Review

The global burden of cirrhosis: A review of disability-adjusted life-

years lost and unmet needs
Peter Jepsen1,2,*, Zobair M. Younossi3,4

Summary
Cirrhosis is a burden on the individual and on public health. The World Health Organization’s metric of Keywords: Liver; Cirrhosis;
Public health; Epidemiology;
public health burden is the disability-adjusted life-year (DALY), the sum of years of life lost due to
DALY; QALY.
premature death and years of life lived with disability. The more DALYs attributable to a disease, the
greater its burden on public health. Cirrhosis was responsible for 26.8% fewer DALYs in 2019 than in 1990, Received 19 August 2020;
received in revised form 17
which is positive, but the reduction in DALYs across the spectrum of diseases in and outside the liver was
November 2020; accepted 17
34.4%. Hepatitis C (26% of DALYs), alcohol (24%), and hepatitis B (23%) contribute almost equally to the November 2020
global burden of cirrhosis. The contribution from non-alcoholic fatty liver disease (8%) is small but
increasing. There is substantial global variation in the burden and causes of cirrhosis. We find that the
poorest countries carry the greatest burden of cirrhosis, and that this burden is primarily caused by
cirrhosis from hepatitis B infection. Interventions targeting hepatitis B infection are known, but not fully
implemented. In more affluent countries, alcohol and hepatitis C are the dominant causes of cirrhosis,
but non-alcoholic fatty liver will likely become a dominant cause of cirrhosis in parallel with the
increasing prevalence of obesity. We also argue that the World Health Organization underestimates the
public health burden associated with cirrhosis because it assigns zero disability to compensated cirrhosis
and considers decompensated cirrhosis as only mildly disabling.
© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction
Cirrhosis is the final stage of liver fibrosis, which
itself results from a perpetuated wound-healing
process after a liver injury that can lead to a wide
range of chronic diseases involving the liver.1 The
most prevalent chronic liver diseases are chronic
viral hepatitis (from hepatitis B or C infection),
alcohol-related liver disease, and non-alcoholic
fatty liver disease (NAFLD).
Cirrhosis negatively impacts on patient-
reported outcomes and health-related quality of
life.2–4 The impact of cirrhosis on quality of life can
add to the existing impairment of quality of life
related to viraemia in patients with hepatitis C.5,6
Conversely, effective treatment of hepatitis C can
lead to significant gains in patients’ quality of life,
especially for patients with decompensated
cirrhosis. In addition, there is evolving evidence
indicating that quality of life is significantly
impaired in patients with NAFLD in the form of
non-alcoholic steatohepatitis.7
Cirrhosis can have economic consequences in
the form of health expenditures and job losses. A
United States study found that patients with
chronic liver disease were less likely to be
employed than comparable people without chronic
liver disease (44.7% vs. 69.6%), that they had lost
work due to disability, and that they had greater
healthcare expenses.8 Caregivers of patients with
1
Department of Hepatology and
cirrhosis also have lower quality of life than pop- Gastroenterology, Aarhus
ulation controls.9 University Hospital, Aarhus,
Clinicians caring for patients with cirrhosis will Denmark;
2
Department of Clinical
recognise the negative impact of cirrhosis on in- Epidemiology, Aarhus University
dividuals and families. This review will focus on Hospital, Aarhus, Denmark;
cirrhosis as a burden on public health, but – as we 3
Betty and Guy Beatty Center for
Integrated Research, Inova
shall return to – we may be underestimating the
Health System, Falls Church, VA,
impact of cirrhosis on public health by under- USA;
estimating its impact on individual health. 4
Department of Medicine, Center
for Liver Diseases, Inova Fairfax
Hospital, Falls Church, VA, USA
The Global Burden of Disease
At the population-level, burden of disease is pri- * Corresponding author.
Address: Department of Hep-
marily measured in terms of mortality and
atology and Gastroenterology,
morbidity, and financial burden is also important Aarhus University Hospital,
because resources are limited. The World Health Palle Juul-Jensens Boulevard
Organization (WHO) uses the Global Burden of 99, DK-8200, Aarhus N,
Denmark. Tel.: +45 2425 2944.
Disease studies to measure the burden of diseases
and injuries, and it now regularly measures the E-mail address: pj@clin.au.dk
(P. Jepsen).
burden of more than 100 diseases in various pop-
ulations. Data for 2019 were made available in https://dx.doi.org/10.1016/
j.jhep.2020.11.042
October 2020 and can be accessed through this
website: http://www.healthdata.org/gbd/2019.
Most of the data presented in this review were
downloaded from http://ghdx.healthdata.org/gbd-
results-tool.10
The Global Burden of Disease study centres on
the disability-adjusted life-year (DALY), which is a
method of weighing a disease according to its
impact on mortality and morbidity. The DALY will

Journal of Hepatology 2021 vol. 75 j S3–S13

Review
also be our focal point, preferred over metrics such
as incidence rate, mortality rate, prevalence, or
healthcare expenditures (Box 1). The DALY is the
sum of years of life lost due to premature death
(YLL) and years of life lived with disability (YLD).
One DALY represents the loss of 1 life-year of full
health. Thus, the more DALYs attributable to a
disease, the greater its burden on public health.
The YLL is the product of the number of deaths
from cirrhosis in the population times the pop-
ulation’s life expectancy at the age of death. Thus,
many deaths and deaths at an early age in an
otherwise long-living population give higher YLL.
The YLD is the product of the cirrhosis prevalence
in the population times the disability weight for
cirrhosis. Cirrhosis prevalence, in turn, is the
number of incident patients with cirrhosis times
the survival time with cirrhosis. Thus, a high dis-
ease incidence, long survival time, and severe
disability give higher YLD. The disability weight is
on a scale from 0 (no disability) to 1 (dead).
Key points
Disability weights are based on valuation by a
The disability-adjusted life- representative population sample and cover 8 do-
year (DALY) is the sum of mains of health: mobility, selfcare, pain and
years of life lost due to
discomfort, cognition, interpersonal activities,
premature death and years
of life lived with disability. vision, sleep and energy, and affect.11 The WHO’s
More DALYs equal greater most recent disability weight for decompensated
burden on public health. cirrhosis was 0.178, increasing to 0.300 if accom-
panied by severe anaemia,10 so decompensated
cirrhosis was similar in disability to “profound
hearing loss” (0.204) and “severe back pain
without leg pain” (0.272). For compensated
cirrhosis the disability weight was 0, meaning that
compensated cirrhosis is believed to have no
impact on health or ability.10,12 The combination of
a high early-age mortality and a low disability
Box 1. Glossary of terms.
DALY
Disability-adjusted life-year. One DALY represents 1 life-year of full health lost. DALY = YLL+
YLD.
YLL
Years of life lost to premature death. For cirrhosis, the product of the number of deaths from
cirrhosis in the population times the population’s life expectancy at the age of death.
YLD
Years of life lived with disability. For cirrhosis, the product of the cirrhosis prevalence in the
population times the disability weight for cirrhosis.
QALY
Quality-adjusted life-year. One QALY represents 1 life-year of full health gained.
Incidence rate
New cases, e.g. new cases of cirrhosis, divided by the population’s total observation time.
The population’s total observation time within a given calendar year may be approximated as the
number of people in the population at the beginning of the year.
Mortality rate
Deaths in the population, e.g. deaths from cirrhosis, divided by the population’s total
observation time. The population’s total observation time within a given calendar year may be
approximated as the number of people in the population at the beginning of the year.
Healthcare expenditure
Money spent on healthcare, e.g. spent on cirrhosis, often expressed as a proportion of a
country’s gross domestic product.
S4 Journal of Hepatology 2021 vol. 75 j S3–S13
weight mean that the DALY for cirrhosis is virtually
identical to the YLL; the YLD is nearly zero.
The DALY is in many respects similar to the
QALY, the quality-adjusted life-year. The QALY is a
measure of life expectancy corrected for disability,
and it can be used to compare interventions by
balancing quantity of life and quality of life. QALYs
are often linked with the costs associated with an
intervention in a cost-utility analysis.13 A source of
confusion is that 1 QALY represents 1 life-year of
full health gained, while 1 DALY represents 1 life-
year of full health lost.
The burden of cirrhosis
In the most recent GBD study, from 2019, cirrhosis
was responsible for 560.4 age-standardised DALYs
per 100,000 population globally. By comparison,
chronic obstructive pulmonary disease was
responsible for 926.1 age-standardised DALYs per
100,000 population,14 skin and subcutaneous dis-
eases for 559.4, depressive disorders for 577.8,
dementia for 338.6, liver cancer for 151.1, and in-
flammatory bowel disease for 20.2.14 Note that
deaths from hepatocellular carcinoma do not count
as deaths from cirrhosis in the Global Burden of
Disease studies, although most of these cancers
develop in patients with cirrhosis.12
The 560.4 age-standardised DALYs per 100,000
population attributable to cirrhosis in 2019 was a
26.8% reduction since 1990.10,14 During that period,
cirrhosis moved from being the 15th-leading cause
of DALYs lost globally to being the 16th-leading
cause, and the reduction in age-standardised DALY
rate across all diseases was 34.4%. Only 3 diseases
saw substantial increases in age-standardised DALY
rates: HIV/AIDS (58.5% increase), musculoskeletal
disorders except rheumatoid arthritis (30.7% in-
crease), and diabetes (24.4% increase).10
For women, cirrhosis was the 20th-leading
contributor of DALYs in 2019, between dementia
and lung cancer, after being the 19th-leading cause
in 2010. The top 5 contributors are neonatal dis-
orders, ischaemic heart disease, stroke, lower res-
piratory tract infections, and diarrhoeal diseases.
For men, cirrhosis was the 9th-leading contributor
of DALYs in 2019, up from 12th in 2010. The top 5
are ischaemic heart disease, neonatal disorders,
stroke, road injuries, and lower respiratory tract
infections.10
Variation in the burden of cirrhosis
The burden of cirrhosis is not evenly distributed
across the world. It varies by gender and age, by
region, and by sociodemographic index. It also
varies in response to the variation in prevalence of
chronic liver diseases that cause cirrhosis, i.e.
hepatitis B and C infection, alcohol-related liver
disease, and NAFLD.
Gender and age extensively in EASL’s 2018 HEPAHEALTH proj-
The age-standardised DALY rate for cirrhosis was ect.15,16 It combined data on cirrhosis prevalence
783.3 per 100,000 for men and 344.0 per 100,000 from the Global Burden of Disease database with
for women in 2019, meaning that men were mortality data from WHO’s European Detailed
responsible for 69% of the total burden of cirrhosis.Mortality and Health for All databases, and added
This proportion was unchanged since 1990. The knowledge from local experts when data were
DALY rate for men peaked at age 60–64 years in insufficient.15 The HEPAHEALTH project examined
2019, as it did in 1990, and between 1990 and 2019 the mortality rate from cirrhosis across Europe. The
the DALY rate in childhood decreased more than it mortality rate from cirrhosis is different from the
DALY rate from cirrhosis, but the 2 measures are
did in other age groups. Specifically, it fell from 202
to 105 per 100,000 (a 48% decline) for boys aged <5 strongly correlated because the DALY for cirrhosis
years compared with 2,942 to 2,168 per 100,000 (a depends almost exclusively on mortality, not on
26% decline) for men aged 60–64 years. Among morbidity, as explained above (Spearman rho =
women, the DALY rate peaked at age 70–74 years in 0.94, Fig. 3).
1990 and at age 75–79 in 2019, and relative The HEPAHEALTH report divided Europe into 4
changes during the 30-year period were similar to groups based on their time-trend in age-adjusted
those seen among men (Fig. 1). Note that we mortality from cirrhosis in 1970–2016 (Fig. 4):
generally present age-standardised rates to ac- decreasing, stable low, increasing, and stable high.
count for regional differences in age distribution. Countries with a decreasing trend were Western
Key points
and Southern European countries, while the stable
Regional variation low countries were scattered across Europe. The Cirrhosis is a major burden
In 2019, the countries with the highest age- countries with a worrying, increasing trend were on the public health,
almost exclusively due to
standardised DALY rates for cirrhosis were Egypt the United Kingdom, Romania, Hungary, Bulgaria,
premature deaths. In their
(2,410 per 100,000 population), Cambodia (1,983 Lithuania, Latvia, Estonia, Kazakhstan, and Finland, analyses, the WHO likely
per 100,000), Turkmenistan (1,872 per 100,000), and they now have the same high mortality from underestimates the
and Mongolia (1,866 per 100,000). However, the cirrhosis as the 2 countries with a stable high disability associated with
cirrhosis.
proportion of DALYs attributable to cirrhosis better mortality: Slovakia and Uzbekistan. The HEP-
reflects the burden of cirrhosis relative to other AHEALTH report stated that “alcoholic liver disease
health burdens. In 2019, this proportion was 1.8% is the largest burden and highest priority in the
globally, up from 1.3% in 1990 and 1.7% in 2010.10 North of Europe, while viral hepatitis is the highest
The 3 countries with the highest proportions priority in the East and South”.16
were Moldova (6.0% of all DALYs in 2019 were lost
to cirrhosis), Turkmenistan (5.8%), and Egypt
(5.8%), and the 3 with the lowest proportions were
Mozambique (0.5%), New Zealand (0.6%), and Ice-
land (0.6%). For comparison, the proportion was
1.1% in China, 1.4% in the United Kingdom, 1.4% in
3,000
Italy, 1.7% in the United States, and 2.7% in Russia Men, 1990
Men, 2019
(Fig. 2). Women, 1990
The proportion of DALYs attributable to 2,500 Women, 2019

cirrhosis in 2019 was low in Africa, but with a

DALYs per 100,000 population

regional spike in Egypt. In other regions, spikes

2,000
were found in Mexico and Cambodia (Fig. 2). In
Egypt, 5.8% of all DALYs were attributable to
cirrhosis, with hepatitis C (43% of cirrhosis DALYs) 1,500
and hepatitis B (26% of cirrhosis DALYs) responsible
for the majority of DALYs attributable to cirrhosis.
In Mexico, by contrast, alcohol (36% of cirrhosis 1,000

DALYs) and hepatitis C (28%) were the main cul-

prits behind the 4.1% of DALYs lost to cirrhosis. In 500
Cambodia, as in Egypt, it was hepatitis C (30%) and
hepatitis B (23%) that were responsible for most of
the 5.3% of DALYs lost to cirrhosis. 0
Within Europe the proportion of DALYs attrib-
0 10 20 30 40 50 60 70 80 90
utable to cirrhosis in 2019 ranges from 0.6% in Age
Iceland and Norway to 3.8% in Romania. The
epidemiology of cirrhosis within Europe (and a Fig. 1. DALYs lost to cirrhosis per 100,000 population by gender, age, and calendar year.
handful of countries outside Europe) was studied DALYs, disability-adjusted life-years.

Journal of Hepatology 2021 vol. 75 j S3–S13 S5

Review

Fig. 2. Proportion of DALYs attributable to cirrhosis in 2019. This illustration is downloaded from the Global Burden of Disease website, https://vizhub.
healthdata.org/gbd-compare/. DALYs, disability-adjusted life-years.

Sociodemographic index and births per woman of fertile age. The socio-
The Global Burden of Disease study assigns a demographic index is scaled from 0 (lowest in-
sociodemographic index to all countries based on come, fewest years of schooling, and highest
income per capita, average educational attainment, fertility) to 1 (highest income, most years of
schooling, and lowest fertility).14
The sociodemographic index correlates with the
age-standardised DALY rate for cirrhosis, meaning
that the burden of cirrhosis is lower in more
3,000
affluent countries (Fig. 5). The 5 countries with the
lowest sociodemographic index are Somalia, Niger,
2,500 Chad, Burkina Faso, and Mali; the 5 with the
highest sociodemographic index are Switzerland,
DALY rate from cirrhosis

Norway, Germany, Luxembourg, and Andorra.

2,000
Countries with a sociodemographic index around
0.5 include Bangladesh (0.483), Cameroon (0.490),
1,500 Honduras (0.496), Mauritania (0.496), Zambia
(0.505), Kenya (0.508), Sudan (0.515), and
1,000 Nicaragua (0.517).

Aetiology of cirrhosis
500
Although there are many risk factors for cirrhosis,
clinical tradition emphasises certain risk factors as
0 aetiologies of cirrhosis. The 2019 Global Burden of
Disease study estimated the breakdown of DALYs
0 20 40 60 80 100
by aetiology. Of the 560.4 total age-standardised
Mortality rate from cirrhosis
DALYs per 100,000 population attributable to
Fig. 3. Association between 195 countries’ DALY rate from cirrhosis and mortality rate from cirrhosis, they estimated that 129.9 (23%) DALYs
cirrhosis. Both rates are crude rates per 100,000 population. DALY, disability-adjusted life-year. per 100,000 were due to hepatitis B, 146.3 (26%)

S6 Journal of Hepatology 2021 vol. 75 j S3–S13

 Trend category Decreasing Increasing Stable high Stable low

Fig. 4. Time trends in age-adjusted mortality from cirrhosis, 1970–2016. From the HEPAHEALTH project report, available at
https://easl.eu/publication/hepahealth-project-report/. We apologise for the missing Albanian sea border.

Key points
19
were due to hepatitis C, 133.3 (24%) were due to (2.1%). With the introduction of direct-acting Hepatitis C (26% of DALYs),
alcohol use, 43.7 (8%) were due to NAFLD, and antivirals to treat hepatitis C infection, prevalence alcohol (24%), and hepatitis
B (23%) contribute almost
107.3 (19%) were due to other causes.14 The largest is going down,20 and elimination has become the
equally to the global
decrease from 2010 to 2019 was by 23% (hepatitis target.21 The poorest and the wealthiest countries burden of cirrhosis. The
B), the smallest by 1% (NAFLD).14 These trends have the lowest burden from cirrhosis due to contribution from non-
indicate that, within cirrhosis, the contribution hepatitis C (Fig. 6). alcoholic fatty liver disease
(8%) is small but increasing.
from NAFLD-cirrhosis is increasing. There is sub-
stantial regional variation, and there is substantial
variation in time trends in the prevalence of these
aetiologies.
2,500
Hepatitis B
The 2016 prevalence of hepatitis B infection
(defined as positive HBsAg) in the general popu- 2,000
Age−standardized DALYs

lation has been estimated at 3.9% globally, with

per 100,000 population

regional estimates of 0.4% in the Pan-American

region, 1.6% in Europe, 2.2% in the Eastern Medi- 1,500

terranean region, 3.5% in South-East Asia region,

5.7% in the Western Pacific region, and 7.2% in Af-
1,000
rica.17 The prevalence is decreasing in most coun-
tries, but increasing in some countries in all
regions.18 More than 80% of patients with hepatitis
500
B infection come from just 21 countries, and 57%
come from China, India, Nigeria, Indonesia, or the
Philippines.17 There is a strong correlation between
0
sociodemographic index and burden from cirrhosis
due to hepatitis B, with the heaviest burden on the 0.0 0.2 0.4 0.6 0.8 1.0
poorer regions (Fig. 6). Sociodemographic index

Hepatitis C
The 2015 global prevalence of viraemic HCV
infection was estimated at 1.0%, with the highest
regional prevalence in Central Asia (3.6%), Eastern
Europe (3.3%), and central sub-Saharan Africa
Fig. 5. Association between the sociodemographic index and the age-standardised DALY
rate for cirrhosis in 2019. Each of the 195 countries in the Global Burden of Disease dataset is
represented by a circle, and the black line is a lowess smoother to facilitate the visual inter-
pretation. The sociodemographic index is based on income per capita, average educational
attainment, and births per woman of fertile age, and more affluent countries have a higher index.
DALYs, disability-adjusted life-years.

Journal of Hepatology 2021 vol. 75 j S3–S13 S7

Review
Alcohol
The per capita alcohol consumption is 6.4 litres
globally, up from 5.5 litres in 2005. The Middle East
and Northern Africa have the lowest alcohol con-
sumption, whereas consumption is highest in the
European region.22 Per capita consumption in
Europe decreased from 12.1 litres in 2000 to 9.8 litres
in 2016, but within Europe consumption has
increased in the East and gone down in the South,
and the pattern of drinking has generally shifted to
earlier, heavier drinking.15 The United Kingdom has
received much attention for its increasing burden
from alcohol, and efforts to counteract this,15,23,24
while alcohol consumption has also increased in
the Western Pacific and Southeast Asia regions.22 In
the United States, too, alcohol consumption has
increased and shifted towards heavier drinking.25–27
This has not increased the prevalence of alcoholic
liver disease, which was stable at 8.1% to 8.8% of the
total population between 2001 and 2016, but pa-
tients were more severely ill in later years. Thus, the
prevalence of stage 3 or 4 fibrosis increased from
2.2% to 6.6%, and the prevalence of complications of
cirrhosis grew in these patients as well.28
There is a strong correlation between socio-
demographic index and the proportion of alcohol
drinkers. In the quintile of countries with the
highest (the most favourable) sociodemographic
index, 72% of women and 83% of men were current
500 Hepatitis B
Hepatitis C
Alcohol
NAFLD
400
Age−standardized DALYs
per 100,000 population
300
200
100
0
0.0 0.2 0.4 0.6 0.8 1.0
Sociodemographic index
Fig. 6. Association between age-standardised DALYs per 100,000 and sociodemographic
index for cirrhosis from hepatitis B, hepatitis C, harmful alcohol consumption, and NAFLD.
The lines are lowess smoothing plots of the actual age-standardised DALY rates, one for each
aetiology for each of the 195 countries in the Global Burden of Disease dataset. The socio-
demographic index is based on income per capita, average educational attainment, and births
per woman of fertile age, and more affluent countries have a higher index. DALY(s), disability-
adjusted life-year(s); NAFLD, non-alcoholic fatty liver disease.
S8 Journal of Hepatology 2021 vol. 75 j S3–S13
drinkers in 2016, compared with 9% of women and
20% of men in the quintile of countries with low-
to-middle sociodemographic index.29 This does
not translate into an increasing age-standardised
DALY rate from alcohol-related cirrhosis with
increasing sociodemographic index, but it may
explain why alcohol is the dominant aetiology of
cirrhosis in affluent countries (Fig. 6).
Non-alcoholic fatty liver disease
Although NAFLD can occur in lean people, its
prevalence correlates strongly with the prevalence
of obesity and type 2 diabetes. NAFLD has a prev-
alence of 32% in the Middle East, 31% in South
America, 27% in Asia, 24% in the United States, 23%
in Europe, and 14% in Africa.30–32 The prevalence of
cirrhosis among these patients is unclear, but the
prevalence of NAFLD is increasing and will
continue to do so. A modelling study predicted
changes in the prevalence of NAFLD from 2016 to
2030 for 8 countries: China, Japan, United States,
France, Germany, Italy, Spain, and United
Kingdom.33 The study predicted that the preva-
lence of NAFLD will increase in all countries, and
the largest increase will come in China. Moreover,
the number of patients with cirrhosis due to NAFLD
will also increase in all countries, with the largest
increase (156%) in France.
Cirrhosis severity
Compensated cirrhosis is associated with lower
mortality and morbidity than decompensated
cirrhosis. Studies have found that patients with
alcohol-related cirrhosis have typically already
decompensated when they are diagnosed with
cirrhosis, whereas this is atypical for patients with
cirrhosis from hepatitis B or C.34,35 As a result, the
prevalence of compensated cirrhosis is low in areas
where alcohol is the most common aetiology of
cirrhosis, if only diagnosed patients are counted.
This will likely change with more widespread
screening for liver disease in the community, e.g.
with transient elastography.
In the 2017 Global Burden of Disease study, the
prevalence of compensated and decompensated
cirrhosis was “modeled on the basis of hospital
data and claims data”, and all hospitalised patients
were assumed to be decompensated.12,16 The
modelling gave age-standardised prevalence esti-
mates indicating that, as a global average, 8.7% of
patients with cirrhosis have decompensated
cirrhosis, and there is little geographic variation.12
Thus, the prevalence of cirrhosis is mainly attrib-
utable to compensated cirrhosis, but the vast ma-
jority of DALYs result from decompensated
cirrhosis; this is because the disability attributed to
compensated cirrhosis is zero, and the mortality The burden of cirrhosis can be reduced by pri-
from compensated cirrhosis is much lower than mary prevention, which involves societal measures Key points
the mortality from decompensated cirrhosis. to prevent development of cirrhosis. Examples of Cirrhosis was responsible
such efforts include minimum-pricing of for 26.8% fewer DALYs in
The financial burden of cirrhosis alcohol,15,44–46 vaccination for hepatitis B, and food 2019 than in 1990, but this
was less than the 34.4%
The financial burden on societies depends on the labelling to prevent obesity.15 Thus, primary pre-
decline for all causes
prevalence of cirrhosis and the costs per patient vention is in the domain of politicians. Secondary combined.
with cirrhosis. The age-standardised prevalence of prevention means early detection of cirrhosis before
compensated cirrhosis increased from 1,355 per it causes symptoms. Such efforts include transient
100,000 population in 1990 to 1,395 per 100,000 in elastography or similar testing of at-risk patients, e.g.
2017. Concurrently, the age-standardised preva- patients with hazardous alcohol consumption,47
lence of decompensated cirrhosis increased from patients with known or suspected chronic viral
111 to 133 per 100,000.12 The prevalence is the hepatitis, and patients with type 2 diabetes and
product of cirrhosis incidence and survival time for other features of the metabolic syndrome.15 Finally,
patients with cirrhosis, and because they are both tertiary prevention involves reducing the incidence
increasing,12,36–39 we can expect cirrhosis preva- or impact of complications of cirrhosis – e.g. ascites,
lence to continue its increase until we manage to variceal bleeding, hepatic encephalopathy, hepato-
curb the incidence. It is likely that we will see cellular carcinoma, and death – following diagnosis.
different time trends for different cirrhosis aetiol-
ogies. The prevalence of cirrhosis from hepatitis B
and hepatitis C will decrease owing to the global Unmet needs
efforts to eliminate them,21 but the prevalence of Although the global number of DALYs attributable
cirrhosis from NAFLD will increase. to cirrhosis per 100,000 population is decreasing, it
A United States study found that the hospital- is not decreasing as fast as for other diseases,
isation costs attributable to cirrhosis grew by 30% hence the proportion of all DALYs that can be
10
between 2008 and 2014. Costs attributable to attributed to cirrhosis is going up. This observa-
compensated cirrhosis grew by 24%, while costs tion suggests that we should do more to reduce the
attributable to decompensated cirrhosis grew by burden of cirrhosis, and indeed we can do more.
36%. The total costs attributable to decompensated With respect to hepatitis B, many interventions
48
cirrhosis were 63% higher than those for compen- are known to be effective but are not implemented.
40 Only 13% of children born to HBsAg-positive mothers
sated cirrhosis. It is overly simplistic to claim that
the financial burden of cirrhosis will grow if the receive hepatitis B immunoglobulin and timely
17
prevalence of cirrhosis continues to grow; patients birth-dose and follow-up vaccination; only around
with cirrhosis may require less treatment than 10% of the 292 million people believed to be infected
17
today, or treatment may be cheaper. For example, are diagnosed; and only around 5% of the 94
17
when patients with cirrhosis from hepatitis C are million people eligible for treatment are treated.
treated with direct-acting antivirals, the prevalence The WHO aims to diagnose 90% of people infected
of compensated cirrhosis goes up because patients with hepatitis B by 2030, and to treat 80% of those
21
live longer, but the total costs can go down because eligible for treatment. This will require large in-
society does not have to pay to treat decom- creases in screening and treatment in most coun-
pensated cirrhosis. More realistically, though, the tries; the greatest improvements so far have been in
17
total costs after introduction of a treatment do go infant vaccination.
up, but because patients live longer and better With respect to hepatitis C, primary prevention
those costs are considered acceptable.41 With includes measures to reduce transmission such as
respect to cirrhosis from NAFLD, the financial screening of blood products and access to
burden will almost certainly continue to increase sterile needles; another major step is to find and
until effective treatments emerge.42,43 treat patients who are already infected.48 The WHO
has a goal to reduce new viral hepatitis infections by
How can we reduce the burden of 90% and deaths from hepatitis C by 65% by 2030.21
cirrhosis? This goal has been met in many areas, but not all.
We can reduce the burden of cirrhosis by reducing Alcohol consumption can be reduced by
the incidence of cirrhosis, by improving the quantity increasing alcohol taxation and by reducing access to
or quality of life for patients with cirrhosis, or by alcohol, but such policies may be unpopular and
reducing the costs of treating cirrhosis. Many soci- opposed by the alcohol industry. Thus, whereas no
eties are willing to accept increased costs (or reduced one opposes primary prevention of viral hepatitis
income) to achieve one or more of the other goals. infection, this is quite different for alcohol, resulting
in an occasional unmet need of the political will to

Journal of Hepatology 2021 vol. 75 j S3–S13 S9

Review
Key points
There is substantial global
variation in the burden and
causes of cirrhosis. Gener-
ally, the burden is lower in
more affluent countries
owing primarily to their
smaller burden of hepatitis
B.
S10
take effective steps.45,49 With respect to secondary
prevention, there is still no evidence from rando-
mised trials that screening for alcohol-related liver
disease reduces the burden of cirrhosis, but there is
weaker evidence that it does.47,50,51 Moreover, it may
be difficult to have the at-risk population referred
from the primary care physician to the screening
examination; treatment of alcohol use disorder is too
often considered futile, and there is an unmet need
for better treatments, particularly ones that can be
offered to patients with liver disease.52
Primary prevention of NAFLD includes policy ac-
tions to reduce obesity, e.g. through taxation of fat
content or restriction on marketing of fatty foods.49
This can be supplemented with information cam-
paigns promoting physical exercise and a diet low in
fat and fructose. Secondary prevention, screening
patients for fatty liver disease, may be successful in
preventing cirrhosis, but due to the sheer volume of
obese patients the question is who to screen.
Areas of controversy
There is controversy over many primary, second-
ary, and tertiary interventions to reduce the burden
of cirrhosis because of the lack of evidence from
randomised trials, but we will highlight a couple of
controversies that are relevant for future studies on
the burden of cirrhosis.
Does the DALY concept underestimate the
burden of cirrhosis?
The DALY is the sum of years of healthy life lost plus
years lived with disability. For cirrhosis, the years
lived with disability contribute virtually nothing to
the DALY because the disability weight of decom-
pensated cirrhosis is very small, and compensated
cirrhosis does not count as disability at all.12 As stated
in the introduction, that conclusion is at odds with
research findings and clinical experience.
The disability weights are based on surveys of the
general public, and respondents were asked which of
2 individuals they would consider to be healthier.53
For that purpose, patients with decompensated
cirrhosis were described to the layperson as “a person
with a swollen belly and swollen legs. The person feels
weakness, fatigue, and loss of appetite”.54 The
disability weight is higher for ‘severe low back pain
without leg pain’ (0.272 vs. 0.178 for decompensated
cirrhosis), which is described like this: “This person
has severe back pain, which causes difficulty dressing,
sitting, standing, walking, and lifting things. The per-
son sleeps poorly and feels worried.” Compare now
with the markedly lower disability weight of 0.054 for
‘moderate low back pain’: “This person has severe
back pain, which causes difficulty dressing, sitting,
standing, walking, and lifting things.” For a clinical
hepatologist it is difficult to accept that the disability
Journal of Hepatology 2021 vol. 75 j S3–S13
associated with decompensated cirrhosis is midway
between moderate and severe low back pain, and
many of our patients certainly have to deal with worry
and poor sleep, e.g. due to pruritus and muscle
cramps.3 Higher, more realistic, disability weights
would increase the burden of cirrhosis in the Global
Burden of Disease studies. With the 2019 study, the
Global Burden of Disease investigators have stratified
the disability weight for decompensated cirrhosis
according to the severity of anaemia, so that patients
with decompensated cirrhosis and severe anaemia
have a disability weight of 0.178 for decompensated
cirrhosis plus 0.122 for severe anaemia for a total of
0.300. Less severe anaemia adds 0.003 (mild anaemia)
or 0.042 (moderate anaemia) to the 0.178 for
decompensated cirrhosis. This principle might be
expanded, so that alcohol-related cirrhosis is given a
disability weight that is the sum of the disability
weight for cirrhosis and the disability weight for
alcohol use disorder, which ranges from 0.123 (very
mild), over 0.235 (mild), and 0.373 (moderate), to
0.570 (severe). Another possibility is to consider
health-state utilities instead of disability weights. A
recent United States study developed health-state
utilities for cirrhosis with 2 different methods, both
ranging from 0 to 1, with 1 representing optimal
health:55 with the standard gamble method, health-
utilities ranged from 0.85 in Child-Pugh A (compen-
sated) to 0.78 in Child-Pugh C (decompensated),
whereas with the visual-analogue scale method they
ranged from 0.70 in Child-Pugh A to 0.55 in Child-
Pugh C.
The Global Burden of Disease studies do not
attribute deaths from hepatocellular carcinoma to
cirrhosis although the majority of hepatocellular
carcinomas develop in patients with cirrhosis.12
Thus, a substantial proportion of the 151.1 age-
standardised DALYs per 100,000 population lost
to liver cancer might have been added to the 560.4
DALYs per 100,000 lost to cirrhosis.
Will a change of names make it more difficult to
study cirrhosis?
NAFLD was introduced as a separate cause of cirrhosis
in the 2017 Global Burden of Disease study. Recently,
an international consensus panel proposed a name
change to metabolic dysfunction-associated fatty liver
disease (MAFLD) and a different set of diagnostic
criteria.56,57 The proposal also included a definition of
‘dual aetiology fatty liver disease’ covering fatty liver
disease that meets the criteria for MAFLD plus the
criteria for another liver disease, e.g. alcohol-related
liver disease or viral hepatitis.56 Because of the high
prevalence of MAFLD, such a change will have a pro-
found impact on epidemiologic studies of cirrhosis.
Patients with MAFLD have been found to be older and
have more severe metabolic comorbidities than
patients with NAFLD,58 and what we currently
describe as alcohol-related cirrhosis or cirrhosis due
to viral hepatitis may come to be categorised as dual
aetiology cirrhosis. Such changes will disrupt studies
of time trends, including the analyses of DALYs
attributable to various cirrhosis aetiologies in the
Global Burden of Disease studies. Other arguments
against the proposed name change have been put
forward, chiefly concerns that it will stunt ongoing
development of drugs to treat NAFLD, require new
regulatory pathways, and sever ties to neighbouring
disciplines, e.g. endocrinology.59
In the long run, the idea of naming a disease
according to the presence or absence of 1 causal
risk factor is untenable, but that it is what we do
when we speak of “alcohol-related cirrhosis”,
“cirrhosis from hepatitis C”, or “cirrhosis from non-
alcoholic fatty liver disease”. Our understanding of
the causes of cirrhosis and their interaction will
evolve, and we will need new names for new ‘types
of cirrhosis’ again. The field will need to discuss
naming conventions for multi-cause cirrhosis.
Abbreviations
DALY(s), disability-adjusted life-year(s); MAFLD,
metabolic dysfunction-associated fatty liver disease;
NAFLD, non-alcoholic fatty liver disease; QALY(s),
quality-adjusted life-year(s); WHO, World Health
Organization; YLD, years of life lived with disability;
YLL, years of life lost due to premature death.
Financial support
PJ was supported by a grant from the Novo Nordisk
Foundation (NNF18OC0054612). The funding
organization was not involved in the conception,
the writing, or the decision to submit the manu-
script for publication.
Conflict of interest
ZMY has served as consultant and or received
research funds from Intercept, NovoNordisk, Gilead,
BMS, Abbott, Siemens, Terns, Merck, Madrigal and
Axcella. PJ reports grants from Novo Nordisk Foun-
dation, during the conduct of the study.
Please refer to the accompanying ICMJE disclo-
sure forms for further details.
Authors’ contributions
Peter Jepsen drafted the manuscript. Both authors
revised and edited the manuscript for content.
Supplementary data
Supplementary data to this article can be found
online at https://doi.org/10.1016/j.jhep.2020.11.042.
Transparency declaration
This article is published as part of a supplement
entitled New Concepts and Perspectives in
Decompensated Cirrhosis. Publication of the sup-
plement was supported financially by CSL Behring.
The sponsor had no involvement in content
development, the decision to submit the manu-
script or in the acceptance of the manuscript for
publication.

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