The Global I mpact

of Hepatic Fibrosis
a nd End - St age Liver
Dis eas e
Young-Suk Lim, MD, W. Ray Kim, MD*

KEYWORDS
 Cirrhosis  End-stage liver disease  Epidemiology
 Global impact  Hepatic fibrosis

Cirrhosis is the end result of many types of liver disease and it consists of fibrosis and
nodular regeneration. Both fibrosis and cirrhosis are the consequences of a sustained
wound-healing response to chronic liver injury.1 Cirrhosis eventually leads to dimin-
ished hepatic function and altered blood flow. Hepatic fibrosis and cirrhosis are, in
principle, defined morphologically and the pattern and extent of the morphologic
changes depend on the cause and stage of fibrosis. Accordingly, there is a wide
spectrum in the degree of fibrosis and in the severity of clinical symptoms. Clinical pre-
sentation may vary widely, ranging from absent to nonspecific symptoms to life-
threatening conditions. In most cases, no clear dividing line can be drawn between
cirrhosis and the preceding liver disease because the transition is gradual and
unapparent.
Chronic liver disease and cirrhosis occur throughout the world, regardless of race,
age or gender. However, there are marked geographic variations in incidence and
prevalence, largely depending on the prevalence of causative factors. Although virtu-
ally any chronic liver disease may progress to cirrhosis, the most common causes of
liver fibrosis and cirrhosis globally are thought to be hepatitis B virus (HBV), hepatitis C
virus (HCV), and alcohol. Other causes include: immune-mediated liver injury, hepato-
toxic drugs, cholestatic diseases, genetic abnormalities, and nonalcoholic steatohe-
patitis. Viral hepatitis, especially HBV, is the leading cause of cirrhosis in developing
countries, whereas alcohol, HCV, and, more recently, nonalcoholic steatohepatitis
are the most significant causes of cirrhosis in the developed world.2

This work was supported by NIH Grant DK-34238.

Division of Gastroenterology and Hepatology (PL 6), Mayo Clinic College of Medicine, 200 First
Street SW, Rochester, MN 55905, USA
* Corresponding author.
E-mail address: kim.ray@mayo.edu (W.R. Kim).

Clin Liver Dis 12 (2008) 733–746

doi:10.1016/j.cld.2008.07.007 liver.theclinics.com
1089-3261/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
734 Lim & Kim

SOURCES AND LIMITATIONS OF GLOBAL EPIDEMIOLOGIC DATA OF CHRONIC LIVER DISEASE

The estimated prevalence of cirrhosis, as identified from autopsy studies ranges from
4.5% to 9.5% of the general population, which would project to hundreds of millions of
patients affected with cirrhosis worldwide.3,4 However, the precise incidence or prev-
alence of cirrhosis is difficult to ascertain because cirrhosis is often clinically silent.2
Up to 40% of patients with cirrhosis are asymptomatic and may remain so for more
than a decade.5,6 While a liver biopsy is required to establish the diagnosis of cirrhosis,
the absence of accurate, validated, noninvasive diagnostic tools makes population
screening difficult.2
The public health impact of chronic liver disease can be gauged from the reported
death rate. However, data based on death certificates have a number of limitations.
First, mortality statistics based on death certificates can only be obtained in settings
when there is necessary infrastructure for data collection. Second, even if these re-
sources are in place, variability in the documentation of cirrhosis will influence its re-
porting.2 The numbers of deaths by cirrhosis or chronic liver disease are likely to be
greatly underestimated, especially if only the primary cause of death is considered.
In fact, deaths from cirrhosis may be classified as a number of other categories. For
example, in a decedent who died of cirrhosis, the primary cause of death may be listed
under the underlying etiology such as, hepatitis B or C or alcoholic liver disease, or un-
der complications of cirrhosis such as, primary liver cancer or upper gastrointestinal
bleeding.7 In a recent report that analyzed chronic liver disease, mortality rates using
databases from a health maintenance organization in northern California, a compre-
hensive approach using a broad spectrum of death codes, including viral hepatitis
and hepatocellular carcinoma, led to detection of almost twice as many confirmed
deaths related to chronic liver disease as did the conventional method that included
only limited codes such as chronic hepatitis and cirrhosis.8 This suggests that
methods used conventionally for national and statewide statistics in the United States
substantially underestimate the true rates of mortality associated with cirrhosis.
Obviously, the death rate may not always be a valid surrogate for prevalence as
there may not necessarily be a 1:1 correlation between prevalence of liver disease
and mortality. For example, if treatment significantly improves over time, the preva-
lence of a condition in the community will rise, but the death rate from the given con-
dition may appear to fall.2 In the case of chronic liver disease and cirrhosis,
widespread application of antiviral agents and liver transplantation, as well as im-
provement in the treatment of complications of cirrhosis, may lead to a decrease in
cirrhosis mortality, especially in developed countries.
All of these factors make it difficult to estimate the true prevalence and burden of
cirrhosis, especially in the absence of hepatic decompensation. Patients with com-
pensated cirrhosis, however, often progress to decompensation including develop-
ment of ascites, variceal hemorrhage, or encephalopathy. In such patients, the
probability of eventual death from liver failure is high. The 5-year mortality has been
reported to be 50% and approximately 70% of these deaths are directly attributable
to liver disease.9

GLOBAL BURDEN OF CHRONIC LIVER DISEASE

Cirrhosis
In 2001, 771,000 people are estimated to have died from cirrhosis worldwide, ranking
14th and 10th as leading cause of death in the world and in developed countries, re-
spectively.10 Worldwide, deaths from cirrhosis have been projected to increase to
make it the 12th cause of death in 2020.11 In the 2001 data, cirrhosis was the sixth
 Global Impact of Hepatic Fibrosis 735

most common cause of death among adults in developed countries, accounting for
4.4% of all deaths. (Fig. 1) In low to middle income countries, cirrhosis was ranked
as the 9th cause of death, claiming 320,000 lives.10
According to a World Health Organization (WHO) database that incorporates mor-
tality data from 41 countries worldwide, age-adjusted mortality rates from cirrhosis
were the highest in some countries in Central and South America (eg, Mexico and
Chile, 55/100,000 in men and 14/100,000 in women) and in southern Europe (eg,
France, Italy, Portugal, Austria, Hungary and Romania, 30–35/100,000 in men and
10–15/100,000 in women) in the early 1980s.12 Since the mid- to late-1970s, mortality
from cirrhosis showed decreasing trends in most countries of Europe and America, co-
inciding with a reduction in alcohol consumption (annual percent change, APC, -5.0%
to -1.5%).12,13 The steadily declining mortality from cirrhosis was particularly obvious in
southern European countries.12,14 In these countries, rates in the early 2000s de-
creased by more than 50% compared with earlier decades. Meanwhile, mortality rates
in central and eastern European countries rose to reach a peak in the mid-1990s (eg,
rates over 58/100,000 men and 22/100,000 women in Hungary in 1990) and then
decreased thereafter. Mortality rates in Northern European countries reportedly show
a gradual yet continued increase.
A substantial increase in cirrhosis mortality over the last two decades has also been
reported for the United Kingdom (UK) (APC around 17% in men and 13% in women in
England and Wales; 19% in men and 17% in women in Scotland). However, cirrhosis
mortality in the UK remained lower than the level reported in Central and Eastern
European countries. Mortality rates from cirrhosis were lower in women from all coun-
tries, but the time trend was similar in both genders.12 Similar to data from neighboring
European countries, the increase in cirrhosis mortality in the UK has largely been at-
tributed to a recent rise in alcohol consumption.12–15 A correlation between the total
alcohol consumption and mortality from cirrhosis has been demonstrated, regardless
of the type of alcoholic beverages consumed (Fig. 2).12,16
The data discussed so far are limited because they did not include data from many
developing countries with high prevalence of Hepatitis B virus (HBV) infection, such as
Southeast Asia, western Pacific countries, and sub-Saharan African countries. This
omission obviously leads to underestimation of the worldwide burden of chronic liver
diseases. HBV infection is a global health problem, affecting approximately 2 billion
people (ie, one third of the world’s population) based on serologic evidence of past
or present HBV infection, including 360 million people with chronic HBV infection.17,18
Of subjects who have chronic HBV infection, 15% to 40% develop serious sequelae
during their lifetime, such as, cirrhosis, hepatic decompensation, and hepatocellular
carcinoma (HCC).19 Globally, most HBV-related deaths result from the chronic se-
quelae of infection. For the year 2000, it was estimated that, of the total 620,000
deaths from HBV-related causes, 580,000 (94%) were from cirrhosis and HCC.20
Although HBV is globally present, its endemic areas include: Southeast Asia, China,
Pacific Islands, Sub-Saharan Africa, Alaska, Peru, and northwestern Brazil.19,21 Peo-
ple living in these areas occupy about 45% of the global population. In developed
countries, HBV infection tends to be more prevalent in certain population groups,
such as, immigrants from endemic areas.22
In endemic areas with HBV infection, almost all infections occur during either the
perinatal period or early in childhood; this pattern accounts for the high rates of
chronic HBV infection in these populations.19 Safe and effective vaccines have
been available to prevent HBV infection since 1981.23,24 In 1992, the WHO recommen-
ded that all countries include HBV vaccine in their routine infant immunization pro-
grams.20 However, in 2000, only 116 of 215 countries had such a policy,
 736
Lim & Kim
High Income Countries Low Income Countries
% of total deaths % of total deaths
0 2 4 6 8 10 12 0 2 4 6 8 10 12 14 16

Ischemic heart disease HIV/AIDS

Self-inflected injuries Ischemic heart disease

Road traffic accidents Tuberculosis

Trachea, bronchus, and lung cancers Road traffic accidents

Cerebrovascular disease Cerebrovascular disease

Cirrhosis of the liver 4.4% Self inflicted injuries

Breast cancer Violence

Colon and rectal cancers Lower respiratory infections

Diabetes mellitus Cirrhosis of the liver 2.2%

Stomach cancer Chronic obstructive pulmonary disease

Fig.1. The 10 Leading Causes of Death in Adults Ages 15 to 59, by Broad Income Group, 2001. (Adapted from Mathers C, Lopez A, Murray C. The burden
of disease and mortality by condition: data, methods, and results for 2001. In: Lopez A, Mathers C, Ezzati M, et al, editors. Global burden of disease and
risk factors. Washington (DC): Oxford University Press and the World Bank; 2006. p. 45–93; with permission of Oxford University Press, Copyright ª
2006.)
 Global Impact of Hepatic Fibrosis 737

Fig. 2. Correlation between cirrhosis mortality (^) and per capital consumption of ethanol
( ): (A) United Kingdom and (B) United States. (From Kerr WC, Fillmore KM, Marvy P. Bev-
erage-specific alcohol consumption and cirrhosis mortality in a group of English-speaking
beer-drinking countries. Addiction 2000;95(3):339–46. Reprinted with permission of Wiley-
Blackwell Publishing, Copyright ª 2007.)

representing 31% of the global birth cohort.25 Although the counties that had adopted
the universal childhood HBV vaccination policies increased to 79% by 2003, vaccina-
tion coverage rate remained low in many countries that had introduced the vaccine.26
Thus, despite the availability of an effective vaccine, a significant number of the
world’s children remain at risk for HBV infection. In addition, because HBV-associated
cirrhosis usually does not manifest until the fifth decade in life or later, chronic liver dis-
ease secondary to HBV is expected to remain a major public health problem world-
wide until the cohort of vaccinated children reach adulthood.27

Hepatocellular Carcinoma (HCC)

The majority of patients with HCC worldwide have underlying liver disease, most com-
monly, cirrhosis.28 With the exception of some areas of the world where the role of cer-
tain oncogenic agents (ie, aflatoxin) may be important, it is uncommon to find HCC in
the absence of advanced hepatic fibrosis or cirrhosis.28 Therefore, HCC is a serious
complication of chronic liver diseases.
Estimates from the 2000 WHO mortality databank indicate that primary liver cancer
was the fifth most common malignancy in men and the ninth in women, accounting for
approximately 5.6% of all human cancers.29 The mortality burden of liver cancer is
738 Lim & Kim

projected to increase through 2020.11 The number of new cases is estimated to be

564,000 per year, including 398,000 in men and 166,000 in women.30 With few excep-
tions, such as areas in the Philippines where intrahepatic cholangiocarcinoma caused
by liver flukes is common, HCC accounts for 70% to 85% of primary liver cancers.31
Liver cancer is rapidly fatal in the majority of patients, which makes its incidence-to-
mortality ratio very close to one.31
As the development of HCC is generally the end result of long-standing, typically
asymptomatic chronic liver disease,32 the incidence of HCC is linked closely to the
prevalence of major causes of cirrhosis, such as, chronic viral hepatitis and excessive
alcohol consumption. By and large, the global geographic variability in the incidence
of HCC is largely explained by the distribution and the natural history of HBV and HCV.
The attributable risk estimates for these infections account for well over 80% of liver
cancer cases worldwide.30 Infection with HBV is the principal risk factor in most
high-risk countries, whereas HCV and alcohol consumption are more important risk
factors in low-risk countries. Finally, during the last two decades, increases of primary
liver cancer incidence rates have been reported from some low-risk regions, such as
Australia, Central Europe, the United Kingdom, Japan, and North America.30

BURDEN OF CHRONIC LIVER DISEASE IN THE UNITED STATES

Mortality from Cirrhosis
In 2002, chronic liver disease was the 12th leading cause of death in the United States,
accounting for 27,045 (1.1%) of the 2,447,862 deaths (mortality rate, 9.4/100,000).33
For the age group of 25–64 years, it was the seventh leading cause of death for all
races combined.33 These data may underestimate the true cirrhosis mortality in the
United States, because they included only death associated with the ICD-10 code
for chronic liver disease or cirrhosis (K70 and K73-K74 codes) as the underlying cause
of death. Thus, 5,706 (0.2%) deaths related to viral hepatitis (B15-B19 codes) and
14,046 (0.6%) deaths from malignant neoplasms of liver, the great majority of which
are HCC that arises in cirrhotic liver, were not included. If these additional diagnoses
were incorporated in the number of deaths attributable to chronic liver disease, the es-
timate would increase to 46,797 (1.9% of all deaths) for 2002, which would place
chronic liver diseases at the ninth leading cause of death in the United States.
Alcohol and HCV are thought to be the most important etiologies of chronic liver dis-
ease in the United States. Vong and colleagues34 analyzed patterns of deaths associ-
ated with chronic liver disease from 1990 through 1998, using an expanded definition
that included deaths from chronic liver disease, viral hepatitis, or other chronic liver
disease-related sequelae. Of 30,933 deaths considered to be from chronic liver dis-
ease in 1998, about 40% of deaths were alcohol-related; about 15% were HCV-re-
lated; and about 4% were HBV-related. In a large proportion (44%), no underlying
cause of liver disease was recorded (Fig. 3).34 Age-adjusted rates were higher among
males (47.6/100,000) than females (32.2/100,000).
According to Vong and colleagues, overall chronic liver disease mortality declined
5% from 1990 through 1994 (12.1 to 11.6/100,000) but remained unchanged from
1995 through 1998. These trends were similar for all causes except HCV, for which
rates increased 220% from 1993 to 1998 (0.57 to 1.67/100,000).34 Projections showed
that although the prevalence of HCV infection may be decreasing currently because of
the decline in incidence in the 1990s, the number of persons infected for 20 years has
been projected to increase substantially before reaching a peak in 2015.35 In a recent
analysis of the United States data about HCV mortality,36 the most dramatic increases
in HCV-related mortality rates between 1995 and 2004 occurred among persons
 Global Impact of Hepatic Fibrosis 739

Fig. 3. Age-adjusted death rates of chronic liver disease by year and cause in the United
States, 1990–1998. (From Vong S, Bell BP. Chronic liver disease mortality in the United States,
1990–1998. Hepatology 2004;39(2):476–83. Reprinted with permission of Wiley-Liss, Inc.,
a subsidiary of John Wiley & Sons, Inc., Copyright ª 2004.)

45–54 years of age with the rate increasing 376% from 1.76 to 8.01 per 100,000, fol-
lowed by people 55–64 years of age, who had a 188% increase from 2.22 to 6.05 per
100,000 (Fig. 4). Although the last two years of observation suggested a small decline
in overall mortality, the increase continued among persons aged 55–64 years.

Fig. 4. Annual hepatitis C mortality rates and 95% confidence intervals for selected age groups,
United States, 1995–2004. (From Wise M, Bialek S, Finelli L, et al. Changing trends in hepatitis
C-related mortality in the United States, 1995–2004. Hepatology 2008;47(4):1128–35. Reprinted
with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc., Copyright ª 2008.)
740 Lim & Kim

Currently, the vast majority of mortality from HCV-related disease is occurring in peo-
ple under the age of 60 years, especially in men.36

Morbidity and Economic Burden of Chronic Liver Diseases

People who have chronic liver diseases, in particular, cirrhosis, have a poor prognosis.
Recent evidence suggests that cirrhosis reduces the estimated life expectancy by 38
years among 30 year-olds and by 20 years among 50 year-olds.37 In addition to the
decrease in longevity, chronic liver disease typically results in a significant reduction
in the quality of life of the patient. One study reported that patients with Child’s class
B and C cirrhosis showed reductions in all aspects of quality of life similar to patients
who survive a stroke.38 Such data confirm the substantial socioeconomic impact of
liver disease on patients and their families.39
In addition, cirrhosis and complications from portal hypertension are recognized as
significant causes of health care resource use. A report by the American Gastroentero-
logical Association (AGA) estimated the direct cost of chronic liver disease and cirrhosis
to be $1.4 billion in the United States, excluding patients with chronic hepatitis C.7,40 The
majority (90%) of these expenses were from hospital or inpatient-based medical care. In
addition, indirect costs were estimated to be $222 million in 1998, with the total costs
attributable to chronic liver disease and cirrhosis at $1.6 billion. These estimates are
likely substantially larger today because of the increased prevalence of chronic liver dis-
ease and health care cost inflation. Also, the study methodology employed in the AGA
report is thought to have led to underestimation of the true burden.7,40
Liver transplantation is by far the most expensive procedure applied in patients with
chronic liver disease. It has become a widely accepted therapy for improving survival
and quality of life for patients with either end-stage liver disease or early HCC, show-
ing a substantial gain in longevity and quality of life compared with conservative treat-
ment. The number of liver transplantations performed each year in the United States
has been steadily increasing (Fig. 5).7,41 The average cost of a liver transplantation is
well over $100,000 per year, which gives an overall expenditure of about $500 million
per year.7,41

Hepatocellular Carcinoma
In the United States, the age-adjusted incidence rates of HCC increased 2-fold be-
tween 1985 and 1998 (Fig. 6).42,43 The increase in HCC became recognizable in the
mid-1980s, while the greatest proportional increase occurred during the latter part
of the 1990s.44 The increase in HCC incidence has been attributed to the aging cohort
of individuals with chronic HCV infection, the incidence of which peaked in the 1980s.
Although the incidence of end-stage liver disease from HCV may level off in the next
few years, that of HCC may continue to rise,44 as the pool of individuals with long-
standing HCV increases over time.30
Simultaneous with the steady rise in mortality from HCC, hospital service use re-
lated to HCC increased substantially in the United States. In the authors’ study that
examined two nationally representative databases, the estimated total charges for
HCC hospitalizations nationwide increased from $241 million in 1988 to $509 million
in 2000 after inflation adjustment.45 This increase was attributable not only to the num-
ber of hospitalizations but also to the intensity of resource use per hospitalization. For
example, the average daily charges increased $2,140 (95% CI: 1966–2315) to $4,007
(95% CI: 3563–4453) after inflation adjustment, indicating more health care services
provided per hospitalization day.
 Global Impact of Hepatic Fibrosis 741

Fig. 5. Number of deceased donor liver transplantations by age, 1997–2006. The number
receiving a deceased donor liver transplant has gradually increased, more steeply in
2004–2006. (From Freeman RB Jr, Steffick DE, Guidinger MK, et al. Liver and intestine trans-
plantation in the United States, 1997–2006. Am J Transplant 2008;8(4 Pt 2):958–76. Reprinted
with permission of Wiley-Blackwell Publishing, Copyright ª 2007.)

Fig. 6. Incidence of HCC in the United States. (Data from El-Serag HB. Hepatocellular carci-
noma: recent trends in the United States. Gastroenterology 2004;127(5 Suppl 1):S27–34.)
742 Lim & Kim

GROWING BURDEN OF NONALCOHOLIC FATTY LIVER DISEASE

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological condition that com-

prises a wide spectrum of liver damage, ranging from steatosis alone to steatohepa-
titis and to advanced fibrosis and cirrhosis, which occurs in patients who do not
consume significant amounts of alcohol.46 Simple hepatic steatosis is believed to
have a generally benign course, whereas nonalcoholic steatohepatitis (NASH) can
progress to cirrhosis, leading to liver failure and HCC.
The significance of NAFLD as a cause of serious liver disease is increasing because
of the rising prevalence of individuals at risk in the general population47–49 as well as its
potential to progress to end-stage liver disease and HCC.50,51 Because of their causal
association with the metabolic syndrome, NAFLD and NASH commonly occur in pa-
tients with obesity, diabetes, and hyperlipidemia. The likelihood of having NAFLD is
directly proportional to body weight.46 In the past 25 years, the prevalence of obesity
in North America has more than doubled, and it continues to rise without any evidence
of slowing down.52 In parallel, NAFLD is being increasingly recognized as a major
cause of liver-related morbidity and mortality.53 It currently is regarded the most com-
mon form of chronic liver disease in the United States and in many parts of the world.54
In unselected populations, the estimated prevalence of NAFLD ranges from 3% to
36.9%.54 In the United States, data from the Third National Health and Nutrition Exam-
ination Survey (NHANES III) showed that as many as 23% of Americans have unex-
plained elevations in liver enzymes. The majority of these persons are presumed to
have NAFLD.53,55 A recent study in the United States found that 34% of the population
had hepatic steatosis.53
In other parts of the world, the prevalence estimates of NAFLD in the general pop-
ulation ranges from 9% to 37%.54 Data from Japan suggest a greater-than-twofold in-
crease in the prevalence of NAFLD in the past 12 years.56,57 In a recent review, using
the ratio of NASH to NAFLD of 1:3 in liver biopsy studies, the prevalence of NAFLD was
estimated to be 17% in the general population and that of NASH was estimated to be
5.7%.54
In selected patient groups, the prevalence of NAFLD is much higher. Although there
is substantial ethnic variation, it is estimated that 90% of people with obesity (body
mass index [BMI] > 30 kg/m2) have some form of fatty liver, ranging from simple stea-
tosis to more severe forms of NASH, including cirrhosis.58 In patients who have abnor-
mal liver enzymes in the absence of serologic or biochemical markers of liver disease,
the prevalence of NASH ranges from 34% to 40%.58,59
NAFLD is increasingly recognized as a risk factor for HCC.50 The association be-
tween NASH and HCC has been examined in studies that correlated the risk of
HCC with diabetes and obesity, established risk factors for NASH.60,61 The incidence
of HCC was more than two-fold higher among patients with diabetes; independent of
age, gender, and race, diabetes was associated with a hazard rate of 2.16 (95% CI:
1.86 –2.52; P<.0001).31,43 Obesity is also recognized as a significant risk for the devel-
opment of liver cancer.62,63 Clearly, HCC is a part of the spectrum of NAFLD. In most
cases, HCC in NASH is thought to occur through the fibrosis-cirrhosis-HCC path-
way.64 In addition, diabetes is also associated with increased levels of insulin and in-
sulin-like growth factors, which are potential cancer promoting factors.65

SUMMARY

Hepatic fibrosis is an integral part in the progression of chronic liver disease, ultimately
leading to cirrhosis and hepatocellular carcinoma. Globally, alcohol consumption,
HBV and HCV have been the main causes of cirrhosis. More recently, the increasing
 Global Impact of Hepatic Fibrosis 743

prevalence of obesity and the metabolic syndrome has resulted in increasing inci-
dence of cirrhosis secondary to NAFLD, especially in developed countries.
Chronic liver disease and cirrhosis are important causes of morbidity and mortality
in the world. Moreover, the burden of chronic liver disease is projected to increase,
due in part to the increasing prevalence of end-stage liver disease and HCC second-
ary to NAFLD and HCV.
The economic burden of chronic liver diseases, cirrhosis, and HCC is high. Preven-
tion of hepatic fibrosis and thus, cirrhosis may be the key to reducing health care costs
and overall disease burden. Globally, immunization against HBV and preventive mea-
sures against HCV infection, as well as identification and treatment of individuals with
chronic hepatitis should all contribute to this objective. In contrast, the burden of liver
disease associated with excessive alcohol consumption, obesity and metabolic syn-
drome both in the United States and globally is less amenable to preventive measures.
In the foreseeable future, it is likely that hepatic fibrosis will remain an important public
health concern. The limitations in preventive measures and lack of universally effective
and affordable treatment for these liver diseases highlight the importance of alterna-
tive therapeutic strategies, such as novel antifibrotic agents.

REFERENCES

1. Rockey DC, Friedman SL. Hepatic fibrosis and cirrhosis. In: Boyer TD, Wright TL,
Manns MP, editors. 5th edition. Zakim and Boyer’s hepatology, vol.1. New York:
Elsevier; 2006. p. 87–109.
2. Guha IH, Iredale JP. Clinical and diagnostic aspects of cirrhosis. In: Rodes J,
Benhamou JP, Blei AT, et al, editors. Textbook of hepatology, from basic science
to clinical practice. 3rd edition. Oxford: Blackwell Publishing Ltd.; 2007. p.
604–19.
3. Graudal N, Leth P, Marbjerg L, et al. Characteristics of cirrhosis undiagnosed dur-
ing life: a comparative analysis of 73 undiagnosed cases and 149 diagnosed
cases of cirrhosis, detected in 4929 consecutive autopsies. J Intern Med 1991;
230(2):165–71.
4. Melato M, Sasso F, Zanconati F. Liver cirrhosis and liver cancer. A study of their
relationship in 2563 autopsies. Zentralbl Pathol 1993;139(1):25–30.
5. Falagas ME, Vardakas KZ, Vergidis PI. Under-diagnosis of common chronic dis-
eases: prevalence and impact on human health. Int J Clin Pract 2007;61(9):
1569–79.
6. Friedman SL. Liver fibrosis—from bench to bedside. J Hepatol 2003;38(Suppl 1):
S38–53.
7. Kim WR, Brown RS Jr, Terrault NA, et al. Burden of liver disease in the United
States: summary of a workshop. Hepatology 2002;36(1):227–42.
8. Manos MM, Leyden WA, Murphy RC, et al. Limitations of conventionally derived
chronic liver disease mortality rates: Results of a comprehensive assessment.
Hepatology 2008;47(4):1150–7.
9. Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated
cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology
1997;112(2):463–72.
10. Mathers C, Lopez A, Murray C. The burden of disease and mortality by condi-
tion: data, methods, and results for 2001. In: Lopez A, Mathers C, Ezzati M,
et al, editors. Global burden of disease and risk factors. Washington (DC):
Oxford University Press and the World Bank; 2006. p. 45–93.
744 Lim & Kim

11. Murray CJ, Lopez AD. Alternative projections of mortality and disability by
cause 1990–2020: Global Burden of Disease Study. Lancet 1997;349(9064):
1498–504.
12. Bosetti C, Levi F, Lucchini F, et al. Worldwide mortality from cirrhosis: an update to
2002. J Hepatol 2007;46(5):827–39.
13. Singh GK, Hoyert DL. Social epidemiology of chronic liver disease and cirrhosis
mortality in the United States, 1935–1997: trends and differentials by ethnicity, so-
cioeconomic status, and alcohol consumption. Hum Biol 2000;72(5):801–20.
14. Ramstedt M. Per capita alcohol consumption and liver cirrhosis mortality in 14 Eu-
ropean countries. Addiction 2001;96(Suppl 1):S19–33.
15. Kerr WC, Fillmore KM, Marvy P. Beverage-specific alcohol consumption and cir-
rhosis mortality in a group of English-speaking beer-drinking countries. Addiction
2000;95(3):339–46.
16. Williams JG, Roberts SE, Ali MF, et al. Gastroenterology services in the UK. The
burden of disease, and the organisation and delivery of services for gastrointes-
tinal and liver disorders: a review of the evidence. Gut 2007;56(Suppl 1):1–113.
17. Kane M. Global programme for control of hepatitis B infection. Vaccine 1995;
13(Suppl 1):S47–9.
18. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337(24):1733–45.
19. Lok AS, McMahon BJ, Chronic hepatitis B. Hepatology 2007;45(2):507–39.
20. Goldstein ST, Zhou F, Hadler SC, et al. A mathematical model to estimate global
hepatitis B disease burden and vaccination impact. Int J Epidemiol 2005;34(6):
1329–39.
21. Seeff LB, Hoofnagle JH. Epidemiology of hepatocellular carcinoma in areas of
low hepatitis B and hepatitis C endemicity. Oncogene 2006;25(27):3771–7.
22. McQuillan GM, Coleman PJ, Kruszon-Moran D, et al. Prevalence of hepatitis B vi-
rus infection in the United States: the National Health and Nutrition Examination
Surveys, 1976 through 1994. Am J Public Health 1999;89(1):14–8.
23. Wong VC, Ip HM, Reesink HW, et al. Prevention of the HBsAg carrier state in new-
born infants of mothers who are chronic carriers of HBsAg and HBeAg by admin-
istration of hepatitis-B vaccine and hepatitis-B immunoglobulin. Double-blind
randomised placebo-controlled study. Lancet 1984;1(8383):921–6.
24. CDC. Recommendations for protection against viral hepatitis. MMWR Morb Mor-
tal Wkly Rep 1985;34(22):313–24, 29–35.
25. Alter MJ. Epidemiology of hepatitis B in Europe and worldwide. J Hepatol 2003;
39(Suppl 1):S64–9.
26. CDC. Global progress toward universal childhood hepatitis B vaccination, 2003.
MMWR Morb Mortal Wkly Rep 2003;52(36):868–70.
27. Yim HJ, Lok AS. Natural history of chronic hepatitis B virus infection: what we
knew in 1981 and what we know in 2005. Hepatology 2006;43(2 Suppl. 1):
S173–81.
28. Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis: in-
cidence and risk factors. Gastroenterology 2004;127(5 Suppl. 1):S35–50.
29. Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: Globocan
2000. Int J Cancer 2001;94(2):153–6.
30. Bosch FX, Ribes J, Diaz M, et al. Primary liver cancer: worldwide incidence and
trends. Gastroenterology 2004;127(5 Suppl. 1):S5–16.
31. El-Serag HB. Epidemiology of hepatocellular carcinoma. Clin Liver Dis 2001;5(1):
87–107.
32. Seeff LB. Introduction: the burden of hepatocellular carcinoma. Gastroenterology
2004;127(5 Suppl. 1):S1–4.
 Global Impact of Hepatic Fibrosis 745

33. Kochanek KD, Smith BL. Deaths: preliminary data for 2002. Natl Vital Stat Rep
2004;52(13):1–47.
34. Vong S, Bell BP. Chronic liver disease mortality in the United States, 1990–1998.
Hepatology 2004;39(2):476–83.
35. Armstrong GL, Alter MJ, McQuillan GM, et al. The past incidence of hepatitis C
virus infection: implications for the future burden of chronic liver disease in the
United States. Hepatology 2000;31(3):777–82.
36. Wise M, Bialek S, Finelli L, et al. Changing trends in hepatitis C-related mortality in
the United States, 1995–2004. Hepatology 2008;47(4):1128–35.
37. Orlewska E. The cost-effectiveness of alternative therapeutic strategies for the
management of chronic hepatitis B in Poland. Value Health 2002;5(5):405–21.
38. Younossi ZM, Boparai N, McCormick M, et al. Assessment of utilities and health-
related quality of life in patients with chronic liver disease. Am J Gastroenterol
2001;96(2):579–83.
39. Burroughs A, McNamara D. Liver disease in Europe. Aliment Pharmacol Ther
2003;18(Suppl. 3):54–9.
40. AGA. The burden of gastrointestinal diseases. Bethesda: AGA; 2001. p. 41–60.
41. Freeman RB Jr, Steffick DE, Guidinger MK, et al. Liver and intestine transplanta-
tion in the United States, 1997–2006. Am J Transplant 2008;8(4 Pt 2):958–76.
42. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the
United States. N Engl J Med 1999;340(10):745–50.
43. El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in hepatocellular
carcinoma: a case-control study among United States Veterans. Am J Gastroen-
terol 2001;96(8):2462–7.
44. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gas-
troenterology 2004;127(5 Suppl. 1):S27–34.
45. Kim WR, Gores GJ, Benson JT, et al. Mortality and hospital utilization for hepato-
cellular carcinoma in the United States. Gastroenterology 2005;129(2):486–93.
46. Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenter-
ology 2002;123(5):1705–25.
47. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among
US adults, 1999–2000. JAMA 2002;288(14):1723–7.
48. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US
adults: findings from the third National Health and Nutrition Examination Survey.
JAMA 2002;287(3):356–9.
49. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and
obesity-related health risk factors, 2001. JAMA 2003;289(1):76–9.
50. Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver Dis 2007;11(1):
191–207.
51. Teli MR, James OF, Burt AD, et al. The natural history of nonalcoholic fatty liver:
a follow-up study. Hepatology 1995;22(6):1714–9.
52. Klein S. The national obesity crisis: a call for action. Gastroenterology 2004;
126(1):6.
53. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis
in an urban population in the United States: impact of ethnicity. Hepatology 2004;
40(6):1387–95.
54. Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH.
Clin Liver Dis 2007;11(1):1–16.
55. Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated
serum alanine aminotransferase activity in the United States. Gastroenterology
2003;124(1):71–9.
746 Lim & Kim

56. Kojima S, Watanabe N, Numata M, et al. Increase in the prevalence of fatty liver in
Japan over the past 12 years: analysis of clinical background. J Gastroenterol
2003;38(10):954–61.
57. Kuntz E, Kuntz H-D. Liver cirrhosis. Hepatology, Principles and Practice. Ger-
many: Springer; 2006. p. 716–49.
58. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of
an AASLD Single Topic Conference. Hepatology 2003;37(5):1202–19.
59. Skelly MM, James PD, Ryder SD. Findings on liver biopsy to investigate abnormal
liver function tests in the absence of diagnostic serology. J Hepatol 2001;35(2):
195–9.
60. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalco-
holic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.
Gastroenterology 2002;123(1):134–40.
61. Marrero JA, Fontana RJ, Su GL, et al. NAFLD may be a common underlying liver
disease in patients with hepatocellular carcinoma in the United States. Hepatol-
ogy 2002;36(6):1349–54.
62. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mor-
tality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med
2003;348(17):1625–38.
63. Ratziu V, Bonyhay L, Di Martino V, et al. Survival, liver failure, and hepatocellular
carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 2002;35(6):
1485–93.
64. Caldwell SH, Crespo DM, Kang HS, et al. Obesity and hepatocellular carcinoma.
Gastroenterology 2004;127(5 Suppl. 1):S97–103.
65. Alexia C, Fallot G, Lasfer M, et al. An evaluation of the role of insulin-like growth
factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in
the resistance of hepatocarcinoma cells drug-induced apoptosis. Biochem Phar-
macol 2004;68(6):1003–15.