Received: 19 December 2017 | Accepted: 24 December 2017

DOI: 10.1111/liv.13682

REVIEW ARTICLE

Liver diseases: A major, neglected global public health problem

requiring urgent actions and large-­scale screening

Patrick Marcellin | Blaise K. Kutala

Hepatology Department and INSERM

CRI, Hôpital Beaujon, APHP, University Paris
Diderot, Clichy, France
Correspondence
Patrick Marcellin, Service d’hépatologie,
Hôpital Beaujon, Clichy, France.
Email: patrick.marcellin@aphp.fr
Handling Editor: Mario Mondelli
Abstract
CLDs represent an important, and certainly underestimated, global public health prob-
lem. CLDs are highly prevalent and silent, related to different, sometimes associated
causes. The distribution of the causes of these diseases is slowly changing, and within
the next decade, the proportion of virus-­induced CLDs will certainly decrease signifi-
cantly while the proportion of NASH will increase. There is an urgent need for effec-
tive global actions including education, prevention and early diagnosis to manage and
treat CLDs, thus preventing cirrhosis-­related morbidity and mortality. Our role is to
increase the awareness of the public, healthcare professionals and public health au-
thorities to encourage active policies for early management that will decrease the
short-­and long-­term public health burden of these diseases. Because necroinflamma-
tion is the key mechanism in the progression of CLDs, it should be detected early.
Thus, large-­scale screening for CLDs is needed. ALT levels are an easy and inexpensive
marker of liver necroinflammation and could be the first-­line tool in this process.

KEYWORDS
alcoholic liver disease, ALT, chronic liver disease, cirrhosis, epidemiology, hepatitis B, hepatitis C,
hepatocellular carcinoma, NAFLD, NASH, screening

1 | INTRODUCTION
Chronic liver diseases (CLDs) represent a major world public health
problem. The liver is, in many ways, the reflection of a person’s health
and should play a central role in worldwide public health policies.
Current, but probably undervalued, worldwide estimations show
that 844 million people have CLDs, with a mortality rate of 2 million
deaths per year.1 This can be compared with other major public health
problems related to chronic diseases such as diabetes (422 million,
1.6 million deaths),2 pulmonary (650 million, 6.17 million deaths)3 and
3,4
cardiovascular diseases (540 million, 17.7 million deaths).
unlike other chronic diseases, a large proportion of CLDs can be
cured (chronic hepatitis C, CHC) and prevented or treated (chronic
hepatitis B, CHB). Indeed, viral (predominantly in Asia, Africa, Latin
America), alcohol-­induced CLD (ALD) and emergent metabolic CLDs
Abbreviations: ALD, alcoholic liver disease; ALT, alanine-amino-transferase; CHB, chronic
hepatitis B; CHC, chronic hepatitis C; CLD, chronic liver disease; NAFLD, non-alcoholic fatty
liver disease; NASH, non-alcoholic steato-hepatitis.
(i.e. non-­alcoholic fatty liver disease, NAFLD and non-­alcoholic steato-­
hepatitis, NASH), predominant in Western countries, have been es-
sentially neglected as public health problems.4 Urgent actions are
needed for the prevention, diagnosis, appropriate management and
treatment of CLDs. To reach this goal, large-­scale screening for CLD is
needed. Public awareness and participation by healthcare systems and
authorities are crucial to reach this goal.5
2 | THE HIGH PREVALENCE OF CLDS
However,
The estimated worldwide prevalence of CHB is 3.6%, ranging from 0.5%
in European countries to more than 8% in sub-­Saharan Africa.6 The es-
timated prevalence of CHC is 2.5%, ranging from 1.8% in the United
States (US) to 5.6% in Africa. The prevalence of ALD is 8.5% with the
highest prevalence (around 12%) found in Europe and the United States.7
The estimated worldwide prevalence of NAFLD is 25% and of
NASH is 3%-­5%.8 The highest prevalence of NAFLD is observed in

2 | © 2018 John Wiley & Sons A/S. wileyonlinelibrary.com/journal/liv Liver International. 2018;38(Suppl. 1):2–6.
Published by John Wiley & Sons Ltd

MARCELLIN and KUTALA
Western countries (17% to 46%) where it is the most common CLD
in adults9 with a high prevalence of NASH in the United States (16%).
However, the accurate respective prevalence of NAFLD and NASH
are not well known because of the lack of liver histology information
(diagnostic gold standard) in most studies.
3 | THE HIGH INCIDENCE OF CLD-­
RELATED MORBIDITY AND MORTALITY
CLDs induce cirrhosis in 633 000 patients per year with a prevalence
of 4.5% to 9% worldwide.10 The prevalence of cirrhosis is probably
underestimated as most patients remain asymptomatic. Indeed, the
risk curve for the incidence of cirrhosis is much flatter than the risk
curve for mortality from cirrhosis. The exact incidence of decompen-
sated cirrhosis is unknown. If decompensation occurs in an estimated
20% to 25% of patients with cirrhosis, this would represent 150 000-­
200 000 patients per year.11
There is a growing incidence of hepatocellular carcinoma (HCC)
worldwide. The annual global incidence of HCC is over 500 000
cases.12
The highest incidence of HCC is observed in Asia and Africa, as-
sociated with the high prevalence of CHB and CHC in these regions
(Table 1).13,14
Decompensated cirrhosis is the 14th most common global cause
of death in adults, the fourth in central Europe. It results in one million
deaths per year worldwide, 170 000 per year in Europe.15
Global mortality from HCC is growing. HCC is the third most com-
mon cause of cancer-­related death (692 000 cases per year) in the
world and the seventh most common cause in the United States16
with an important number of new cases estimated in 2013, associated
with a corresponding number of deaths. In Europe, HCC is responsi-
ble for 49 000 deaths per year.11,15 By 2020, the mortality rates will
increase by an estimated 1.5 times.16 The highest incidence rates of
HCC are found in Eastern Asia and sub-­Saharan Africa where around
85% of cases occur (Table 1).4
In the United States, a total of 41 734 liver transplantations (LTs)
were performed between 1992 and 2001. Of these, 12.5% were per-
formed in patients with ALD, 5.8% in those with ALD and associated
CHC and 54% in those with CHC or CHB. The proportion of patients
transplanted for HBV has declined in last decade because of HBV anti-
viral treatments. The effect of the recent availability of HCV antivirals
has not yet been demonstrated. In Europe, 5500 LTs are performed
every year. Because the diagnosis is usually made late, HCC accounts
15,17
for only 5% of all LTs.
4 | THE HIGH COST OF CLDS
The cost of CLDs is underestimated because of the lack of data. In
2004, the direct cost of CLDs in the United States including cirrhosis
(excluding patients with CHC) was estimated to be $2.5 billion. The es-
timated cost was $22 752 per patient with HCV-­related compensated
14783231, 2018, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/liv.13682 by Cochrane Romania, Wiley Online Library on [20/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
| 3
Key points
• The worldwide prevalence and incidence of CLDs are
high.
• NAFLD and NASH will still increase.
• CLDs are a major and increasing cause of morbidity and
mortality.
• Public and health authorities need to be more aware of
the significant problem of CLDs.
• CLDs are silent and under-diagnosed and large-scale
screening is needed.
• Management and access to treatment need to be
improved.
• Liver necroinflammation is the key step to fibrosis.
• ALT, a marker of liver necroinflammation, is the easiest
available tool for large-scale screening.
cirrhosis and a total cost of $10.6 billion for CHC (before direct anti-
viral agents, DAAs, became available). The estimated annual cost of
patients with HCV and end-­stage CLD was $59 995.18
In 2010, the average per-­
patient-­
per-­
year cost was found to
steadily increase along with disease stage, from $137 000 for
Barcelona Clinic Liver Cancer criteria (BCLC) stage 0 and $133 000
for stage A, $178 000 for stage B, $269 000 for stage C, $467 000
for stage D.19
The estimated annual cost for NASH is $103 billion according to
a prevalence model. The estimated average 3-­year healthcare cost
per patient who underwent LT was $539 955 in 2010 in the United
States.20
5 | A NEGLECTED PUBLIC
HEALTH PROBLEM
The extent of the global public health burden of CLDs, whatever
the cause, is not well known and is certainly underestimated. First,
an accurate evaluation of the incidence and prevalence in large re-
gions is not available, especially those in which CHB21 and/or CHC is
highly endemic as well as in areas with a high risk of ALD or NASH.9
Moreover, an accurate global evaluation of the impact of CLDs, in par-
ticular the morbidity and mortality related to decompensated cirrhosis
and HCC, is needed.22 Finally, the real cost of CLDs must be assessed
according to the specific management in each country. This is true
for all causes of CLD, but especially true for NASH, an emerging CLD
that is responsible for an increasing rate of cirrhosis and HCC, and for
which specific markers for screening are not available.
National and international programmes on CLDs are lacking.
Although national programmes on CHC have been developed in some
countries,5 programmes do not exist in most, including regions with
the highest prevalence. There are HBV vaccination programs world-
wide, however their efficacy needs to be assessed. Knowing that
 14783231, 2018, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/liv.13682 by Cochrane Romania, Wiley Online Library on [20/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
4 | MARCELLIN and KUTALA

T A B L E 1 The global epidemiology of

Current
chronic liver diseases
estimation Future estimation
Incidence (million) Prevalence (%) (million) 2030 (million)

HBV 4.5-­6 3.6 240 120a

HCV 3-­4 2.5 170 85a
ALD 16.6 4.5 Not available 19.3b
NAFLD 13.6 5-­8 570 16.2b
NASH 2.5 <4 145 3.8b
a
Estimation according to a prevalence model.
b
Estimation according to an incidence model.

mother-­to-­infant transmission accounts for almost all cases of CHB
in Africa and Asia, the recommended strategy to vaccinate newborns
at birth should be extended and applied. So far, there are no national
or international programmes for NASH because of the lack of clear
screening and management strategy, and the absence of specific
treatments.
Indeed, the real issue is the limited public and political awareness
of the extent of the public health burden of CLDs. Effective actions
require appropriate funding. Although it has not been proven, early
diagnosis would certainly be cost-­effective, since it allows optimal
management and/or administration of available drugs that can prevent
cirrhosis and HCC. Obviously, increasing easy access to antiviral treat-
ment is crucial for CHB and CHC.
6 | URGENT ACTIONS ARE NEEDED
One priority should be to increase awareness about CLDs in the pub-
lic, healthcare professionals and the authorities. Information on the
frequency and causes of CLDs should be widely diffused (Table 1).
The progression of CLDs is known to depend upon the combination
of different causes (i.e. HBV-­HCV co-­infection, excess alcohol con-
sumption or NASH associated with CHB or CHB). Also co-­infection
with HIV accelerates the progression of CHB and CHC unless it is
effectively treated.
Cultural, societal, environmental, as well as psychological and life
style factors play an important role, in particular excess alcohol con-
sumption for NASH, but also CHB and CHC. Education of the public
about the potential impact of certain behaviours that increase the risk
of CLD is crucial.
Indeed, the public is not aware of CLDs because they are silent
and symptoms develop late. CLDs are not generally recognized by
physicians because of the absence of symptoms, a normal clinical
examination and limited biochemical abnormalities. Also, physicians’
knowledge about CLDs, including the interpretation of serological
markers of CHB and CHC as well as biochemical markers suggesting
NASH is not optimal. Physicians should be made aware of the fre-
quency of NASH in patients with clinical signs (even moderate) and the
presence of a metabolic syndrome (often incomplete) in particular pa-
tients who have overweight, hypertension, diabetes or dyslipidaemia.
Available specific treatments for NASH are needed.

7 | LIVER INFLAMMATION: THE KEY

OF PROGRESSION

F I G U R E 1 Necroinflammation the key to the progression of
chronic liver disease
The main mechanism for the progression of CLD, whatever the cause,
is liver inflammation.23 Hepatocyte necrosis is mainly the result of
inflammation that is related to the immune response to target cells.
Necroinflammation induces the progression of fibrosis to cirrhosis
then HCC, causing morbidity and the mortality.24
In the last two decades, the assessment of CLDs has focused
upon the stage of fibrosis. However, fibrosis is a consequence, not
the cause. Because of the availability of serum fibrosis tests or scores,
which are easier to use than liver biopsy, the central role of necroin-
flammation, the main step in the progression of CLD, has been nearly
forgotten. Necroinflammation is known to be independent of viral load
in CHB and CHC and is not correlated with the amount of alcohol
intake in ALD or the amount of fat in NASH (Figure 1). Indeed, the
presence and grade of necroinflammation was initially used to de-
fine the “agressivity” or “activity” of disease, differentiating “chronic

MARCELLIN and KUTALA
active hepatitis” from “chronic persistent hepatitis”. Histological scores
included the grade of inflammation (activity) in addition to the stage
of fibrosis, to determine the prognosis of CLD and the indication for
therapy. Also, non-­progressive ALD versus progressive ALD is defined
by the presence of inflammation (alcoholic hepatitis). Non-­progressive
NAFLD is differentiated from progressive NAFLD (NASH) by the pres-
ence of inflammation.
The grade of necroinflammation is known to be correlated with
the stage of fibrosis and its prognosis in CLD. Indeed, in large histology
studies performed in CHC patients (liver histology was the primary
end-­point in large pivotal trials of successive drugs), the stage of fibro-
sis is correlated with the grade of necroinflammation.
The progression of CLD is driven by necroinflammation. This
is demonstrated by the histological effect of antiviral treatments
in CHB and CHC, which are associated with the disappearance of
necroinflammation and the regression of fibrosis, even in patients
with cirrhosis.25
Finally, stopping inflammation stops the fibrogenesis process and
allows natural fibrolysis to occur. Thus, inflammation should be the
target of therapy and better knowledge of the mechanisms responsi-
ble for the excessive immune response in different CLDs is needed to
develop more effective therapies.
8 | TRANSAMINASES: AN ALARM AND
THE EASIEST AVAILABLE LARGE SCALE
SCREENING TEST
Elevated alanine-­amino-­transferase (ALT) levels are correlated with
the grade of necroinflammation but not with the stage of fibrosis.
Even if the correlation is not highly accurate, this is the only easy, in-
expensive test available to detect CLD, whatever the cause. Although
ALT is not specific, it is an alarm, signalling the presence of liver dis-
orders requiring an etiological and prognostic evaluation. Therefore,
measurement of ALT should be part of routine blood testing, such as
glycaemia or cholesterolaemia.
The prognosis of the CLD is determined by an assessment of the
fibrosis stage, based on scores, blood tests or devices such as elasto-
metry, which are not always available and are quite expensive. Liver
biopsy is an invasive procedure associated with some morbidity; how-
ever, it is currently the only procedure that provides an accurate as-
sessment of the grade of necroinflammation, to help determine the
prognosis.
The sensitivity of ALT is not perfect. However, if a slight or mild ele-
vation above the upper limit of normal is taken in account, the sensitiv-
ity for the presence of CLD is significantly increased. A more accurate
definition of normal ALT levels must also be determined. In addition,
the repetition of ALT measurements is easy, improves sensitivity and is
useful to assess the efficacy of the management/treatment of CLDs.
Finally, ALT measurement meets all the criteria for the screening
for CLD. It is a simple, inexpensive test that is easily available, with
satisfactory sensitivity. Thus, ALT is the best available tool for large-­
scale screening for CLD.
14783231, 2018, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/liv.13682 by Cochrane Romania, Wiley Online Library on [20/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
| 5
9 | CONCLUSION
CLDs represent an important, and certainly underestimated, global
public health problem. CLDs are highly prevalent and silent, related to
different, sometimes associated causes. The distribution of the causes
of these diseases is slowly changing, and within the next decade, the
proportion of virus-­induced CLDs will certainly decrease significantly
while the proportion of NASH will increase. There is an urgent need
for effective global actions including education, prevention and early
diagnosis for management and treatment to prevent cirrhosis-­related
morbidity and mortality. Our role is to increase the awareness of
the public, healthcare professionals and public health authorities to
encourage active policies for early overall management that will de-
crease the short-­and long-­term public health burden of these dis-
eases. CLDs meet all the criteria in favour of systematic screening.
Because necroinflammation is the key mechanism in the progression
of CLDs, it should be detected early. Thus, large-­scale screening for
CLDs is needed. ALT levels are an easy and inexpensive marker of liver
necroinflammation and they could be the first-­line tool in this process.
CO NFL I C TS O F I NT ER ES T
The authors do not have any disclosures to report.
O RC I D
Blaise K. Kutala http://orcid.org/0000-0001-8877-9239
REFERENCES
1. Byass P. The global burden of liver disease: a challenge for methods
and for public health. BMC Med. 2014;12:159.
2. Emerging Risk Factors Collaboration, Sarwar N, Gao P, et al. Diabetes
mellitus, fasting blood glucose concentration, and risk of vascular dis-
ease: a collaborative meta-­analysis of 102 prospective studies. Lancet
Lond Engl. 2010;375:2215‐2222.
3. Ward BW, Schiller JS, Goodman RA. Multiple chronic conditions
among US adults: a 2012 update. Prev Chronic Dis. 2014;11:E62.
4. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators.
Global, regional, and national incidence, prevalence, and years lived
with disability for 328 diseases and injuries for 195 countries, 1990-­
2016: a systematic analysis for the Global Burden of Disease Study
2016. Lancet Lond Engl. 2017;390:1211‐1259.
5. Lemoine M, Thursz M, Njie R, Dusheiko G. Forgotten, not neglected:
viral hepatitis in resource-­limited settings, recall for action. Liver Int
Off J Int Assoc Study Liver. 2014;34:12‐15.
6. Hope VD, Eramova I, Capurro D, Donoghoe MC. Prevalence and estima-
tion of hepatitis B and C infections in the WHO European Region: a review
of data focusing on the countries outside the European Union and the
European Free Trade Association. Epidemiol Infect. 2014;142:270‐286.
7. European Association for the Study of Liver. EASL clinical practi-
cal guidelines: management of alcoholic liver disease. J Hepatol.
2012;57:399‐420.
8. Kim WR, Lake JR, Smith JM, et al. OPTN/SRTR 2015 Annual Data
Report: liver. Am J Transplant Off J Am Soc Transplant Am Soc Transpl
Surg. 2017;17(Suppl 1):174‐251.
9. Vernon G, Baranova A, Younossi ZM. Systematic review: the epi-
demiology and natural history of non-­alcoholic fatty liver disease

6 |
and non-­alcoholic steatohepatitis in adults. Aliment Pharmacol Ther.
2011;34:274‐285.
10. Scaglione S, Kliethermes S, Cao G, et al. The epidemiology of cirrhosis
in the United States: a population-­based study. J Clin Gastroenterol.
2015;49:690‐696.
11. Marcellin P, Pequignot F, Delarocque-Astagneau E, et al. Mortality
related to chronic hepatitis B and chronic hepatitis C in France: ev-
idence for the role of HIV coinfection and alcohol consumption. J
Hepatol. 2008;48:200‐207.
12. European Association For The Study Of The Liver, European
Organisation For Research And Treatment Of Cancer. EASL-­EORTC
clinical practice guidelines: management of hepatocellular carcinoma.
J Hepatol. 2012;56:908‐943.
13. Spearman CW, Sonderup MW. Health disparities in liver dis-
ease in sub-­ Saharan Africa. Liver Int Off J Int Assoc Study Liver.
2015;35:2063‐2071.
14. Blachier M, Leleu H, Peck-Radosavljevic M, Valla D-C, Roudot-
Thoraval F. The burden of liver disease in Europe: a review of available
epidemiological data. J Hepatol. 2013;58:593‐608.
15. Lewis DR, Chen H-S, Cockburn MG, et al. Early estimates of SEER
cancer incidence, 2014. Cancer. 2017;123:2524‐2534.
16. McGlynn KA, Petrick JL, London WT. Global epidemiology of hepato-
cellular carcinoma: an emphasis on demographic and regional variabil-
ity. Clin Liver Dis. 2015;19:223‐238.
17. Adam R, Karam V, Delvart V, et al. Evolution of indications and results
of liver transplantation in Europe. A report from the European Liver
Transplant Registry (ELTR). J Hepatol. 2012;57:675‐688.
18. Younossi ZM, Park H, Dieterich D, Saab S, Ahmed A, Gordon SC.
Assessment of cost of innovation versus the value of health gains
associated with treatment of chronic hepatitis C in the United
States: the quality-­ adjusted cost of care. Medicine (Baltimore).
2016;95:e5048.
14783231, 2018, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/liv.13682 by Cochrane Romania, Wiley Online Library on [20/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
MARCELLIN and KUTALA
19. Kaplan DE, Chapko MK, Mehta R, et al. Healthcare costs related to
treatment of hepatocellular carcinoma among veterans with cirrho-
sis in the United States. Clin Gastroenterol Hepatol Off Clin Pract J Am
Gastroenterol Assoc. 2017;16:106‐114.
20. Younossi ZM, Blissett D, Blissett R, et al. The economic and clinical
burden of nonalcoholic fatty liver disease in the United States and
Europe. Hepatol Baltim Md. 2016;64:1577‐1586.
21. European Association for the Study of the Liver. Electronic address:
easloffice@easloffice.eu, European Association for the Study of the
Liver. EASL 2017 Clinical Practice Guidelines on the management of
hepatitis B virus infection. J Hepatol. 2017;67:370‐398.
22. Kutala BK, Guedj J, Asselah T, et al. Impact of treatment against hep-
atitis C virus on overall survival of naive patients with advanced liver
disease. Antimicrob Agents Chemother. 2015;59:803‐810.
23. Asselah T, Boyer N, Guimont M-C, et al. Liver fibrosis is not asso-
ciated with steatosis but with necroinflammation in French patients
with chronic hepatitis C. Gut. 2003;52:1638‐1643.
24. Neuman MG, Schmilovitz-Weiss H, Hilzenrat N, et al. Markers of in-
flammation and fibrosis in alcoholic hepatitis and viral hepatitis C. Int
J Hepatol. 2012;2012:231210.
25. Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treat-
ment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-­year
open-­label follow-­up study. Lancet Lond Engl. 2013;381:468‐475.
How to cite this article: Marcellin P, Kutala BK. Liver diseases:
A major, neglected global public health problem requiring
urgent actions and large-­scale screening. Liver Int.
2018;38(Suppl. 1):2–6. https://doi.org/10.1111/liv.13682