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World Journal of 
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Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2021 June 21; 27(23): 3223-3237
DOI: 10.3748/wjg.v27.i23.3223 ISSN 1007-9327 (print) ISSN 2219-2840 (online)
REVIEW
Assessment of liver disease in patients with chronic hepatitis C and 
unhealthy alcohol use
Daniel Fuster, Xavier García-Calvo, Paola Zuluaga, Ferran Bolao, Robert Muga
ORCID number: Daniel Fuster 0000-
0003-1262-5860; Xavier García-Calvo 
0000-0001-8165-8717; Paola Zuluaga 
0000-0002-0247-0351; Ferran Bolao 
0000-0002-9104-6615; Robert Muga 
0000-0001-6301-431X.
Author contributions: Fuster D and 
García-Calvo X performed the 
literature review; Fuster D drafted 
the initial version of the 
manuscript; Muga R and García-
Calvo X revised the initial version 
of the manuscript and provided 
feed-back and suggestions; all 
authors revised and approved the 
final version of the manuscript.
Supported by Institute of Health 
Carlos III, No. RETICS 
RD16/0017/0003, No. PI17/00174, 
and No. PI20/00883; Institute of 
Health Carlos III, Juan Rodes 
Program, No. JR20/00016; Institute 
of Health Carlos III, Sara Borrell 
Program, No. CD19/00019; 
Institute of Health Carlos III, 
Physician Intensification Program, 
No. INT19/00026; National Plan 
on Drugs, Spain, No. 2018/020, 
and No. 2020/024, Spain; and 
Autonomous Government of 
Catalonia, Spain, Consolidated 
Research Group, No. 2017-SGR-
316.
Conflict-of-interest statement: No 
conflict declared.
Open-Access: This article is an 
Daniel Fuster, Xavier García-Calvo, Paola Zuluaga, Robert Muga, Department of Internal 
Medicine, Addiction Unit, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma 
de Barcelona, Badalona 08916, Spain
Ferran Bolao, Department of Internal Medicine, Hospital Universitari Bellvitge, Institut 
d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08907, 
Spain
Corresponding author: Daniel Fuster, MD, PhD, Associate Professor, Staff Physician, 
Department of Internal Medicine, Addiction Unit, Hospital Universitari Germans Trias i Pujol, 
Universitat Autònoma de Barcelona, Carretera de Canyet s/n, Badalona 08916, Spain.  
dfuster.germanstrias@gencat.cat
Abstract
Hepatitis C virus (HCV) infection and unhealthy alcohol use are major drivers of 
the burden of liver disease worldwide and commonly co-occur. Assessment of 
underlying liver damage is a cornerstone of the clinical care of patients with 
chronic HCV infection and/or unhealthy alcohol use because many of them are 
diagnosed at advanced stages of disease. Early diagnosis of liver disease before 
decompensated liver cirrhosis becomes established is essential for treatment with 
direct acting antivirals and/or abstinence from alcohol consumption, which are 
the main therapeutic approaches for clinical management. In this review, we 
discuss current knowledge around the use of non-invasive methods to assess liver 
disease, such as abdominal ultrasound, controlled attenuation parameter, 
transient elastography, magnetic resonance imaging, and indices based on serum 
markers of liver injury.
Key Words: Hepatitis C virus; Alcohol; Liver fibrosis; Non-invasive methods; Ultrasound; 
Transient elastography
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Core Tip: In this review, we discuss current knowledge around the use of non-invasive 
methods to assess underlying liver disease in patients with hepatitis C virus infection 
and/or unhealthy alcohol use. A timely diagnosis of liver disease is of the outmost 
Fuster D et al. Liver disease assessment in hepatitis C and alcohol
WJG https://www.wjgnet.com 3224 June 21, 2021 Volume 27 Issue 23
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Manuscript source: Invited 
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Specialty type: Gastroenterology 
and hepatology
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First decision: February 27, 2021 
Revised: March 11, 2021 
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Published online: June 21, 2021
P-Reviewer: Gupta T, Shen ZY 
S-Editor: Fan JR 
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importance to avoid progression to decompensated liver disease and liver cancer. 
Antiviral treatment and abstinence from alcohol use are cornerstones of clinical care 
for these patients.
Citation: Fuster D, García-Calvo X, Zuluaga P, Bolao F, Muga R. Assessment of liver disease in 
patients with chronic hepatitis C and unhealthy alcohol use. World J Gastroenterol 2021; 
27(23): 3223-3237
URL: https://www.wjgnet.com/1007-9327/full/v27/i23/3223.htm
DOI: https://dx.doi.org/10.3748/wjg.v27.i23.3223
INTRODUCTION
Chronic hepatitis C virus (HCV) infection and unhealthy alcohol intake are common 
co-occurring conditions, in part because people with HCV often consume more alcohol 
than the general population[1]. Conversely, alcohol use is associated with a higher 
prevalence of HCV infection exposure and greater HCV infection persistence; patients 
with alcohol use have a lower likelihood of spontaneously clearing acute HCV 
infection[2]. For these reasons, the prevalence of HCV infection among patients with 
alcohol use is higher than in the general population[3], which is usually around 1% in 
Western countries[4]. We have found a prevalence > 20% in our cohort of patients with 
alcohol use disorder (AUD) and admitted for hospital detoxification[5], which is much 
higher than many values reported in a meta-analysis published in 2013[3]. This 
contrast underscores the relevance of a history of prior injection drug use and other 
risk factors for the acquisition of HCV in an urban population of patients with AUD[6].
In addition to higher infection exposure and persistence, alcohol use may affect 
HCV viral replication in certain subsets of patients[7] and is associated with progre-
ssive liver fibrosis and more extensive liver injury than in patients without alcohol use
[8]. HCV is also associated with increased mortality and other poor health outcomes in 
different subsets of patients with alcohol-use problems[9,10].
Currently, alcohol use is a major contributor to decompensated cirrhosis in patients 
with HCV infection[11]. Moreover, with the current availability of efficacious treat-
ments for viral hepatitis, alcohol-related liver disease is becoming a major driver of 
liver disease burden worldwide[12].
HCV infection needs to be detected as early as possible among patients with 
unhealthy alcohol intake, and accurate assessment of alcohol intake is necessary in 
patients with HCV infection[12]. Assessment of underlying liver disease is crucial, 
given that many patients are diagnosed only after their liver disease has reached an 
advanced stage[13].
ASSESSMENT OF ALCOHOL USE IN PATIENTS WITH LIVER DISEASE
The American Association for the Study of Liver Diseases and European Association 
for the Study of the Liver guidelines for the treatment of alcohol-related liver disease 
recommend using the alcohol use disorders identification test (AUDIT) to identify 
patients with AUD[14,15]. AUDIT includes 10 questions and explores consumption, 
dependence and alcohol-related problems according to the number of positive 
answers[16]. For patients with an AUDIT > 7, Diagnostic and Statistical Manual of 
Mental Disorders 5th edition is an appropriate tool used for the assessment of clinical, 
personal and social alcohol-related problems[17]. The severity of AUD, that 
encompasses both alcohol dependence and alcohol abuse, is based on the number of 
criteria that the patient meets (mild AUD: 2-3 criteria, moderate AUD: 4-5 criteria and 
severe AUD > 6). AUD represents the more extreme form of unhealthy alcohol use, a 
term that will be used throughout the manuscript[17].
In terms of amount, unhealthy alcohol use means drinking more than the 
recommended amount of alcohol by the National Institute of Alcohol abuse and 
Alcoholism [2 United States standard drinks (12oz of beer or 5oz of wine) per day or 14 
drinks per week for men and 1 drink per day or 7 United States standard drinks per 
week for women or men aged > 65], what includes the spectrum from risky alcohol 
use to AUD[18].
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It is important to note that for those who already have HCV infection there is no 
safe threshold of alcohol consumption and abstinence from alcohol should be the main 
treatment goal[12].
PATHOLOGIC FEATURES OF HCV-RELATED LIVER DISEASE AND 
ALCOHOL-RELATED LIVER DISEASE
The natural history of HCV-related liver disease is characterized by progressive liver 
fibrosis that eventually leads to liver cirrhosis and hepatocellular carcinoma[19]. Many 
cofactors are associated with a faster progression of liver fibrosis in patients with HCV 
infection, including age, duration of HCV infection, male sex, obesity, the presence of 
hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) co-infection, 
alcohol use, and immune suppression[20].
Alcohol-related liver disease includes several histological abnormalities ranging 
from simple steatosis to cirrhosis and liver cancer[21,22]. These various histological 
abnormalities can be present at the same time in a liver biopsy[21,22]. Alcoholic 
hepatitis is a complication associated with acute liver failure, an increased risk of 
infection, and high mortality that can be seen at any point in the natural history of 
alcohol-related liver disease[12].
Liver fibrosis is the best predictor of progression to decompensated cirrhosis in both 
chronic HCV infection and alcohol-related liver damage[23]. Liver biopsy is the 
preferred method to evaluate liver fibrosis, but it is costly, invasive[24] and rarely 
performed in patients with current alcohol or other substance use disorders[25]. In the 
present review, we will not discuss the particularities of liver biopsy[26] and focus 
instead on currently available non-invasive methods to assess the extent of liver 
damage in patients with HCV and/or unhealthy alcohol use.
THE NEED FOR ASSESSMENT OF LIVER DAMAGE
A timely diagnosis of liver disease in asymptomatic patients with HCV infection 
and/or AUD contributes to a better prognosis and facilitates treatment[27,28]. As 
noted, in patients with AUD, liver involvement is the main culprit of alcohol-related 
disease burden, and liver disease is usually detected in the advanced stages[28]. 
Almost 75% of patients with alcohol-related liver disease present with a non-elective 
hospital admission because of decompensated cirrhosis[29], so efforts should prioritize 
early identification of patients at risk for end-stage liver disease.
Despite the availability of efficacious treatments for viral hepatitis, the liver disease 
burden is expected to increase because of the growing prevalence of overweight and 
obesity and other unhealthy lifestyles in developed countries, which is predicted to 
drive an increase in the prevalence of non-alcoholic liver disease. In addition, many 
patients with metabolic syndrome also drink alcohol, and many patients with AUD 
have overweight or obesity and/or a sedentary lifestyle[30].
NON-INVASIVE METHODS FOR ASSESSMENT OF LIVER DAMAGE
Liver ultrasound
Liver ultrasound is both inexpensive and easily available, but it is rarely performed in 
patients with AUD and no apparent liver disease. The latest American Association for 
the Study of Liver Diseases guidelines for the management of chronic HCV infection 
are focused on the test-and-treat paradigm but recommend abdominal ultrasound for 
hepatocellular carcinoma surveillance only if the patient has already developed 
cirrhosis[31]. Although the latest European guidelines recommend liver ultrasound to 
early detect non-alcoholic steatohepatitis[32], there are no guidelines for the early 
detection of liver abnormalities among patients with high alcohol intake. Screening 
approaches for patients at risk for alcohol-related liver disease thus are a matter of 
debate[33,34]. It is also important to note that, in general, liver cancer surveillance 
among individuals with alcohol-related liver disease is far from optimal, and hepato-
cellular carcinoma is usually diagnosed at an advanced stage[22].
On abdominal ultrasound, liver steatosis has a hyperechogenic appearance because 
of the increased parenchymal reflectivity of intracellular fat accumulation[35]. Fat 
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content affects the sensitivity of abdominal ultrasound for detecting liver steatosis, and 
sensitivity severely decreases at fat contents lower than 10%–20%[28].
The precision of abdominal ultrasound in differentiating between steatosis and 
fibrosis is higher when liver fibrosis is more advanced because of an increase in coarse 
echoes without posterior beam attenuation[35-37]. Steatosis is usually classified as 
“mild,” “moderate,” or “severe”[37,38].
Despite operator dependency for the assessment of steatosis, there is agreement that 
liver ultrasound is inexpensive and reliable for the detection of moderate or severe 
liver steatosis[39,40]. The accuracy of abdominal ultrasound is lower for mild steatosis, 
however, it can be increased with a computer-aided method[40]. Ultrasound findings 
contribute to the detection of alcohol-related liver disease features in addition to liver 
steatosis, including (among others): Liver size, edge bluntness, parenchyma coarse-
ness, surface nodularity, inferior vena cava abnormalities, the presence of portal 
hypertension, and spleen size[41].
The authors of a Cochrane review published in 2016 commented on the need for 
studies of large sample size to assess the efficacy of abdominal ultrasound in patients 
with alcohol-related liver disease[42], in part because their review could only include 
two studies[42]. Of these two studies, the first was performed in France in 1985 and 
included 126 patients with alcoholism[43]. In addition to abdominal ultrasound 
performed in the entire cohort, 100 patients also underwent liver biopsy. In that group 
of 100 patients, cirrhosis of the liver was confirmed in 72, and abdominal ultrasound 
had a sensitivity of 81% and a specificity of 79% to detect cirrhosis[43].
The second study was published in 2013 and performed in Korea and included 230 
patients (81% male) who underwent liver biopsy, elastography and abdominal 
ultrasound[44]. The mean age of participants was 50.4 years. Ultrasound suggested 
heterogeneous liver in 199 patients (86.5%) and liver cirrhosis in 170 (74%). Cirrhosis 
of the liver was found in 111 participants, for a sensitivity of 94% and specificity of 
49% for ultrasound detection of cirrhosis of the liver[44]. Because of the small number 
of patients included and the differences in the selection criteria in each of these two 
studies, the authors of the review could not reach any conclusion about the use of 
abdominal ultrasound for detecting underlying advanced liver disease among patients 
with unhealthy alcohol use[42].
In 2018, we published a study describing ultrasound findings among 301 
consecutive AUD patients without clinically relevant liver disease who were admitted 
for hospital treatment of the disorder at Hospital Universitari Germans Trias i Pujol 
[34].
We obtained clinical and laboratory parameters at admission. An ultrasound was 
performed so as to identify the presence of liver steatosis, hepatomegaly, hetero-
geneous liver, and portal hypertension.
For this work, we studied unadjusted associations of ultrasound abnormalities with 
three prevalent conditions: Alcohol-related liver injury (ALI), advanced liver fibrosis 
(ALF) and HCV infection. ALI was defined as the presence of at least two of the 
following: Aspartate aminotransferase (AST) levels ≥ 74 < 300 U/L, AST/alanine 
aminotransferase (ALT) ratio > 2, and total bilirubin> 1.2 mg/dL. ALF was measured 
with fibrosis-4 (FIB-4)[45] and was defined as a FIB-4 score ≥ 3.25. We performed 
logistic regressions to detect if ALI, ALF and/or HCV were associated with having 
two or more abnormalities in the liver ultrasound.
In summary, 80% of the patients were male, had a median age of 46 years, drank a 
median of 180 grams of alcohol per day upon admission and 21.2% had HCV infection. 
Median serum AST was 42 U/L, median serum ALT was 35 U/L, the prevalence of 
ALI and ALF was 16% and 24%, respectively. A total of 57.2% patients had steatosis, 
49.5% had hepatomegaly, 17% had heterogeneous liver, while 16% had portal 
hypertension. Of interest, 77% of patients had one abnormality, and 45% had ≥ 2.
In the multivariate models, both ALI and ALF were significantly associated with the 
presence of ≥ 2 abnormalities, with odds ratios (ORs) of 5.2 for ALI and 4.7 for ALF. 
HCV infection did not predict the presence of more than two abnormalities[34].
Most patients included in the study who had only one ultrasound abnormality had 
mild to moderate steatosis or hepatomegaly, which are both potentially reversible with 
alcohol cessation. In light of those findings, we believe that abdominal ultrasound 
could be implemented in the everyday clinical care of patients seeking treatment for 
AUD, as it could help in clinical decision-making and treatment selection.
Liver abnormalities were quite common in the study, even in patients without HCV, 
ALI, or ALF, and only 31% of patients without any of those conditions had a 
completely normal ultrasound. Accordingly, we think that sharing information about 
ultrasound abnormalities may promote alcohol cessation in patients with AUD who 
are unaware of their underlying liver disease[34]. Other researchers have previously 
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reported that sharing findings suggestive of poor health outcomes with patients leads 
to a decrease in unhealthy alcohol use[46].
Liver cancer has an incidence of 2.9% per year in individuals who have cirrhosis of 
the liver[22]. Hepatocellular carcinoma entails a dire prognosis if not detected early
[47], which is why patients with alcohol-related end stage liver disease should 
undergo an abdominal ultrasound every 6 months[22]. However, periodic surveillance 
is challenging because many patients miss appointments[22], and less than 30% of 
liver cancers are detected by surveillance in Europe and the United States[22,48]. In 
our series, liver cancer was found in two participants[34].
Besides the early identification of steatosis or cirrhosis of the liver, abdominal 
ultrasound could be used for detecting other forms of liver damage. In fact, alcohol use 
is common among individuals with other forms of liver disease, and there is no safe 
level of alcohol consumption in these situations[8,30]. As previously mentioned, 
alcohol use is a cofactor in liver disease progression in individuals with HCV, HBV, 
non-alcoholic fatty liver disease, and hemochromatosis, among others. A threshold of 
a consumption of more than 30 grams of alcohol per day for men and 20 g for women 
is arbitrarily used to support the diagnosis of alcohol-related liver disease[12]. 
Nevertheless, as overweight and obesity are highly prevalent in the developed world, 
alcohol-related and non-alcoholic steatosis can co-occur[49]. In our case series of AUD 
patients, the median body mass index was 24.7, indicating that a sizable proportion of 
participants were overweight or obese[34].
In addition, liver ultrasound can also detect other forms of liver disease that are less 
prevalent, like parenchymatous or vascular diseases (non-cirrhotic portal hyperten-
sion, hepatic vein congestion, and Budd Chiari).
Transient elastography 
Transient elastography has been used for more than a decade to accurately assess liver 
fibrosis, measuring liver stiffness in patients with chronic HCV infection or HBV 
infection, with or without HIV co-infection, and in non-alcoholic liver disease[50-52]. 
In transient elastography, a piston vibrator that is placed in the intercostal space 
generates a shear wave, and velocity is measured below the skin surface. It measures 
liver stiffness in kilopascals (kPa), and elastography readings usually range from 2.5 to 
75 kPa[53].
The method has also been used to a lesser extent for analyzing liver injury in 
patients with AUD. A study that included 199 consecutive patients at risk for alcohol-
related liver disease found that transient elastography provided an assessment of 
fibrosis (either significant fibrosis, Ishak score ≥ 3) and cirrhosis (Ishak score ≥ 5) that 
was comparable to liver biopsy with high accuracy (area under the curve ≥ 0.92)[33]. 
Some authors have pointed out that steatohepatitis may lead to overestimation of liver 
fibrosis[54]. The risk of overestimation especially applies in patients who are abstinent, 
as liver stiffness decreases with cessation of alcohol use, especially with baseline 
values higher than 7 kPa[55].
In 2016, a systematic review and meta-analysis found that transient elastography 
could reliably exclude ALF or cirrhosis of the liver. The authors suggested that the 
same cut-offs described for viral hepatitis-related liver disease should be applied with 
caution to other forms of liver damage, particularly alcohol-related liver disease[56]. 
Mueller and colleagues have suggested adapting elastography cut-offs in patients who 
present with elevated AST or bilirubin[54]. The studies in that meta-analysis, which 
included only patients with alcohol-related liver disease, had a wide range of 
participant numbers and an ALF prevalence ranging from 53% to 80%[57-61].
Results of an individual-level meta-analysis published in 2018 that included 1026 
patients suggested that cut-offs for transient elastography should be higher[58]. In that 
study, higher concentrations of AST and bilirubin were significantly associated with 
higher liver stiffness values (P < 0.01)[58]. In addition, the presence of non-severe 
alcoholic hepatitis was associated with liver stiffness (P < 0.0001). Also, higher AST (P 
< 0.01) and higher bilirubin (P = 0.01) levels and increased prothrombin activity (P = 
0.01) were significantly associated with non-severe alcoholic hepatitis. That meta-
analysis described specific liver stiffness cut-offs based on concentrations of AST and 
bilirubin[58].
French researchers used transient elastography to assess ALF in a cohort study of 
patients with HCV/HIV co-infection. They found that ALF was more prevalent among 
patients with an alcohol-related diagnosis (OR 3.06; 95%CI: 1.42–6.60) compared to 
those with non-hazardous alcohol intake[62].
A recently published study describes the use of transient elastography for the 
measurement of liver and spleen stiffness (a surrogate marker of portal hypertension), 
as well as spleen length in a retrospective cohort of 499 patients with HCV or alcohol-
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related liver disease[63]. Participants with HCV had higher mean spleen stiffness and 
spleen length but lower liver stiffness when compared to participants with alcohol-
related liver disease. The authors concluded that the use of those measurements, as 
well as the spleen stiffness/liver stiffness and spleen length/spleen stiffness ratios, 
could be helpful to measure burden of disease and risk for disease-specific complica-
tions[63].
Other researchers have confirmed that elastography is a good predictor of clinical 
events[64]. Transient elastography has also been proven to be cost-effective in primary 
care[65], and other authors have used it to detect chronic alcohol-related liver disease 
after alcohol cessation[66] or to detect improvements in liver fibrosis after successful 
HCV antiviral therapy[67].
Transient elastography thus represents a promising tool for assessing underlying 
liver damage in patients with unhealthy alcohol use and/or HCV infection[28]. It is 
important to note that transient elastography results may be affected by the thickness 
of subcutaneous fat, width of intercostal spaces, by the presence of ascites, by the 
patients’ breathing or by an uneven distribution of liver fibrosis. In addition, the 
presence of hepatic congestion or steatosis may also distort transient elastography 
results[28,56].
Table 1 includes a summary of the most relevant studies that have used transient 
elastography in patients with alcohol-related liver disease.
Controlled attenuation parameter
The controlled attenuation parameter (CAP) is a non-invasive tool for detecting 
steatosis. It measures ultrasound attenuation during transmission through fatty liver 
tissue[68]. CAP software can be incorporated into transient elastography devices, thus 
facilitating the non-invasive measurement of steatosis and fibrosis[28].
Cut-offs for moderate and severe liver steatosis were defined in a recently published 
patient-level meta-analysis that included 2735 participants with liver biopsy and CAP. 
Their diagnostic accuracy ranged from 0.65 to 0.90[69]. The etiology of liver disease 
was HBV in 37% of patients, HCV in 36% and or non-alcoholic fatty liver disease in 
20%, and participants with unhealthy alcohol use were under-represented[69]. As all 
patients included had liver diseases that are strongly associated with liver fibrosis, 
these cut-offs require further validation in other and healthier populations[70].
A study by Thiele and colleagues included 562 patients with alcohol-related liver 
steatosis and found that CAP above 290 dB/m ruled in any steatosis with a 88% 
specificity and a 92% positive predictive value, whereas CAP below 220 dB/m ruled 
out steatosis with a 90% sensitivity but with a 62% negative predictive value[71]. The 
authors concluded that it was useful for the diagnosis of severe alcohol-related 
steatosis and could also rule in any liver steatosis.  In patients admitted for alcohol 
detoxification who did not have obesity, CAP rapidly declined[71]. This finding 
underscores the synergic effect of obesity and alcohol use in patients seen in clinical 
practice[72].
A study by Unalp-Arida and colleagues measured liver stiffness and CAP in 4870 
participants in the National Health and Nutrition Examination Survey cohort, and 
found that liver stiffness in the highest quartile was associated, among others, with 
HCV infection, increased age and body mass index and CAP[73].
Virtual touch quantification
Virtual touch quantification is a point shear wave elastography technique, using 
acoustic radiation force impulse technology also offers good diagnostic accuracy for 
liver fibrosis assessment[74]. It has been used in patients with chronic liver disease of 
different origins, mainly due to viral hepatitis[75,76].
Magnetic resonance imaging
Magnetic resonance imaging and proton magnetic resonance spectroscopy are 
promising methods for quantifying hepatic fat content[35]. Magnetic resonance 
measurement of liver steatosis does not appear to be affected by the type of liver 
disease or the presence of liver inflammation or iron overload, features that may 
distort results obtained with other non-invasive methods. Despite these potential 
advantages, magnetic resonance imaging is costly and time-consuming[28]. Moreover, 
information is scarce about its applicability in alcohol-related liver disease.
Laboratory-driven indices 
There are several non-invasive indices that are derived from laboratory parameters 
aimed for the estimation of liver fibrosis. Some of those parameters are used in 
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Table 1 Studies that have used transient elastography in patients with alcohol-related liver disease
Ref. Number of patients Advanced liver fibrosis (≥ 3) Sensitivity1 Specificity1
Nguyen-Khac et al[58], 2018 103 51% 87% 80%
Nahon et al[59], 2008 147 75% 87% 89%
Kim et al[107], 2009 45 80% 97% 78%
Mueller et al[57], 2010 101 45% 91% 75%
Janssens et al[60], 2010 49 65% 72% 76%
Fernandez et al[61], 2015 135 53% 91% 68%
1Sensitivity and specificity are calculated using liver biopsy as the gold standard.
everyday clinical practice, including AST, ALT, and platelets. As far back as 1991, 
Poynard and colleagues described the poly-gamma-l-glutamic acid index, which 
included prothrombin time, gamma-glutamyl transferase (GGT), and apolipoprotein 
A1[77]. In a group of 333 individuals with high alcohol consumption, the index 
correctly classified a heavy drinker as harboring liver cirrhosis most of the time (89%) 
at a value ≥ 9[77]. The accuracy increased with the addition of alpha-2 macroglobulin 
(known as the PGAA index)[78].
Other tests, such as the enhanced liver fibrosis (ELF) test, FibroTest (FT), and 
HepaSCORE, are commercially available and combine different serum markers that 
are not used in everyday clinical practice. ELF includes type III procollagen peptide, 
hyaluronic acid, and tissue inhibitor of metalloproteinase-1[79]. FT, also known as 
FibroSure in the United States, combines age and sex, alpha-2 macroglobulin, 
haptoglobulin, apolipoprotein A1, GGT, total bilirubin, and ALT[80]. HepaSCORE 
includes bilirubin, GGT, hyaluronic acid, alpha-2 macroglobulin, age, and sex[81]. The 
patented indices seem to perform better than non-patented versions against the gold 
standard of liver biopsy[82], but because of their cost, they are less frequently used in 
health systems with budget constraints.
Among the indices that include routinely measured parameters, the most com-
monly used are FIB-4[45] and the AST/platelet ratio index (APRI)[83]. Both indices 
have been validated against liver biopsy in patients with HCV and in patients with 
HCV and HIV co-infection[84-86]. Both FIB-4 and APRI are better suited for the 
detection of the absence of liver fibrosis or the presence of ALF[45,83]. Experience with 
their use in patients with unhealthy alcohol use is far more limited[87], and some 
authors have expressed concerns around the potential overestimation of liver fibrosis 
in patients with alcohol-related liver disease[87,88].
Lieber and colleagues, publishing in 2006, reported assessment results for 1308 
patients from two United States veterans’ administration cooperative studies of 
alcoholic liver disease for the accuracy of APRI in non-invasive detection of liver 
fibrosis[87]. APRI had low sensitivity (13.2%) and specificity (77.6%) for the non-
invasive estimation of significant fibrosis in individuals with alcohol-related liver 
disease, including those who also had HCV.
In different series of patients with HCV with or without co-infection, results have 
been mixed regarding if non-invasive indices are able to detect the association between 
alcohol use and liver fibrosis, probably because of how alcohol consumption was 
assessed and because of unmeasured confounding in the different cohorts studied. A 
cross-sectional study in a cohort of patients with HIV/AIDS in Baltimore found that 
heavy alcohol use was associated with ALF measured with the APRI score[89]. 
However, when patients were stratified according to the presence of HCV infection, 
the association between APRI score and unhealthy alcohol use was only found among 
those with no HCV infection[89].
In a cohort that only included women, Blackard and colleagues did not find an 
association between alcohol use and FIB-4 values as a continuous variable among 
patients with HCV/HIV co-infection, whereas immune suppression was associated 
with higher FIB-4 values[90]. In a more recent study in the same cohort, Kelly and 
colleagues found that light or moderate alcohol consumption (1-7 drinks per week), 
which was reported in 35.7% of the 686 patients included, was not associated with 
fibrosis progression measured by several FIB-4 determinations over time[91]. 
Conversely, drinking 8–14 drinks per week was associated with minimal acceleration 
of fibrosis progression, while drinking more than 14 drinks per week was clearly 
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associated with increased fibrosis progression[91].
In a study performed in our cohort of patients with AUD who were admitted for 
hospital treatment in 2012, FIB-4 used as a continuous variable was significantly 
higher among those with HCV/HIV co-infection compared to those with HCV 
infection only[92]. When we stratified results by the presence of HIV infection, we 
found that alcohol use affected FIB-4 values only in those with HCV infection, whereas 
immune depression exerted a more negative role than alcohol consumption in those 
with co-infection[92].
In the HIV-LIVE cohort in Boston, involving a cohort of patients with HIV infection 
and alcohol problems, lifetime alcohol consumption measured with the Lifetime 
Drinking History questionnaire was not associated with FIB-4 values < 1.45 consistent 
with the absence of fibrosis. The adjusted (A)ORs were 1.12 (95%CI: 0.25–2.52) for a 
lifetime consumption of 150–600 kg of alcohol vs < 150 kg (reference category) and 1.11 
[(95%CI: 0.52–2.36) for > 600 kg vs < 150 kg; global P = 0.95][93]. Similar results were 
found for the presence of ALF (FIB-4 >  3.25) and with the use of APRI instead of FIB-4. 
Results did not differ among patients with HCV co-infection[93].
An analysis from the veterans aging cohort study (VACS) included a large number 
of patients (701 with HIV/HCV coinfection, 1410 with HIV infection, with 296 HCV 
infection, and 1158 with neither HIV nor HCV infection) and a different measure of 
alcohol consumption (AUDIT-C questionnaire and/or presence of alcohol-related 
diagnoses). The authors reported greater risks for ALF (measured with FIB-4) among 
patients with co-infection who had nonhazardous drinking (OR = 14.2; 95%CI: 
5.91–34.0) or hazardous/binge drinking (OR = 18.9; 95%CI: 7.98–44.8), or who 
exhibited alcohol-related diagnoses (OR = 25.2; 95%CI: 10.6–59.7) in comparison to 
uninfected Veterans who were nonhazardous drinkers[94].
In a more recent study by our group that included 1313 patients with AUD who 
were admitted for hospital detoxification, 30.6% had ALF, estimated with a FIB-4 
value > 3.25. Patients with HCV infection, who represented 18% of the total study 
population, were two times more likely than those without HCV infection to present 
with ALF (OR = 2.1; 95%CI: 1.5–3.1, P < 0.01)[25].
Despite these different results in terms of accuracy or the ability to detect associ-
ations between the presence either of AUD or HCV and ALF, non-invasive indices are 
performed in patients with alcohol or other substance use disorders that will not 
undergo a biopsy[93,95]. In addition, non-invasive indices can predict mid-term 
mortality in epidemiological studies[95,96], which is why FIB-4 has been included in 
the VACS cohort index[97]. This index, initially intended to predict mortality, also 
predicts the occurrence of other health outcomes[98], such as incident heart failure in 
patients living with HIV[99].
The Forns index, which was described in 2002, has been less frequently used in 
patients with unhealthy alcohol use[100]. Originally developed for detection of the 
absence of liver fibrosis in a cohort of patients with HCV, it includes platelets, 
cholesterol, and GGT levels, as well as age[100]. In a study by Naveau and colleagues 
published in 2009, the accuracy of the Forns index for detecting biopsy-proven ALF 
was lower than that of other non-patented biomarkers (APRI and FIB-4)[82]. Further-
more, other researchers have expressed concerns regarding the use of the Forns index 
in alcohol-related liver disease, given that GGT levels differ between patients with 
HCV or alcohol-related liver disease[101]. Despite those concerns, in our group, we 
have used the Forns index to estimate liver fibrosis in drug users with HCV infection 
with or without HIV infection[96] and in patients with AUD[25]. The Forns index 
accurately predicted mid-term mortality and detected ALF in a fashion that was 
comparable to APRI and FIB-4[25].
Table 2 includes a summary of the more relevant papers describing assessment of 
alcohol use with non-patented indices to estimate liver fibrosis in patients with HCV 
infection.
Combination of non-invasive methods
Because non-invasive indices are better suited for the detection of either the absence of 
liver fibrosis or the presence of ALF, several approaches of the sequential use of 
different methods have been proposed. A study published in 2017 by Spanish 
researchers showed that use of the ELF test with or without a confirmation elasto-
graphy was cost-effective compared with a single liver biopsy for the detection of liver 
fibrosis in patients with HCV and alcohol-related liver disease[102].
Another new approach is the use of both FIB-4 and transient elastography to detect 
ALF in patients with FIB-4 values within the intermediate range (1.45–3.25)[103]. This 
approach has been used in a Russian cohort of individuals with high alcohol intake, 
HIV infection, and a high prevalence of chronic HCV infection[103].
Fuster D et al. Liver disease assessment in hepatitis C and alcohol
WJG https://www.wjgnet.com 3231 June 21, 2021 Volume 27 Issue 23
Table 2 Studies that used non-patented indices to estimate liver fibrosis in patients with hepatitis C virus infection and unhealthy 
alcohol use
Ref. Setting Non-invasive method
Method for detecting 
alcohol consumption Finding
Lieber et al[87], 
2006 
Veterans' affairs studies (2) of 
alcoholic liver disease
APRI1 Average alcohol intake Low sensitivity and specificity of APRI in 
comparison to liver biopsy, especially in 
patients with HCV
Chaudhry et al[89], 
2009 
HIV Hopkins clinical cohort APRI1 Past 6 mo of hazardous 
drinking
No effect of alcohol on APRI values in 
HCV/HIV co-infection
Blackard et al[90], 
2011 
WIHS cohort FIB-42 Recent drinking No association between alcohol intake and FIB-
4 values in HCV/HIV co-infection
Muga et al[92], 
2012 
Patients with AUD admitted 
for detoxification 
FIB-42 Past 6 mo of unhealthy 
drinking
No association between FIB-4 and alcohol use 
in HCV/HIV co-infection
Fuster et al[93], 
2013 
HIV-LIVE cohort FIB-42 and APRI1 LDH No association between LDH and liver fibrosis 
measured with FIB-4 or APRI
Lim et al[94], 2014 VACS cohort FIB-42 AUDIT-C3 Advanced liver fibrosis correlated with alcohol 
use
Kelly et al[91], 2017 WIHS cohort FIB-42 Average number of drinks per 
week, past 6 mo
Light/moderate drinking was not associated 
with accelerated fibrosis progression
Sanvisens et al[25], 
2018
Patients with AUD admitted 
for detoxification
FIB-42; APRI1; 
Forns
Past 6 mo, daily alcohol 
intake
Patients with HCV were two times as likely to 
present with advanced liver fibrosis
1Aspartate aminotransferase (AST)/platelet ratio index: AST to platelet ratio index = {[Patient AST/AST upper limit of normal (IU/L)]/platelet count (109
/L)} × 100.
2FIB-4 = Age × AST (IU/L)/platelet count (109/L) × alanine aminotransferase (IU/L)1/2.
3AUDIT-C: Alcohol use disorders identification test. HCV: Hepatitis C virus; AST: Aspartate aminotransferase; APRI: AST/platelet ratio index; FIB-4: 
Fibrosis-4; AUD: Alcohol use disorder; HIV: Human immunodeficiency virus; LDH: Lifetime drinking History; WIHS: Women's interagency HIV study; 
VACS: Veterans aging cohort study.
Future directions for the non-invasive assessment of liver damage
The measurement of small non-coding microRNAs (miRNAs) is a promising field
[104]. In fact, miR-155 and miR-122 have been proposed as potential markers of 
different forms of liver diseases, including those related to HCV and alcohol[105].
Other markers that could be used in the future are extracellular vesicles, the small 
membrane vesicles released by cells that transport mRNA, miRNA, proteins, and 
lipids, and circulating nucleic acids, including cell-free DNA and cell-free non-coding 
RNA[106].
CONCLUSION
Underlying liver disease can be accurately estimated with the use of several non-
invasive methods that spare the necessity of performing a liver biopsy. The 
widespread use of these methods can help to accurately identify patients at risk for the 
development of end-stage liver disease. In addition to treatment with direct-acting 
antivirals for those with HCV infection, abstinence from alcohol consumption should 
be strongly recommended, given the overlap between alcohol-related and metabolic 
liver diseases.
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