CLINICAL AND SYSTEMATIC REVIEWS
Viral Hepatitis in the Elderly
Andres F. Carrion, MD1 and Paul Martin, MD, FACG2
As life expectancy continues to rise, elderly adults represent a rapidly growing proportion of the population. The
likelihood of complications of acute and chronic liver disease and overall mortality are higher in elderly populations.
Several physiological changes associated with aging, greater prevalence of co-morbid conditions, and cumulative
exposure to hepatotropic viruses and environmental hepatotoxins may contribute to worse outcomes of viral hepatitis
in the elderly. Although pharmacotherapy for hepatitis B and C continues to evolve, the efficacy, tolerability, and side
effects of these agents have not been studied extensively in elderly adults. Immunization against hepatitis A and B in
naïve elderly adults is an important public health intervention that needs to be revised and broadened.
Am J Gastroenterol 2012; 107:691–697; doi:10.1038/ajg.2012.7; published online 31 January 2012
Viral hepatitis has some unique clinical characteristics in
older individuals who comprise an increasingly large segment
of the US population. According to data from the US Census
Bureau 12.7% of the US population is older than 65 years of
age. The “Baby Boom” generation refers to individuals born
between 1946 and 1964 and is the largest birth cohort in the
US history, reflecting a marked increase in births following
World War II. As the first Baby Boomers started turning 65 in
2011, the US Census Bureau projects that the elderly population will increase twofold by 2030 (72 million people) and will
comprise ~20% of the US population (1–3). There are important differences in the epidemiology, clinical presentation,
and management of viral hepatitis in the elderly compared
with younger individuals. For example, acute hepatitis A
is more clinically severe in older individuals and, although
acute hepatitis B and C are most commonly recognized in
young adults with high-risk behaviors, acute infection can
also occur in the elderly. With the aging of the cohort of individuals chronically infected with hepatitis C, it is anticipated
that there will be an increasing burden of decompensated cirrhosis and hepatocellular carcinoma (HCC) for the next two
decades (4). It is also well established that elderly individuals
with viral hepatitis have higher mortality rates than younger
patients, reflecting in part a higher prevalence of co-morbid
conditions (5). Furthermore, physiological changes associated
with aging, such as diminished immune response (“immune
senescence”), metabolic derangements, nutritional deficiencies, and greater cumulative exposure to environmental
hepatotoxins may also contribute to worse outcomes of viral
hepatitis in the elderly (6). Among the multiple age-related
changes of the liver, significant reductions of up to 30–40%
in parenchymal volume, liver blood flow, and perfusion have
been noted (7). Although there are no age-specific alternations in serum bilirubin levels, aminotransferases, and fractionated alkaline phosphatase levels, the hepatic metabolism
of multiple substances (i.e., hepatic nitrogen clearance and
aminopyridine demethylation) may be significantly impaired
(up to 50%) with advanced age (8). The age-related decline
of liver regeneration has been described in animal models in
which the mitogenic capacity of hepatocytes is reduced with
aging (up to 70% lower than in younger animals) (9). This
finding has also been recently corroborated in humans with
significant reductions in liver regeneration noted in individuals older than 50 years compared with younger adults undergoing living donor liver transplantation (10).
HEPATITIS A
The age-specific incidence of hepatitis A virus (HAV) infection in
children and adults in the United States declined rapidly following implementation of vaccination of children and individuals at
risk (11). Data from 2009 published by the Centers for Disease
Control and Prevention demonstrate a low incidence of acute
HAV infection of 0.6 per 100,000 people (12). The seroprevalence of anti-HAV immunoglobulin (Ig) G, a marker of prior
infection with HAV, increases proportionally with age reflecting
a cumulative risk of HAV infection throughout life. Data from
the third National Health and Nutrition Examination Survey
(NHANES III) indicate that 31% of the overall US population
had serological evidence of prior HAV infection (data collected
before implementation of HAV vaccination): 9% of children aged
6–11 years, 19% of young adults aged 20–29 years, 33% of middle age adults aged 40–49 years, and 75% of those older than 70
years of age (13).
1
Department of Medicine, Miller School of Medicine, University of Miami, Miami Veterans Affairs Medical Center, Miami, Florida, USA; 2Division of Hepatology, Miller
School of Medicine, University of Miami, Miami, Florida, USA. Correspondence: Andres F. Carrion, MD, Department of Medicine, Miller School of Medicine, University
of Miami, Miami Veterans Affairs Medical Center, 1201 NW 16th Street, Office B-1039, Miami, Florida 33125, USA. E-mail: [email protected]
Received 27 October 2011; accepted 1 January 2012
© 2012 by the American College of Gastroenterology
691
REVIEW
nature publishing group
The American Journal of GASTROENTEROLOGY
REVIEW
692
Carrion and Martin
Recovery from acute HAV infection is usually uneventful,
especially in children and younger adults in whom the infection
is often subclinical (14). However, elderly individuals with acute
HAV are likely to have more profound hepatocellular dysfunction
with frequent jaundice and coagulopathy, as well as a higher incidence of complications such as prolonged cholestasis, pancreatitis, and ascites (15,16). Multiple factors have been implicated in
the greater severity of HAV infection in the elderly. Of these putative factors, an attenuated immune response due to age-related
qualitative impairment of cell-mediated immune function has
been postulated to be the most significant (15). The more severe
clinical course of HAV in the elderly is reflected in higher hospitalization rates and mortality. For example, during an outbreak of
HAV infection in Memphis, TN, USA (1994–1995) 42% of individuals aged 70 years or older required hospitalization compared
with 3–20% of adults aged 40–49 years (17). Epidemiological
data from the United Kingdom reveals mortality rates from HAV
infection in individuals older than 75 years as high as 15%, which
markedly contrasts with the very low mortality in adults aged
25–35 years (0.03–0.06%) (18). Case fatality rates due to HAV
infection in the United States between 1983 and 1987 were lower
than in the United Kingdom; however, age-related differences in
outcomes were similar with 0.004% deaths in the 5–14 years of
age group, and 2.7% in adults older than 49 years (15,19). More
recent data from the Centers for Disease Control and Prevention
(2004–2007) show a downward trend in mortality from hepatitis A
as the cause of death in all age groups. Importantly, the largest reduction in mortality associated with acute HAV infection
(~50%) between 2004 and 2007 was observed in elderly adults
aged ≥ 75 years. These data also confirm that mortality due to
HAV increases with age with no fatalities reported in individuals younger than 34 years of age, 0.05 per 100,000 adults aged
between 45–54 years, and 0.11 per 100,000 adults ≥ 75 years of
age (20). Higher mortality in elderly individuals was also noted
during a HAV outbreak in Dallas County, TX, USA in 1999.
Of the 232 reported cases of HAV, 25% occurred in individuals
older than 60 years of age and the only two fatalities reported
were in individuals older than 70 years (15). Overall, the basis
for worse outcomes in the elderly is thought to be multifactorial
and influenced by higher prevalence of co-morbid conditions,
decline in immune function, and reduced regenerative capacity
of the liver with advanced age (21). There are no specific data
about age-related differences of the antibody-mediated response
against HAV in the elderly; however, evidence suggests that older
individuals have decreased antibody affinity against antigens in
general (22).
Although no formal recommendations from the Centers for
Disease Control and Prevention for HAV vaccination in elderly
adults have been issued, individuals without serological evidence
of immunity to HAV should be considered candidates for immunization (8). Data from the NHANES III indicate that the seroprevalence of anti-HAV IgG is > 33% in adults older than 40 years
of age in the United States; therefore, prevaccination screening
for serological evidence of HAV immunity may be a cost-effective strategy (13,23). In general, seroprotection from HAV vacThe American Journal of GASTROENTEROLOGY
cine is inversely related to age at the time of immunization. For
example, 100% seroprotection has been reported in adults aged
18–45 years vs. 93% in adults older than 60 years of age based
on the development of anti-HAV IgG antibodies following two
doses of HAV vaccine (21). In developed countries, HAV infection in adults has become less common; however, international
travel, particularly to developing countries, remains a significant
risk for acquisition. The median age of travelers from areas of low
endemicity to areas of high endemicity is > 40 years of age (24).
In addition, outbreaks of HAV infection continue to occur within
the United States, most typically traced to an infected food handler or contaminated fruits or vegetables (25,26). Thus, even in
the absence of formal recommendations, there are cogent reasons
to advise vaccination in HAV-naïve adults.
HEPATITIS B
The NHANES III indicated that the prevalence of chronic hepatitis B virus (HBV) infection, defined in that cohort as detectable
total anti-hepatitis B-core antibody and hepatitis B surface antigen (HBsAg), is 0.42% in the United States. Adults older than 50
years of age have on average a 1.5 to twofold higher prevalence
of this infection across different ethnic groups compared with
younger individuals (27). The NHANES (1999–2006) showed
an overall seroprevalence of past/present HBV infection in the
United States of 4.7% (defined as positive total anti-hepatitis Bcore). These data also show marked variations of the seroprevalence of the disease among different age groups with adults aged
≥ 50 having a 1.7 and 12.8 times higher seroprevalence of past/
present infection than individuals aged 20–49 and 6–19 years,
respectively. When compared with the prior NHANES survey
(1988–1994), there was a significant decrease in the seroprevalence of past/present HBV infection in younger individuals but
elderly adults had a non-significant increase (28). Furthermore,
there was a non-significant decrease in the seroprevalence of
chronic HBV infection in all age groups when data from both
surveys were compared (28). Importantly, these surveys exclude
the incarcerated, homeless, institutionalized, and recent immigrants; therefore, the seroprevalence estimates of past/present
and chronic HBV infection are likely to be underestimated (29).
As expected foreign-born individuals living in the United States
have a 4.4 higher prevalence of HBV infection compared with
US born individuals (27).
Clinical manifestations of acute HBV infection in the elderly may
be different than in younger adults. During an outbreak of acute
HBV in elderly nursing home residents, most infected individuals
were asymptomatic with only a few presenting with jaundice and
non-specific symptoms such as anorexia, nausea, and vomiting.
No fatalities or individuals requiring hospitalization were reported
during the outbreak (30).
The natural course of chronic HBV infection is determined
by multiple variables including age (31). The risk of progression to chronic hepatitis B is inversely related to age at the time
of infection. For example, progression to chronic hepatitis B
has been reported in > 90% of infants, 25–50% of children aged
VOLUME 107 | MAY 2012 www.amjgastro.com
1–5 years, and < 5% of older children and young adults following an episode of acute HBV infection (30). However, the rate
of progression to chronic hepatitis B is higher in elderly individuals than in younger adults. Data from an outbreak of acute
HBV infection in a nursing home in Japan showed that 59% of
patients older than 65 years of age developed chronic infection
(30). The rate of spontaneous HBsAg seroclearance is also different in younger and elderly adults with chronic HBV infection. Individuals older than 60 years of age have a greater than
twofold and 1.75 higher rates of cumulative HBsAg seroclearance compared with adults aged 40–49 years and 50–59 years,
respectively (adjusted for several variables such as sex, baseline
HBV-DNA level, baseline alanine aminotransferase (ALT) level,
ethnicity, and body mass index). Importantly, this difference is
even more pronounced when elderly and younger adults with
HBV-DNA levels > 10,000 copies/ml are compared (32). Elderly
individuals with acute HBV infection have similar rates of hepatitis B e antigen (HBeAg) positivity as younger adults (~77% for
both groups) but significantly lower rates of antibodies to hepatitis e antigen (5.5% vs. 18.6%, respectively) (33). Among individuals with chronic HBV infection, the prevalence of HBeAg is
inversely related to the patient’s age. For example, adults older
than 60 years of age have a fourfold higher prevalence of HBeAg
compared with younger individuals aged 30–39 years (34). No
correlation was found between patient age and HBV precore
mutant/total HBV ratio in one study including individuals aged
18–52 years (35). With respect to HBV-DNA levels in patients
naïve to treatment, age older than 40 years was associated with
a 2.5 higher odds of serum HBV-DNA levels > 108 copies/ml
in a multicenter cross-sectional study from the United States
(mainly HBV genotypes A, B, C, and a small proportion of
genotypes D, E, F, and G). Patients with wild-type and variant
precore/core promoter sequences were comparable in age (36).
However, data from a large Asian cohort show that adults older
than 60 years of age infected with HBV genotypes B and C have
lower HBV-DNA levels compared with individuals aged 30–59
years (HBeAg positive and negative). This difference persisted
when only HBeAg-negative younger and elderly individuals were compared (31). Additional data from the same Asian
cohort demonstrate that progression to cirrhosis is mainly correlated with HBV-DNA levels but older age and male sex are
also important risk factors (37).
Therapeutic options for HBV have greatly expanded since the
mid-1990s with the introduction of oral therapies. Clinical trials
showed equivalent therapeutic efficacy of standard and pegylated
interferons in the elderly compared with younger adults (38).
Lamivudine was also equally effective in individuals younger and
older than 60 years of age as evidenced by response to therapy,
loss of HBV-DNA, and development of viral resistance (39).
Unfortunately, the use of lamivudine is limited by the high rate of
development of resistant mutants. Anti-HBV therapy with newer
nucleoside or nucleotide analogs (tenofovir, entecavir, and adefovir) is associated with high rates of recurrence after treatment
is stopped; therefore, most individuals require long-term therapy
with these drugs (40). Interferon-based therapy may also be effec© 2012 by the American College of Gastroenterology
tive; however, virologic relapse is more frequent in the elderly
(defined as reappearance of HBV-DNA and/or HBeAg) (41).
Vaccination against HBV is recommended in elderly individuals at risk for infection, including all nursing home residents
because of the higher risk of transmission of HBV in these facilities (42). Nursing home residence is associated with an increased
risk for HBV infection due to breaches in standard precautions
and cross-contamination with blood and other body fluids.
Therefore, HBV immunization should also be recommended
for care providers at these institutions (42). The prevalence of
HBsAg has been reported to be higher in nursing home residents compared with non-institutionalized populations in the
same geographic area (42). Normal aging is associated with a
decline in immune function; therefore, elderly individuals have
an attenuated immune response to HBV vaccination compared
with younger adults (70% vs. 98%, respectively) (43). The major
factor implicated is T-cell dysfunction in elderly adults. Supporting this hypothesis, in vitro studies have demonstrated that
production of antibodies against HBsAg is normal when T cells
from young individuals are added to serum from older adults
(43). Furthermore, aging is also associated with a decreased
number of T cells. In an attempt to overcome this disadvantage,
particularly the quantitative deficiency of T cells, growth factors
(i.e., granulocyte-monocyte colony stimulating factor) have been
used as an adjuvant to enhance vaccine-induced seroprotection
in elderly individuals (44). However, a pilot trial evaluating
this intervention did not show a clinically significant effect on
immune response in healthy elderly individuals following HBV
immunization (45).
HCC is a major complication of chronic HBV infection. Older
age is a predictor for development of HCC in patients with
chronic hepatitis B by increasing the risk of this neoplasm by a
2.7 increment with every decade of life (46,47). Therefore, age
is a factor in determining initiation of surveillance for HCC in
patients with chronic HBV infection but current guidelines only
provide age-specific recommendations for HCC surveillance in
hepatitis B carriers of Asian ethnicity (men > 40 years of age and
women > 50 years of age) (48). Spontaneous annual seroclearance rates of HBsAg are higher in older adults compared with
younger individuals; however, HBsAg seroclearance (either
spontaneous or as a result of antiviral therapy) does not eliminate the risk of HCC (32,49). Furthermore, recent data suggest
that HBsAg seroclearance after 45–50 years of age is associated
with higher incidence of HCC compared with seroclearance at
a younger age. The increased incidence of HCC in patients with
“late” HBsAg seroclearance may reflect the oncogenic nature of
HBV (50).
Reactivation of HBV infection with elevated HBV-DNA and
ALT levels may occur in up to 50% of HBV-infected individuals following immunosuppressive chemotherapy (48). Although
the majority of cases of HBV reactivation in this setting are
asymptomatic, fatal hepatic decompensation is well recognized
(51). Reactivation of HBV in patients receiving antineoplastic
chemotherapy typically results in interruption of treatment
with reduced antineoplastic efficacy (52). However, data from
The American Journal of GASTROENTEROLOGY
693
REVIEW
Viral Hepatitis in the Elderly
REVIEW
694
Carrion and Martin
prospective studies suggest that older adults receiving antineoplastic chemotherapy are at lower risk for HBV reactivation
compared with younger individuals (51,53). Rituximab and
systemic corticosteroids, two key agents in the treatment of
lymphoid neoplasms, which occur more commonly in younger
adults, have been associated with a higher risk of HBV reactivation (54,55). Current recommendations for testing for HBsAg
and anti-hepatitis B-core in individuals at risk for HBV infection before initiation of immunosuppressive chemotherapy are
not different for younger and elderly adults (48). Prophylactic
use of antiviral agents in HBV carriers regardless of age is indicated if immunosuppressive therapy is to be initiated: lamivudine or telbivudine if the anticipated duration of treatment is
≤ 12 months, and tenofovir or entecavir if longer treatment is
anticipated (48).
HEPATITIS C
The incidence and prevalence of hepatitis C virus (HCV) infection continue to decline, particularly among younger individuals. In the United States, the prevalence of HCV infection in the
general population is 1.6% but varies among different age groups
with adults 40–49 years of age now having the highest seroprevalence (4.3%). Elderly individuals aged 60–69 and 70 years or
older have lower prevalence rates (0.9% and 1%, respectively)
(56,57). Data from a European study show that the proportion
of individuals infected with HCV genotype 1 increases with age:
57% in adults aged < 65 years, 72% in those 65–80 years of age,
and 84% in adults older than 80 years of age (58). Risk factors
for HCV infection in older individuals include blood product
transfusions before 1992, military service, injection drug use,
tattoos, hemodialysis, and employment as a health care worker
(59). The true prevalence of HCV infection among elderly adults
residing in nursing homes is largely unknown; however, data
from a prospective cohort study including residents of three different nursing homes in St Louis, MO, USA demonstrated that
the seroprevalence of anti-HCV antibodies is surprisingly high
in this population (4.5%) (60). Importantly, adults older than 65
years of age more often present with complications of cirrhosis
particularly hepatic failure and HCC as initial manifestations of
HCV infection compared with younger individuals (58). Older
age at the time of initial infection is an important factor associated with more advanced fibrosis score, even after adjusting for
sex, alcohol consumption, body mass index, HIV status, and
diabetes (58). Furthermore, progression to fibrosis may be more
rapid when initial HCV infection occurs in older individuals,
regardless of duration of infection (58,61,62). For example, the
median time to development of cirrhosis from infection was 33
years in individuals infected with HCV between 21 and 30 years
of age compared with 16 years in individuals older than 40 years
of age (63). Elderly individuals with HCV-RNA viremia are also
more likely to have normal ALT levels than younger adults (46%
vs. 10.6%, respectively; Table 1) (64). Similarly, the prevalence
of elevated ALT levels is comparable in individuals older and
younger than 65 years of age despite an apparent greater prevaThe American Journal of GASTROENTEROLOGY
Table 1. Characteristics of HCV infection in elderly individuals
Risk factors for HCV infection
Blood transfusions before 1992, military
service, injection drug use, tattoos,
hemodialysis, and health care work
Clinical course of the disease
Complications are often the initial
manifestation of the disease
Faster progression to fibrosis
Laboratory findings
Approximately one-half of viremic patients
have normal ALT levels
ALT, alanine aminotransferase; HCV, hepatitis C virus.
lence of fibrosis in the former group as determined by serological markers of fibrosis (Fibrotest-Fibrosure and Actitest) (58).
Although the use of serological markers of fibrosis in patients
older than 80 years of age has not been validated, preliminary
investigations suggest that the characteristics of these tests are
not affected by older age. The use of these non-invasive serological tests for assessment of fibrosis may potentially be valuable in
older populations particularly when ALT levels are normal, as up
to one third of elderly adults may have significant fibrosis despite
elevation of the ALT (58).
The National Institute of Health consensus conference on hepatitis C identified elderly patients with chronic HCV infection
as a difficult-to-treat group. Although current practice guidelines
do not establish an upper age limit for antiviral therapy, elderly
individuals with HCV infection are more likely to have contraindications to antiviral therapy than younger adults (65). Typically,
major clinical trials have excluded individuals older than 65 years
of age and, in general, adults over the age of 60 have a higher
prevalence of co-morbidities compared with younger individuals (38% vs. 18%, respectively), particularly cardiovascular, renal,
pulmonary, and hematological diseases that often preclude antiHCV therapy in this population (66). This was demonstrated on
a study of 208 Japanese patients naïve to antiviral therapy (predominantly genotype 1) who underwent treatment with interferon-α-2b and ribavirin for a total of 24 weeks. Patients were
stratified by age ( < 50, 50–59, and > 60 years). A significantly
higher prevalence of systemic hypertension, impaired renal function, anemia, thrombocytopenia, and leukopenia was noted at
baseline in the elderly group. Discontinuation of therapy or dose
reductions were twice more common in the elderly (77%) than
in younger adults (38%). Importantly, patient age and systemic
hypertension were found to be independently associated with
adherence to therapy (66). However, elderly individuals are less
likely to have other barriers to anti-HCV therapy such as substance abuse and psychiatric disorders (67).
Older age is an independent factor associated with a lower
likelihood of being considered for antiviral therapy. For example, treatment eligibility based on accepted guidelines is lower
in elderly individuals compared with younger adults (16% vs.
26%, respectively) (66). Older adults are also less likely to accept
antiviral treatment and discontinuation of therapy and dose
VOLUME 107 | MAY 2012 www.amjgastro.com
reductions are more frequently required in this age group compared with younger adults (67). For example, data from an observational study of 220 patients treated with interferon-α-2b and
ribavirin demonstrated that discontinuation rates of ribavirin
were significantly more frequent in the elderly compared with
younger adults. Reasons for discontinuation of therapy were
similar in both age groups and consisted mainly of anemia,
constitutional symptoms (fatigue and anorexia), and depression (67). In clinical practice, < 15% of adults treated with
interferon and ribavirin discontinue therapy; however, discontinuation rates have been reported to be as high as 30%
and dose reductions are required in >70% of individuals aged
60 years or older within the first 12 weeks of therapy (61,66).
Despite these limitations, sustained virological response rates
following combination therapy with standard interferon and
ribavirin are similar in individuals older than 60 years of age
and those younger than 60 years of age (66,67). Results of
treatment with pegylated interferon and ribavirin in elderly
individuals are scarce. A pilot study of 33 patients naïve to
treatment (mean age of 70.2 years) suggested lower sustained
virological response rates with a pegylated interferon-based
regimen in the elderly compared with younger adults (46% vs.
69.7%) (68). The proportion of patients developing side effects
that led to discontinuation of therapy was twofold higher
in elderly compared with younger adults (24.2% vs. 12.2%,
respectively) (68).
Current practice guidelines recommend not withholding antiviral therapy based purely on advanced age but suggested that
special attention should be paid to co-morbid conditions and
tolerance for potential side effects (69,70). Adverse effects typically resolve spontaneously within 2–3 weeks of discontinuing
treatment; however, depression may take longer to resolve in the
elderly compared with younger adults and often requires continuing pharmacotherapy (71). Although the recently licensed direct
acting antiviral agents (boceprevir and telaprevir) significantly
increase sustained virological response, there are no data assessing the efficacy and/or toxicity of these drugs in elderly populations (72–74).
HEPATITIS E
Hepatitis E virus (HEV) infection is endemic and epidemic
in Asia, Africa, and Mexico, whereas in the United States and
Western Europe only sporadic cases have been reported. The
NHANES III indicated, however, that the seroprevalence of
anti-HEV IgG antibodies in the US population is 21% (75).
This data concurs with a previously reported seroprevalence
of anti-HEV IgG in blood donors in the United States (18.3%)
implying that subclinical HEV infection is frequent in nonendemic areas (76). Although only limited data on acute HEV
infection in the elderly are available, the seroprevalence of antiHEV IgG antibodies in Indonesia has been reported to increase
with age: 38% in children 5–9 years of age, and 70% in adults
older than 60 years. The high seroprevalence of anti-HEV IgG
reflects cumulative risk for infection throughout life in areas of
the world where the infection is endemic (77). Similarly, the
seroprevalence of anti-HEV IgG was higher among elderly
vs. younger immigrants from the former Soviet Union living
in Germany (7.6% vs. 1–2%, respectively) (78). Differences in
the seroprevalence of anti-HEV IgG in different age groups
have also been reported in the United States. For example, 16%
of blood donors younger than 60 years of age had positive
Table 2. Differences of hepatitis A, B, C, and E in young and elderly adults
Hepatitis A
Hepatitis B
Hepatitis C
Hepatitis E
Young adults
Elderly adults
Lower seroprevalence (19-33%) of anti-HAV IgG
Higher seroprevalence (75%) of anti-HAV IgG
Infrequent hospitalization
Hospitalization required in 42% of patients
Very low mortality rate
Higher mortality 2.7–15%
Uneventful recovery in the majority of cases following acute
infection
Higher incidence of prolonged cholestasis, pancreatitis, and ascites following acute infection
Post-immunization seroconversion: 100%
Post-immunization seroconversion: ~93%
Lower risk of chronic infection (~5%)
Higher risk of chronic infection (up to 59%)
Multiple clinically effective agents for treatment of chronic HBV
infection
Efficacy data on treatment of HBV extrapolated from younger adults
Immunization recommended for the high-risk groups
Consider immunization for nursing home residents
Slower progression to fibrosis
Faster progression to fibrosis
Low prevalence of co-morbid conditions limiting treatment
High prevalence of co-morbid conditions which limit treatment eligibility
Higher SVR
Lower SVR reflect more frequent dose-reductions and higher drop-out rates
Lower seroprevalence of anti-HEV IgG in endemic and nonendemic regions of the world
Higher seroprevalence of anti-HEV IgG in endemic and non-endemic
regions of the world
HAV, hepatitis A virus; HBV, hepatitis B virus; HEV, Hepatitis E virus; Ig, immunoglobulin; SVR, sustained virological response.
© 2012 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
695
REVIEW
Viral Hepatitis in the Elderly
REVIEW
696
Carrion and Martin
anti-HEV IgG compared with 25.5% in those older than 60
years (79). Importantly, a recent study demonstrated that a
small but important proportion (3%) of patients with of acute
liver injury in the United States suspected to be drug-induced
were also seropositive for anti-HEV IgM. After reassessment
and causality analysis, HEV was considered a probable etiology
of acute liver injury in these cases. The majority of patients with
serology consistent with acute HEV infection (78%) were older
than 60 years of age (80).
In conclusion, exposure to HEV also occurs frequently in
Western industrialized countries and until the epidemiology of this
virus is better understood, HEV should be considered a potential
etiology of acute hepatitis in the elderly.
CONCLUSIONS
Elderly adults represent a rapidly growing population with distinct epidemiological, pathological, and therapeutic characteristics of multiple disease processes, including viral hepatitis A, B,
C, and E (Table 2). This population has a greater risk of complications of acute and chronic liver disease as well as higher risk of
mortality because of high prevalence of co-morbid conditions.
Therapeutic regimens for chronic hepatitis B and C have not been
studied exclusively in this age group and their true effectiveness
and tolerance in elderly adults warrants further research. Indications for immunization against hepatitis A and B in elderly individuals need to be revised and broadened as many of them are at
increased risk for infection and, even though elderly adults have
an attenuated response to immunization, this remains an effective preventive measure.
CONFLICT OF INTEREST
Guarantor of the Article: Paul Martin, MD, FACG.
Specific author contributions: Both authors conceived, initiated,
wrote the manuscript, and approved the final draft of the manuscript.
Financial Support: None.
Potential competing interests: None.
REFERENCES
1. US Census Bureau current population reports. 65+ in the United States:
2005. Available at: http://www.census.gov/prod/2006pubs/p23-209.pdf
Accessed 6 June 2011.
2. US Census Bureau Selected characteristics of baby boomers 42 to 60 years
old in 2006. Available at: http://www.census.gov/population/www/
socdemo/age/2006%20Baby%20Boomers.pdf, Accessed 6 June 2011.
3. US Census Bureau The older population in the United States: 2010.
Available at: http://www.census.gov/population/socdemo/age/2010_older_
table1.xls, Accessed 6 June 2011.
4. Davis GL, Roberts WL. The healthcare burden imposed by liver disease in
aging baby boomers. Curr Gastroenterol Rep 2010;12:1–6.
5. Marcus EL, Tur-Kaspa R. Viral hepatitis in older adults. J Am Geriatr Soc
1997;45:755–63.
6. Goodson JD, Taylor PA, Campion EW et al. The clinical course of acute
hepatitis in the elderly patient. Arch Intern Med 1982;142:1485–8.
7. Wynne HA, Cope E, Mutch E et al. The effect of age upon liver volume and
apparent liver blood flow in healthy man. Hepatology 1989;9:297–301.
8. James OF. Parenchymal liver disease in the elderly. Gut 1997;41:430–2.
9. Schmucker DL, Sanchez H. Liver regeneration and aging: a current
perspective. Curr Gastroenterol Geriatr Res 2011;2011:526379.
The American Journal of GASTROENTEROLOGY
10. Ono Y, Kawachi S, Hayashida T et al. The influence of donor age on liver
regeneration and hepatic progenitor cell populations. Surgery 2011;150:
154–61.
11. Wasley A, Samandari T, Bell BP. Incidence of hepatitis A in the United
States in the era of vaccination. JAMA 2005;294:194–201.
12. Centers for Disease Control and Prevention (CDC). Viral hepatitis statistics
and surveillance. Available at: http://www.cdc.gov/hepatitis/Statistics/
2009Surveillance/Table2.1.htm, Accessed 29 November 2011.
13. Bell BP, Kruszon-Moran D, Shapiro CN et al. Hepatitis A virus infection
in the United States: serologic results from the Third National Health and
Nutrition Examination Survey. Vaccine 2005;23:5798–806.
14. Hautlin Y, Pool V, Cramer E et al. A multistate, foodborne outbreak of
hepatitis A. N Engl J Med 1998;340:595–602.
15. Brown GR, Persley K. Hepatitis A epidemic in the elderly. South Med J
2002;95:826–33.
16. MacMahon M, James OFW. Liver disease in the elderly. J Clin Gastroenterol 1994;18:330–4.
17. Willner IR, Uhl MD, Howard SC et al. Serious hepatitis A: an analysis
of patients hospitalized during an urban epidemic in the United States.
Ann Intern Med 1998;128:111–4.
18. Forbes A, Williams R. Increasing age, an important adverse prognostic
factor in hepatitis A virus infection. J R Coll Physicians Lond 1998;22:
237–9.
19. D’Acremont V, Herzog C, Genton B. Immunogenicity and safety of a virosomal hepatitis A vaccine (Epaxal) in the elderly. J Travel Med 2006;13:
78–83.
20. Centers for Disease Control and Prevention (CDC). Viral hepatitis statistics
and surveillance. Available at: http://www.cdc.gov/hepatitis/Statistics/
2009Surveillance/Table2.3.htm, Accessed 29 November 2011.
21. Ragev A, Schiff ER. Liver disease in the elderly. Gastroenterol Clin North
Am 2001;30:547–63.
22. Ponnappan S, Ponnappan U. Aging and immune function: molecular
mechanisms to interventions. Antioxid Redox Signal 2011;14:1551–85.
23. Centers for Disease Control and Prevention (CDC). Prevention of hepatitis
A through active or passive immunization: recommendations of the
Advisory Committee on Immunization Practices (ACIP). MMWR
Recomm Rep 2006;55 (RR-7): 1–23.
24. Genton B, D’Acremont V, Furrer HJ et al. Hepatitis A vaccines and the
elderly. Travel Med Infect Dis 2006;4:303–12.
25. Wheeler C, Vogt TM, Armstrong GL et al. An outbreak of hepatitis A
associated with green onions. N Engl J Med 2005;353:890–7.
26. Centers for Disease Control and Prevention (CDC). Foodborne transmission of hepatitis A-Massachussetts, 2001. MMWR 2003;52:565–7.
27. McQuillan GM, Coleman PJ, Kruszon-Moran D et al. Prevalence of hepatitis
B virus infection in the United States: the National Health and Nutrition
Examination Surveys, 1976 through 1994. Am J Public Health 1999;89:14–8.
28. Wasley A, Kruszon-Moran D, Kuhnert W et al. The prevalence of hepatitis
B virus infection in the United States in the era of vaccination. J Infect Dis
2010;202:192–201.
29. Gish RG, Gadano AC. Chronic hepatitis B: current epidemiology in the
Americas and implications for management. J Viral Hepat 2006;13:787–98.
30. Kondo Y, Tsukada K, Takeuchi T et al. High carrier rate after hepatitis B
virus infection in the elderly. Hepatology 1993;18:768–74.
31. Chen CJ, Yang HI, Iloeje UH et al. Hepatitis B virus DNA levels and outcomes in chronic hepatitis B. Hepatology 2009;49:S72–84.
32. Liu J, Yang HI, Lee MH et al. Incidence and determinants of spontaneous
hepatitis B surface antigen seroclearance: a community-based follow-up
study. Gastroenterology 2010;139:474–82.
33. Zauli D, Crespi C, Fusconi M et al. Different course of acute hepatitis B in
elderly adults. J Gerontol 1985;40:415–8.
34. Yang HI, Lu SN, Liaw YF et al. Hepatitis B e antigen and the risk of
hepatocellular carcinoma. N Engl J Med 2002;347:168–74.
35. Chu CM, Yeh CT, Lee CS et al. Precore stop mutant in HBeAg-positive
patients with chronic hepatitis B: clinical characteristics and correlation
with the course of HBeAg-to-anti-HBe seroconversion. J Clin Microbiol
2002;40:16–21.
36. Chu CJ, Keeffe EB, Han SH et al. Prevalence of HBV precore/core promoter
variants in the United States. Hepatology 2003;38:619–28.
37. Iloeje UH, Yang HI, Su J et al. Predicting cirrhosis risk based on the level of
circulating hepatitis B viral load. Gastreonterology 2006;130:678–86.
38. Rudin D, Shah S, Kiss A et al. Interferon and lamivudine vs. interferon
for hepatitis B e antigen positive hepatitis B treatment: meta-analysis of
randomized controlled trials. Liver Int 2007;27:1185–93.
VOLUME 107 | MAY 2012 www.amjgastro.com
39. Kawaoka T, Suzuki F, Akuta N et al. Efficacy of lamivudine therapy
in elderly patients with chronic hepatitis B infection. J Gastroenterol
2007;42:395–401.
40. Girndt M. Viral hepatitis in elderly haemodialysis patients. Drugs Aging
2008;25:823–40.
41. Song BC, Suh DJ, Lee HC et al. Which patients with chronic hepatitis B are
more likely to relapse after interferon alpha-induced hepatitis B e antigen
loss in Korea? J Clin Gastroenterol 2004;38:124–9.
42. Sugauchi F, Mizokami M, Orito E et al. Hepatitis B virus infection among
residents of a nursing home for the elderly: seroepidemiological study and
molecular evolutionary analysis. J Med Virol 2000;62:456–62.
43. Cook JM, Gualde N, Hessel L et al. Alterations in the human immune
response to the hepatitis B vaccine among the elderly. Cell Immunol
1987;109:89–96.
44. Fabrizi F, Ganeshan SV, Dixit V et al. Meta-analysis: the adjuvant role of
granulocyte macrophage-colony stimulating factor on immunological
response to hepatitis B virus vaccine in end-stage renal disease.
Aliment Pharmacol Ther 2006;24:789–96.
45. Hess G, Kreiter F, Kösters W et al. Hepatitis B immunization of healthy
elderly adults: relationship between naïve CD4+ T cells and primary
immune response and evaluation of GM-CSF as an adjuvant. J Clin
Immunol 2001;21:30–6.
46. Chen JD, Yang HI, Iloeje UH et al. Carriers of inactive hepatitis B virus
are still at risk for hepatocellular carcinoma and liver-related death.
Gastroenterology 2010;138:1747–54.
47. Chen CJ, Yang HI, Su J et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65–73.
48. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hpatology
2009;50:1–36.
49. Kim JH, Lee SY, Lee HJ et al. HbsAG seroclearance in chronic hepatitis B:
implications for hepatocellular carcinoma screening. J Clin Gastroenterol
2011;45:64–8.
50. Yuen MF, Wong DK, Fung J et al. HBsAg seroclearance in chronic hepatitis
B in Asian patients: replicative level and risk of hepatocellular carcinoma.
Gastroenterology 2008;135:1192–9.
51. Yeo W, Chan PK, Zhong S et al. Frequency of hepatitis B virus reactivation in
cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626
patients with identification of risk factors. J Med Virol 2000;62 (3): 299–307.
52. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B
virus reactivation during anticancer therapy. Hepatology 2006;43:209–20.
53. Lok AS, Liang RH, Chiu EK et al. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study.
Gastroenterology 1991;100:182–8.
54. Cheng AL, Hsiung CA, Su IJ et al. Steroid-free chemotherapy decreases risk
of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma.
Hepatology 2003;37:1320–8.
55. Yeo W, Chan TC, Leung NW et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy
with or without rituximab. J Clin Oncol 2009;27:605–11.
56. Armstrong GL, Wasley A, Simard EP et al. The prevalence of hepatitis C
virus infection in the United States, 1999 through 2002. Ann Intern Med
2006;144:705–14.
57. Mindikoglu AL, Miller RR. Hepatitis C in the elderly: epidemiology, natural
history, and treatment. Clin Gastroenterol Hepatol 2009;7:128–34.
58. Thabut D, Le Calvez S, Thibault V et al. Hepatitis C in 6,865 patients
65 yr or older: a severe and neglected curable disease. Am J Gastroenterol
2006;101:1260–7.
© 2012 by the American College of Gastroenterology
59. Brind AM, Watson JP, James OF et al. Hepatitis C virus infection in the
elderly. QJM 1996;89:291–6.
60. Chien NT, Dundoo G, Horani MH et al. Seroprevalence of viral hepatitis in
an older nursing home population. J Am Geriatr Soc 1999;47:1110–3.
61. Tsui JI, Currie S, Shen H et al. Treatment eligibility and outcomes in elderly
patients with chronic hepatitis C: results from the VA HCV-001 study.
Dig Dis Sci 2008;53:809–14.
62. Ponyard T, Ratziu V, Charlotte F et al. Rates and risk factors of liver fibrosis
progression in patients with chronic hepatitis C. J Hepatol 2001;34:730–9.
63. Minola E, Prati D, Suter F et al. Age at infection affects the long-term outcome of transfusion-associated chronic hepatitis C. Blood 2002;99:4588–91.
64. Monica F, Lirussi F, Pregun I et al. Hepatitis C virus infection in a resident
elderly population: a 10-year follow-up study. Dig Liver Dis 2006;38:336–40.
65. NIH Consensus Statement on Management of Hepatitis C: 2002. NIH
Consens State Sci Statements 2002;19:1–46.
66. Iwasaki Y, Ikeda H, Araki Y et al. Limitation of combination therapy of
interferon and ribavirin for older patients with chronic hepatitis C.
Hepatology 2006;43:54–63.
67. Honda T, Katano Y, Urano F et al. Efficacy of ribavirin plus interferon-alpha
in patients aged > or = 60 years with chronic hepatitis C. J Gastroenterol
Hepatol 2007;22:989–95.
68. Floreani A, Minola E, Carderi I et al. Are elderly patients poor candidates
for pegylated interferon plus ribavirin in the treatment of chronic hepatitis
C. J Am Geriatr Soc 2006;54:549–50.
69. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and
treatment of hepatitis C: an update. Hepatology 2009;49:1335–74.
70. Craxi A. EASL clinical practice guidelines: management of hepatitis C virus
infection. J Hepatol 2011;55:245–64.
71. Floreani A. Hepatitis C: should antiviral therapy be offered to elderly
patients? Nat Rev Gastreonterol Hepatol 2009;6:503–4.
72. Jacobson IM, McHutchison JG, Dusheiko G et al. Telaprevir for previously
untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:
2405–16.
73. Poordad F, McCone Jr J, Bacon BR et al. Boceprevir for untreated chronic
HCV genotype 1 infection. N Engl J Med 2011;364:1195–206.
74. Zeuzem S, Andreone P, Pol S et al. Telaprevir for retreatment of HCV
infection. N Engl J Med 2011;364:2417–28.
75. Kuniholm MH, Purcell RH, McQuillan GM et al. Epidemiology of hepatitis
E virus in the United States: results from the Third National Health and
Nutrition Examination Survey, 1988–1994. J Infect Dis 2009;200:48–56.
76. Meng XJ, Wiseman B, Elvinger F et al. Prevalence of antibodies to hepatitis
E virus in veterinarians working with swine and in normal blood donors
in the United States and other countries. J Clin Microbiol 2002;40:117–22.
77. Corwin A, Jarot K, Lubis I et al. Two years’ investigation of epidemic
hepatitis E virus transmission in West Kalimantan (Borneo). Trans R Soc
Trop Med Hyg 1995;89:262–5.
78. Trautwein C, Kiral G, Tillmann HL et al. Risk factors and prevalence of
hepatitis E in German immigrants from the former Soviet Union. J Med
Virol 1995;45:429–34.
79. Dalton HR, Stableforth W, Thurairajah P et al. Autochtonous hepatitis
E in Southwest England: natural history, complications and seasonal
variation, and hepatitis E virus IgG seroprevalence in blood donors, the
elderely and patients with chronic liver disease. Eur J Gastroenterol Hepatol
2008;20:784–90.
80. Davern TJ, Chalasani N, Fontana RJ et al. Acute hepatitis E infection
accounts for some cases of suspected drug-induced liver injury.
Gastroenterology 2011;141:1665–72.
The American Journal of GASTROENTEROLOGY
697
REVIEW
Viral Hepatitis in the Elderly