EJINME-03391; No of Pages 5

European Journal of Internal Medicine xxx (2016) xxx xxx

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European Journal of Internal Medicine

journalhomepage:www.elsevier.com/locate/ejim

Original Article

Characteristics of liver cirrhosis in Italy: Evidence for a decreasing role of HCV

aetiology
a b c b d
Tommaso Stroffolini , Evangelista Sagnelli , Giovanni Battista Gaeta , Caterina Sagnelli , Angelo Andriulli ,
c e f g a
Giuseppina Brancaccio , Mario Pirisi , Guido Colloredo , Filomena Morisco , Caterina Furlan ,
h,
Piero Luigi Almasio , on behalf of EPACRON study group

EPACRON study group:

Coordinating group: Piero Luigi Almasio, Giovanni Battista Gaeta, Evangelista Sagnelli, Tommaso Stroffolini
1 2
Peripheral centres: Angelo Andriulli, Sergio Babudieri , Giuseppina Brancaccio, Bruno Cacopardo ,
3 4 5
Guido Colloredo, Nicola Coppola , Massimo De Luca , Caterina Furlan, Anna La Licata , Filomena Morisco, Mario
6 7 8 9
Pirisi, Mariantonietta Pisaturo , Floriano Rosina , Maurizio Russello , Caterina Sagnelli, Teresa Santantonio ,
10
Antonina Smedile
1 Clinical of Infectious Disease, University of Sassari, 07100 Sassari, Italy
2 Infectious Diseases, University of Catania, Italy
3 Department of Mental Health and Public Medicine, Second University of Naples, Italy
4 Liver Unit, Department of Transplantation, Division of Hepatology, Cardarelli Hospital, Italy
5 Gastroenterology & Hepatology Unit, Di. Bi.MI. S., University of Palermo, Italy
6 Division of Infectious Diseases, AORN Sant'Anna e San Sebastiano di Caserta, 81100 Caserta, Italy
7 Hepatogastroenterology Division, Ospedale Gradenigo, 10153 Torino, Italy
8 Liver Unit, Hospital G. Garibaldi Catania, Catania, Italy
9 Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy
10 Department of Gastroenterology, Molinette Hospital, C.so Bramante 88, 10126 Turin, Italy

a Department of Tropical and Infectious Diseases, Policlinico Umberto Primo, Rome, Italy
b Department of Mental Health and Public Medicine, Second University of Naples, Italy
c Infectious Diseases, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Italy
d Gastroenterology Unit, Fondazione Casa Sollievo della Sofferenza IRCCS Hospital, San Giovanni Rotondo, Foggia, Italy
e Department of Translational Medicine, Universit del Piemonte Orientale, Novara, Italy
f Department of Internal Medicine, San Pietro Hospital, Ponte San Pietro, Italy
g Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples Federico II, Naples, Italy
h Gastroenterology & Hepatology Unit, Di. Bi.MI. S., University of Palermo, Italy

article info abstract

Article history: Background: Previous cross-sectional studies have shown that hepatitis C virus (HCV) infection had been the main agent
Received 16 June 2016 associated with liver cirrhosis in Italy.
Received in revised form 21 September 2016 Aim: To assess epidemiological, laboratory and clinical features of liver cirrhosis in Italy in 2014.
Accepted 17 October 2016 Available online Patients: Out of the 2557 consecutive subjects evaluated in 16 hospitals located throughout Italy in 2014, 832 (32.6%) had
xxxx liver cirrhosis and were enrolled in this study.
Results: The mean age of subjects was 60.3 years, with a male/female ratio of 1.7; 74.9% of cases had Child A cirrhosis and
Keywords:
17.9% superimposed hepatocellular carcinoma. HCV infection, alone or in combination with other aetiologic agents, was
HCV
HBV responsible of 58.6% of cases, HBV aetiology accounted for the 17.6% and alcohol abuse for the 16.0%. Compared with
Alcohol abuse virus-related cirrhotic patients, those alcohol-related more frequently showed decompensation (p = 0.02).
Liver cirrhosis
Liver cirrhosis epidemiology

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatitis delta virus (HDV) hepatocellular carcinoma; ISTAT, Italian Institute of Statistic; NAFLD, non-alcoholic fatty liver
disease; NASH, non-alcoholic steatohepatitis.
Financial support: an unrestricted grant for the study was provided by Gilead.
Corresponding author at: Biomedical Department of Internal and Specialized Medicine (Di. Bi. MI. S.), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy. E-mail
address: piero.almasio@unipa.it (P.L. Almasio).

http://dx.doi.org/10.1016/j.ejim.2016.10.012
0953-6205/ 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Stroffolini T, et al, Characteristics of liver cirrhosis in Italy: Evidence for a decreasing role of HCV aetiology, Eur J Intern Med
(2016), http://dx.doi.org/10.1016/j.ejim.2016.10.012
2 T. Stroffolini et al. / European Journal of Internal Medicine xxx (2016) xxxxxx

Conclusions: Compared to previous surveys performed in 1992 and in 2001, we observe a statistically signi ficant (p b 0.05)
decreasing role of both HCV infection and alcohol abuse as aetiologic agents of liver cirrhosis in Italy, explaining, at least in
part, the slow, progressive decline of the mortality rate for liver cirrhosis in the last decades in this country (from 34.5
deaths/100,000 inhabitants in1980 to 10.8 in 2012).
2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction 3. Methods

Liver cirrhosis, the end-stage of chronic liver diseases of different
etiologies, accounts for more than one million deaths each year world-wide
[1]. The leading causes of cirrhosis in Europe are a risky alcohol intake, B and
C hepatitis viruses and metabolic syndrome [2].
Hepatitis B virus (HBV) and hepatitis C virus (HCV) have been the major
causes of liver cirrhosis in Italy over the last decades. In the early 70s, HBV
accounted for nearly one third of cirrhosis cases [3], a de-cade later its
associated defective hepatitis delta virus (HDV) accounted for most cases of a
so-called juvenile cirrhosis [4] and HCV has been found responsible of
more than half of cirrhosis cases since its discovery in 1989 [5,6].
According to the official vital statistics reported by the Italian Insti-tute of
Statistic (ISTAT), the mortality rate (deaths/100,000 inhabitants) for liver
cirrhosis has continuously decreased from 34.5 in 1980 to 10.8 in 2012 [7]
(Fig. 1). This favourable trend is most probably due to both improvement of
treatments (wide use of more effective antiviral drugs, improvement of
managing complications of cirrhosis and hepa-tocellular carcinoma (HCC)
and extended use of liver transplantation), and to a decreasing role of both
HBV [810] and HCV [11] infections.
Two cross-sectional nationwide surveys performed in 1992 and in 2001
[5,6] have shown that HCV was present, even with other etiologi-cal factor, in
72.1% and 69.9% cirrhosis cases, respectively.
In 2014, we have carried out a further cross-sectional study on cirrhotic
patients. In this study the end-points were:
- primary, to evaluate the current role of different etiological factors;
- secondary, to assess changes, if any, of different risk factors over time.
2. Material and methods
Chronic hepatitis was diagnosed based on liver histology, when available
or on persistence for more than 6 months of abnormal ALT in the absence of
clinical, biochemical, and ultrasound markers of liver cirrhosis [12]. Liver
cirrhosis was diagnosed by liver biopsy, when available, or on the presence of
characteristic clinical, biochemical and ultrasound signs [12]. The diagnosis
of hepatocellular carcinoma (HCC) was based on histological and/or imaging
findings and on alfa-1-fetoprotein serum levels, according to accepted criteria
[13].
The aetiology of liver disease was based on detection of viral markers
(HBsAg, anti-HCV), presence of autoantibodies at significant titres, markers
of iron or copper overload, amount and duration of alcohol intake
(corroborated by relatives), or presence of criteria to identify a metabolic
syndrome. The presence of serum HBsAg identified an HBV aetiology, and
the detection of anti-HCV an HCV aetiology. Autoimmune chronic hepatitis
and primary biliary cholangitis were diagnosed ac-cording to standardized
international criteria [14,15]. The diagnosis of hereditary hemochromatosis
was made based on abnormal ferritin serum values and transferrin saturation
serum values, genetic markers, or liver histology [16]. The diagnosis of
Wilson's disease was made on the basis of accepted criteria [17]. Abnormal
serum alanine aminotrans-ferase (ALT) values and a histological and/or
ultrasound pattern of he-patic steatosis, in the absence of other known causes
of chronic liver disease, were considered related to non-alcoholic fatty liver
disease. The amount of alcohol intake was determined using a standard ques-
tionnaire containing information on the daily intake of various alcoholic
beverages and the lifetime duration of alcohol consumption. A patient was
considered as having alcohol-related cirrhosis if he/she had a history of an
alcohol intake of more than 40 g/day for males and 30 g/day for fe-males for
at least 5 years, without any other pathogenic factor [18,19]. The aetiology of
chronic liver disease was considered undefined in the absence of any viral,
autoimmune or evident metabolic agents.

2.1. Patients
The study population consisted of persons aged over 18 with altered
hepatic biochemistry, consecutively admitted in 2014, as either inpa-tients or
outpatients, for liver disease evaluation to one of the 16 liver units
participating to this investigation. The 16 liver units were scattered all over
the country.
The collection of personal data was made in full compliance with Italian
law on personal data protection, and each patient gave his/her informed
consent to participate. All procedures applied in the study were in accordance
with the international guidelines, with the stan-dards of human
experimentation of the local Ethics Committees and with the Helsinki
Declaration of 1975, revised in 1983. At the time of the first observation, each
patient signed their informed consent for the collection of personal data,
established in full agreement with the roles of the Ethic Committee of the
coordinating centre (A.O.U.P. of the University of Palermo, Italy). Patients
who agreed to undergo liver biopsy signed an appropriate informed consent
before this procedure was performed. All patients were included in the study
only once, i.e., at their first observation during the study period. For each
patient a pre-coded questionnaire containing demographic, epidemiological
and clinical data was filled in.

Percutaneous liver biopsy (LB) was performed, if requested by the

Fig. 1. Number of deaths of liver cirrhosis 100,000 inhabitants in Italy, 19802012.
Source of Data: National Institute of Statistic (ISTAT).
physician in care for diagnostic purposes, under US guidance using a
disposable modified Menghini needle. In each Liver Unit, a skilled pa-
thologist unaware of the clinical and laboratory data evaluated liver histology.
In particular, liver necroinflammation and fibrosis were assessed by the Ishak
[20] or Metavir scoring system [21], and standard-ized criteria were used to
convert the Ishak score to a Metavir score [22]. Transient elastometry was
performed by Fibroscan [2325]. Serum HBsAg and antibody to HCV, HDV
and HIV were sought using commer-cial immunoenzymatic assays. Plasma
HBV DNA was determined by

Please cite this article as: Stroffolini T, et al, Characteristics of liver cirrhosis in Italy: Evidence for a decreasing role of HCV aetiology, Eur J Intern Med
(2016), http://dx.doi.org/10.1016/j.ejim.2016.10.012
 T. Stroffolini et al. / European Journal of Internal Medicine xxx (2016) xxxxxx 3

Table 1 Table 3
Characteristics of liver cirrhosis in Italy over time. Overtime prevalence of cirrhosis cases due to the main etiologic agents, alone or associ-ated
with other agents.
Characteristic 1992 (Ref. [3]) 2001 (Ref. [4]) 2014
No. of cases 1829 2185 832 Etiologic agents 1992 2001 2014 p-value
(Ref. [3]) (Ref. [4]) (present report)
Age, mean S.D., years 59.0 11.8 62.9 11.2 60.3 13.3
No. = 1829 No. = 2185 No. = 832
Sex ratio (M/F) 1.6 1.3 1.7
ChildPugh score , %: Patients with HBV 13.8% 13.0% 17.6% n.s.
-A 63.6% 55.9% 74.9% Patients with HCV 72.1% 69.9% 58.6% b0.05
- B/C 36.4% 44.1% 25.1% Patients with Alcohol 32.9% 31.9% 16.0% b0.05
Presence of HCC 11.9% 11.2% 17.9%
p b 0.05.

Some demographic and clinical characteristics of the three main etiologic

real-time polymerase chain reaction (PCR); by this method, the detec-tion groups, namely HBV alone, HCV alone and alcohol alone, are reported in
limit in plasma samples is estimated at around 40 IU/mL. HCV RNA was Table 3. Mean age was similar in these three groups and males predominated
detected and quantified by a real-time PCR in a Light cycler 1.5; by this in HBV group. In alcoholic group, Child A liver cir-rhosis was less frequently
method, the detection limit in plasma samples is estimated at around 40 diagnosed than in other etiologic groups, but, conversely, Child B and C were
IU/mL. HCV genotyping was performed using a commer-cial Line-Probe more frequently observed (p = 0.02). Finally, a quite similar proportion of
assay. HCC was observed in these three etiologic groups (Table 4).
Routine tests were applied to seek the etiologic markers of autoim-mune
hepatitis, primary biliary cholangitis, iron and copper overload and liver Cirrhotic patients from Southern Italy, Sardinia and Sicily compared with
functions. those from Northern and Central Italy, more frequently showed HBV
aetiology and less frequently HCV aetiology (p b 0.05). Besides, more
3.1. Statistical analysis frequently they were males (p b 0.05) and showed decompen-sated cirrhosis
(p b 0.001) and presence of HCC (p b 0.05) (Table 5).
Data were collected in a pre-established electronic CRF data-base (web-
based data collection, e-CRF provided by Air-Tel, Airon Telematica, Milan, 5. Discussion
ITALY). Differences in the distribution of the charac-teristics of the subjects
in the different groups were evaluated applying the analysis of variance and The large number of patients investigated and the geographical
the Chi-square analysis for continuous and categorical variables, respectively. distribution across the country of the participating liver units make it possible
A p value less than 0.05 was consid-ered to be statistically significant. All p to generalize the observed findings to Italy.
values were two-tailed. Several of the units participating in the present survey have partici-pated
even in the previous ones [5,6], so that results may be considered comparable
overtime in terms of methodology adopted, area of resi-dence of patients, and
4. Results
facility of access to a referral centre.
As many as 87.6% of subjects in our study had a diagnosis of liver
Out of 2557 subjects evaluated in this study, 832 (32.6%) had liver
cirrhosis using not invasive techniques combined with clinical signs, outlining
cirrhosis. The proportion of cases who underwent elastography was 28.6%
the current limited need of liver biopsy in these cases.
and that of those who underwent liver biopsy 12.4%. All these subjects had a
HCV infection continues to be the most common aetiological factor
fibrosis score of F4.
observed in cirrhotic patients in Italy, a figure widely differing from what
Some characteristics of liver cirrhosis cases are reported in Table 1. The
observed in North Europe, where alcohol overconsumption is the most
mean age was 60.3. There was a male preponderance with a male to female
ratio of 1.7. The proportion of subjects with compensated cir-rhosis (Child common cause of liver cirrhosis, as recently confirmed by a Swedish study
grade A) was 74.9% and the rate of cirrhotic patients with HCC 17.9%. [26] showing that 58% of cirrhosis cases were due to a risky alcohol intake.
Distribution by aetiology of cirrhosis cases is reported in Table 2. Chronic
However, the role of HCV infection on the burden of liver cirrhosis in
HCV infection was the most frequent etiologic agent of liver cirrhosis, acting
Italy is significantly (p b 0.05) decreasing over time, from the 72.1% in 1992
alone in the 49.4% of cases and with other etio-logic factors in the 58.6%.
[5] to the current 58.9%. This figure is in line with the progressive decline of
HBV alone was the etiologic agent of the 15.0% of the cases and with other
mortality rate for liver cirrhosis in Italy, and with a recent population survey
etiologic factors of 17.6%. Acting alone, alco-hol abuse was responsible for
in Southern Italy showing, fourteen years apart, a de-cline of anti-HCV
the 7.0% of the cases and with other etio-logic factors for 16.0%.
positive subjects from 12.6% to the 5.7% in 2010, with the majority of cases
NAFLD/NASH were responsible of the 7.3% of the cases. One patient had
ageing more than 70 years [11]. We predicted this decline based on the
primary biliary cholangitis and in the remaining 11.1%.the aetiology
different rates of HCV aetiology in incident and prevalent cases observed in
remained undefined.
the 2001 survey [27]. These findings follow the intensive epidemic wave most
probably occurred in the 50s and 60s,
Table 2
Distribution of the 832 cases of cirrhosis investigated in 2014, by aetiology.
Table 4
Etiologic agents Number (%) Initial characteristics of the 594 cirrhosis patients with a main single aetiology observed in
HBV alone 125 (15.0) 2014.
HCV alone 411 (49.4)
Characteristics HBV alone HCV alone Alcohol alone p-value
Alcohol abuse 58 (7.0)
(No. = 125) (No. = 411) (No. = 58)
HBV plus HCV 10 (1.2)
HBV plus Alcohol abuse 8 (1.0) Age, mean S.D., years 59.1 12.7 60.5 12.9 59.7 15.3 n.s.
HCV plus Alcohol abuse 63 (7.6) Sex ratio (M/F) 2.0 1.5 1.1 n.s.
HBV plus HCV plus Alcohol abuse 3 (0.4) Child grade:
NAFLD/NASH 61 (7.3) -A 78.4% 74.7% 53.4% 0.02
Primary biliary cholangitis 1 (0.1) - B/C 21.6% 25.3% 46.4%
Undefined 92 (11.1) Presence of HCC 15.2% 18.2% 15.5% n.s.

NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis. HCC: hepatocellular carcinoma.

Please cite this article as: Stroffolini T, et al, Characteristics of liver cirrhosis in Italy: Evidence for a decreasing role of HCV aetiology, Eur J Intern Med
(2016), http://dx.doi.org/10.1016/j.ejim.2016.10.012
4 T. Stroffolini et al. / European Journal of Internal Medicine xxx (2016) xxxxxx

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(2016), http://dx.doi.org/10.1016/j.ejim.2016.10.012
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