients with chronic liver disease against hepatitis A and B unless they are already immune (Grade 1B). However, there remains uncertainty about how chronic liver disease should be defined. It is possible, for example, that patients with nonalcohol-associated fatty liver disease alone may not be at the same risk for serious morbidity from acute viral hepatitis as those with underlying hepatitis C virus infection. Until further data are available to better define the risks with specific forms of liver disease and the cost-effectiveness of vaccination strategies, we suggest immunization for patients with all forms of liver disease regardless of its severity. The benefits of vaccination are expected to be greatest in those with relatively advanced disease or those at risk for progressive liver disease. This recommendation also considers the safety of the available vaccinations. (See 'Vaccines in chronic liver disease' above.)
●Patients with liver disease should receive standard immunizations that are applicable to an otherwise healthy population (figure 1). This includes routine diphtheria and tetanus booster immunizations every 10 years. (See "Tetanus-diphtheria toxoid vaccination in adults".)
●Haemophilus influenzae and meningococcal vaccines should be administered to those who may require a splenectomy. (See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations'.)
●We do not routinely obtain antibody titers after immunization to determine efficacy. Exceptions may be testing for response to hepatitis B vaccine in patients with advanced disease and those at increased risk for recurrent exposure. This includes healthcare workers, patients on chronic hemodialysis, and other individuals ( eg, men who have sex with men, persons who inject drugs, and sexual partners of hepatitis B virus [HBV] carriers). (See "Hepatitis B virus immunization in adults".)
●COVID-19 vaccination is recommended for patients with chronic liver disease and is discussed separately. (See "COVID-19: Issues related to liver disease in adults", section on 'COVID-19 vaccination'.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Raymond S Koff, MD, now deceased, who contributed to an earlier version of this topic review.