Journal of Hepatology 34 (2001) 570575

www.elsevier.com/locate/jhep

Serum a-fetoprotein for diagnosis of hepatocellular carcinoma in

patients with chronic liver disease: inuence of HBsAg and
anti-HCV status
Franco Trevisani 1,*, Paola Emanuela D'Intino 1, Antonio Maria Morselli-Labate 2,
Giuseppe Mazzella 2, Esterita Accogli 2, Paolo Caraceni 1, Marco Domenicali 1,
Stefania De Notariis 1, Enrico Roda 2, Mauro Bernardi 1
1
Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, University of Bologna, Via Massarenti, 9, 40138 Bologna, Italy
2
Dipartimento di Medicina Interna e Gastroenterologia, University of Bologna, Bologna, Italy

See Editorial, pages 603605

Background: It is not established whether virological status affects the efciency of a-fetoprotein (AFP) as a hepa-
tocellular carcinoma (HCC) marker among patients with chronic liver disease (CLD).
Methods: We enrolled in a case-control study 170 HCC and 170 CLD patients, matched for age, sex, CLD and
HBsAg/anti-HCV status. The AFP sensitivity, specicity, positive (PPV) and negative (NPV) predictive values were
calculated. PPV and NPV were evaluated for three additional HCC prevalences (5, 10, and 20%).
Results: The best discriminating AFP value was 16 ng/ml. A value of 20 ng/ml (above which investigations for HCC
are recommended) had equivalent sensitivity (60.0 vs. 62.4%) and specicity (90.6 vs. 89.4%). PPV of 20 ng/ml was
84.6% but decreased to 25.1% at 5% tumor prevalence. NPV was 69.4% and rose to 97.7% at 5% prevalence. In the
different groups of infected patients PPV ranged from 80.0 to 90.9%, falling to 17.434.5% at 5% prevalence. In non-
infected patients PPV was 100% at any HCC prevalence. NPV ranged from 59.0 to 73.0%, reaching 96.598.1% at 5%
prevalence.
Conclusions: In CLD patients, AFP monitoring misses many HCCs and inappropriately arouses suspicion of malig-
nancy in many patients. Its usefulness is barely affected by the infection responsible for CLD. An AFP elevation could
be more indicative of HCC in non-infected patients.
q 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.
Keywords: a-Fetoprotein; Hepatocellular carcinoma; Chronic liver disease; Diagnosis; Hepatitis virus B; Hepatitis
virus C

1. Introduction lance programs based on serial abdominal ultrasonography

Hepatocellular carcinoma (HCC) is one of the most
common cancers in humans, mostly occurring in patients
with chronic liver disease (CLD) [1]. Its early detection
may be important, since effective treatments are now avail-
able for the management of non-advanced neoplasms [2]. In
high-risk patients, this goal is accomplished through surveil-
Received 23 March 2000; received in revised form 12 September 2000;
accepted 20 October 2000
* Corresponding author. Tel.: 139-051-6364918; fax: 139-051-340877.
E-mail address: trevi@unibo.it (F. Trevisani).
and serum a-fetoprotein (AFP) assay [3]. Although recent
evidence indicates that the fucosilated fraction of AFP may
be a more useful marker than total AFP [47], the availability
of this assay is still conned to few laboratories. Moreover,
des-gamma-carboxyprothrombin, another commercially
available marker of HCC, has a sensitivity highly dependent
on cancer size, being superior to AFP only in large HCCs [8].
Thus, AFP remains the oncomarker universally utilized for
monitoring high-risk patients for HCC in clinical practice.
The hepatitis B virus (HBV) surface antigen (HBsAg)
status may modulate the diagnostic accuracy of AFP. In

0168-8278/01/$20.00 q 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.
PII: S01 68-8278(00)0005 3-2
 F. Trevisani et al. / Journal of Hepatology 34 (2001) 570575
endemic areas of HCC, AFP seems to be less useful in
HBsAg positive than HBsAg negative patients [9], leading
to many false positive results in the former [10,11]. This
observation has not been tested in the Caucasian population,
where several features of HCC may differ from those found
in endemic areas [12,13]. Other studies have shown that
HCCs occurring in hepatitis C virus (HCV)-infected
patients are more often associated with AFP elevation
than those harboring in HBsAg carriers [14,15]. However,
this nding has not been conrmed [1618]. Therefore, the
impact of virological status on the diagnostic accuracy of
AFP in HCC detection still remains largely unsettled.
This case-control study aimed to identify the best cut-off
value of serum AFP to discriminate CLD patients with and
without HCC, and to assess whether HBV and HCV infec-
tions can modulate the reliability of AFP.
2. Patients and methods
Among patients with HCC superimposed on CLD seen from January
1993 to June 1996 in our institution, we retrospectively selected those in
whom information on HBsAg, antibody to HCV (anti-HCV), AFP level and
disease of the extratumoral liver was reported in the clinical record. Patients
with liver disease due to genetic and autoimmune disorders, primary biliary
cirrhosis and sclerosing cholangitis were excluded. Two hundred and ten
cases fullled these criteria. Among them, we were able to match 170 cases
(135 males and 35 females) with 170 controls with CLD seen during the
same period according to the following criteria: age (within 6 years), sex,
underlying CLD (cirrhosis/chronic hepatitis), HBsAg and HCV status. In
control patients, the presence of HCC was ruled out by ultrasonography and
also by excluding patients who developed HCC during the following 6
months.
The diagnosis of HCC was based on histologic or cytologic ndings in
128 patients, while it was conrmed by clinical and imaging data or
necropsy in the remainder. The diagnosis of cirrhosis was supported by
biopsy in 132 patients, and was based on the presence of clinical and
laboratory features of portal hypertension (the presence of esophageal
varices and/or collateral circulation at endoscopy and ultrasonography) in
the remainder. The diagnosis of chronic hepatitis or brosis was based on
liver histology.
Liver function tests (serum bilirubin, alkaline phosphatase, g-glutamyl-
transpeptidase (g-GT), alanine aminotranspherase (ALT) and albumin, and
prothrombin activity (PT)) were determined using commercially available
kits.
HBV markers were tested by radioimmunoassay or enzyme-linked
immunosorbent assay (Abbott Laboratories, Chicago, IL; Sorin Biomedica,
Saluggia, Italy). Anti-HCV was detected by ELISA II (Ortho Diagnostic
Systems, Raritan, NJ) (until November 1993) and III (Ortho Diagnostic
Systems, Neckargemund, Germany).
AFP was measured by conventional assays (radioimmunoassay, Eiken
Chemical Co., Tokyo, Japan; LA-AFP test, Poli, Milan, Italy; immunoen-
zymatic assay, Abbott Laboratories, Rome, Italy). The analysis of the clin-
ical utility of AFP was conducted using the following cut-off values:
the best discriminating value provided by the receiver-operating char-
acteristic (ROC) curve,
the value of 20 ng/ml, above which investigations for HCC are currently
recommended [19,20],
the values of 100, 200 and 400 ng/ml these two latter values are
currently utilized as conrmatory tests for HCC diagnosis in the
presence of focal solid lesions of the liver [8,2123].
The severity of liver cirrhosis was assessed according to ChildPugh
571
classication [24]. HCC gross pathology was evaluated according to
previous studies [20,25] as solitary, multinodular, diffuse (tumor mass
not clearly dened with an indistinct boundary) and massive. A more
detailed stratication was also used: single #3 cm, single .3 cm without
satellites (contiguous lesions much smaller in size), single .3 cm with
satellites, and multinodular plus diffuse. In this classication massive
tumors were included among single HCCs of .3 cm with or without
satellites, as appropriate. The degree of cellular anaplasia was dened
according to Edmondson and Steiner [26]. The size of HCC was measured
by ultrasonography and in patients with multiple lesions the diameter of the
largest node was utilized for statistics. The presence of portal or caval vein
thrombosis was dened according to the imaging technique work-up
including angiography in 64 patients. To detect distant metastases, patients
underwent chest X-ray and abdominal ultrasonography. Bone scintigraphy
and CT scans of the chest and brain were made when clinically indicated.
2.1. Statistical analysis
The results were expressed as the mean ^ standard deviation (SD) or
median and range. The statistical evaluation was performed by means of
MannWhitney U-test, x 2-test (with the Yates correction for dichotomous
variables), McNemar test, Wilcoxon matched-pairs signed-ranks test and
hierarchical log-linear models [27].
The ROC curve and the corresponding area under the curve were calcu-
lated to provide the accuracy of serum AFP in distinguishing HCC and CLD
patients [28]. Non-parametric estimates of the area under the ROC curve
and the respective standard error were applied [29]. The best cut-off value
was chosen as the value that maximized the likelihood ratio (LR) obtained
using the following formula: LR (probability of true positive1probabil-
ity of true negative)/(probability of false positive1probability of false nega-
tive) [30].
Since positive (PPV) and negative (NPV) predictive values depend on
the prevalence of the disease [31], these variables were evaluated not only
in our population but also considering three HCC prevalences (5, 10, and
20%) closer to a clinical setting [22,23,3236].
In HCC patients, stepwise logistic regression analysis was performed to
control simultaneously for age, sex, ALT, virological status, ChildPugh
class, cancer stage, vascular thrombosis and metastases in determining an
elevated AFP level (.20 ng/ml). Categorical variables were considered as
follows: HBsAg1/anti-HCV2, HBsAg2/anti-HCV1, HBsAg1/anti-
HCV1, and HBsAg2/anti-HCV2; HCC stage: single #3 cm, single .3
cm without satellites, single .3 cm with satellites, and multinodular plus
diffuse; vascular thrombosis: no/yes; metastases: no/yes. Edmondson's
grade was not included in this model to prevent a great reduction in the
sample size. In the subgroup of patients in whom Edmondson's grade was
available, an additional analysis was performed including this variable
(dichotomized as grades III and IIIIV), together with those signicantly
associated with an elevated AFP in the rst model.
All statistical evaluations were performed running the SPSS/PC1 statis-
tical package on a personal computer [37]. A two-tailed P value less than
0.05 was considered statistically signicant.
3. Results
The mean age was 60.2 ^ 8.9 years in HCC and
60.0 ^ 9.2 years in control patients.
HCC was solitary in 84 patients, multinodular in 63,
diffuse in 18 and massive in 5. HCC was single #3 cm in
23 patients, single .3 cm without satellites in 48, and single
.3 cm with satellites in 18. Edmondson's grade was speci-
ed in 91 cases (3 grade I, 37 grade II, 42 grade III, and 9
grade IV). Information on portal or caval thrombosis was
available in 149 HCC patients. Thrombosis was present in
572 F. Trevisani et al. / Journal of Hepatology 34 (2001) 570575

19 cases, 12 of them showing a multinodular or diffuse

HCC. Metastases were detected in 6 patients.
HCC was associated with a non-cirrhotic CLD (chronic
hepatitis or brosis) in 13 patients (7.6%) and with cirrhosis
in 157 patients (92.4%).
Twenty-seven HCC patients were HBsAg1/anti-HCV2,
103 were HBsAg2/anti-HCV1, 17 were HBsAg1/anti-
HCV1, and 23 were HBsAg2/anti-HCV2.
Information on alcohol intake was available in 157 HCC
and 128 control patients. Forty-eight HCC patients (30.6%)
and 38 control patients (29.7%) were heavy drinkers (.80
g/day of alcohol for at least 5 years) (P 0:238). Among
seronegative cases (HBsAg2/anti-HCV2), liver disease
was due to alcohol abuse in 13 HCC and 12 control patients,
while it was considered cryptogenic in the remainders.
The ChildPugh class was available in 150 HCC and 155
control individuals. An advanced cirrhosis was more
frequent in the latter (class A: 46.0 vs. 32.3%; class B:
40.0 vs. 33.5%; class C: 14.0 vs. 34.2%; P , 0:001). Plasma
ALT (76.1 ^ 57.2 vs. 70.7 ^ 55.1 IU/l, P 0:262), alka-
line phosphatase (246.2 ^ 132.0 vs. 287.7 ^ 561.7 IU/l,
Fig. 1. Receiver-operating characteristic (ROC) curve of serum AFP to
P 0:926), and PT (71.2 ^ 15.7 vs. 63.0 ^ 18.3, discriminate between patients with HCC and those with CLD. The area
P 0:051) did not signicantly differ. Conversely, HCC under the ROC curve was 0.819 ^ 0.023. The gure reports the best
patients showed higher levels of g-GT (99.0 ^ 117.3 vs. discriminating value between patients with or without HCC found in
79.5 ^ 100.5 IU/l, P 0:032) and albumin (3.54 ^ 0.49 our population (16 ng/ml), the limit above which investigations for this
vs. 3.37 ^ 0.65 g/dl, P , 0:001), and a lower bilirubin cancer are currently recommended (20 ng/ml), and three abnormal
values (100, 200, and 400 ng/ml).
(2.19 ^ 2.84 vs. 3.39 ^ 5.87 mg/dl, P 0:028).

3.1. AFP levels HCC prevalences. When the cut-off value of 20 ng/ml was
considered, the decline in cancer frequency had an impress-
Serum AFP was signicantly higher in HCC than control ive impact on the PPV, which fell to an estimated value of
patients (median 41 ng/ml (range 2100 000 ng/ml) vs. 6 25.1% at the lowest prevalence. The best PPV at the lowest
ng/ml (range 1450 ng/ml), P , 0:001). In the two groups, HCC prevalence was observed by using 200 ng/ml, which
AFP was .20 ng/ml in 60.0 and 9.4% of cases (P , 0:001), provided a correct allocation of two-thirds of cases. Each
respectively. cut-off value reached a good NPV (.90%) when a HCC
Fig. 1 depicts the ROC curve of AFP in the whole popu- prevalence of 10% was considered.
lation. The best discriminating value was 16 ng/ml, but both
sensitivity and specicity of 20 ng/ml were almost equiva- 3.2. Virological status and AFP
lent (Table 1). Therefore, 20 ng/ml was used as the best cut-
In each group, an elevated AFP (.20 ng/ml) was more
off for the analyses performed in patient subgroups. The
frequent in HCC than in control patients (HBsAg1/anti-
sensitivity of the other cut-off values was exceedingly low.
HCV2: 59.3 vs. 14.8%, P 0:004; HBsAg2/anti-
In HCC patients, ChildPugh class did not affect the
HCV1: 67.0 vs. 10.7%, P , 0:001; HBsAg1/anti-
probability of showing an elevated AFP (class A: 59.4%;
HCV1: 58.8 vs. 5.9%, P 0:004; HBsAg2/anti-HCV2:
class B: 61.7%; class C: 57.1%; P 0:995). The same was
30.4 vs. 0%, P 0:016).
true for the gross pathology of cancer (solitary: 52.4%;
multinodular: 69.8%; diffuse: 61.1%; massive: 60.0%; Table 1
P 0:205; single #3 cm: 52.2%; single .3 cm without Sensibility and specicity of ve serum levels of AFP for the diagnosis
satellites: 54.2%; single .3 cm with satellites: 50.0%; of HCC in the population under study a
multinodular plus diffuse: 67.9%; P 0:333) and Edmond-
AFP cut-off (ng/ml) Sensitivity (%) Specicity (%)
son's grade (grade III: 57.5%; grade IIIIV: 64.7%;
P 0:628). Finally, no correlation was found between 16 62.4 89.4
HCC diameter, available in 136 patients, and AFP elevation 20 60.0 90.6
(P 0:427). 100 31.2 98.8
200 22.4 99.4
Table 2 reports the PPV and NPV of the AFP cut-offs 400 17.1 99.4
obtained in our population, where the tumor prevalence was
a
50%, and those that were calculated for three additional AFP, a-fetoprotein; HCC, hepatocellular carcinoma.
 F. Trevisani et al. / Journal of Hepatology 34 (2001) 570575 573

Table 2 Table 4
PPV and NPV for the diagnosis of HCC of four serum levels of AFP PPV and NPV of serum AFP (20 ng/ml) for the diagnosis of HCC
calculated for our population (where the cancer prevalence was 50%) according to the virological status of patients a
and for three additional tumor prevalences a
Patients HCC prevalence (%) PPV (%) NPV (%)
AFP cut-off (ng/ml) HCC prevalence (%) PPV (%) NPV (%)
HBsAg1/anti-HCV2 50 80.0 67.6
20 50 84.6 69.4 20 50.0 89.3
20 61.4 90.1 10 30.8 95.0
10 41.5 95.3 5 17.4 97.5
5 25.1 97.7 HBsAg2/anti-HCV1 50 86.3 73.0
100 50 96.4 58.9 20 61.1 91.5
20 86.9 85.2 10 41.1 96.1
10 74.6 92.8 5 24.8 98.1
5 58.2 96.5 HBsAg1/anti-HCV1 50 90.9 69.6
200 50 97.4 56.1 20 71.4 90.1
20 90.5 83.7 10 52.6 95.4
10 80.9 92.0 5 34.5 97.7
5 66.7 96.1 HBsAg2/anti-HCV2 50 100.0 59.0
400 50 96.7 54.5 20 100.0 85.2
20 87.9 82.7 10 100.0 92.8
10 76.3 91.5 5 100.0 96.5
5 60.4 95.8 a
They were calculated for our population (cancer prevalence: 50%) and
a
PPV, positive predictive value; NPV, negative predictive value; HCC, for three additional tumor prevalences. PPV, positive predictive value;
hepatocellular carcinoma; AFP, a-fetoprotein. NPV, negative predictive value; AFP, a-fetoprotein; HCC, hepatocellular
carcinoma; HBsAg, hepatitis B surface antigen; anti-HCV, antibody to
hepatitis C virus.
Table 3 reports the sensitivity and specicity of AFP of
.20 ng/ml according to the virological status. The sensitiv- analysis, the model retained 139 HCC patients. In this
ity was higher in HBsAg2/anti-HCV1 patients model, only the ALT value was an independent predictor
(P 0:025) and lower in seronegative individuals of an elevated AFP level (P 0:001). In the additional
(P 0:011) as compared to the overall cohort. Conversely, model including ALT and Edmondson's grade (84 patients),
the specicity did not signicantly differ between the ALT remained the only independent predictor of abnormal
groups. AFP levels (P 0:007).
Table 4 shows the PPV and NPV of AFP of .20 ng/ml
evaluated at different tumor prevalences. In all three groups
of infected patients, PPV markedly decreased with the 4. Discussion
decline of tumor prevalence. On the contrary, in the group
of seronegative patients PPV did not change according to Serum AFP is the most widely used oncomarker for
cancer prevalence due to the lack of false positive cases. A suspecting HCC. In our population, AFP showed an accu-
fairly elevated NPV was seen in every group at each HCC racy of 82% and according to previous studies [38] 16 ng/ml
prevalence. was the best cut-off to identify HCC superimposed to CLD.
Nonetheless, we adopted 20 ng/ml as the best cut-off since
3.3. Stepwise logistic regression analysis this value had an equivalent sensitivity and specicity, and
it is currently considered the limit above which investiga-
When age, sex, ALT, virological status, ChildPugh tions for HCC are needed [19,20].
class, cancer stage, vascular thrombosis and metastases This cut-off had a rather good specicity but a low sensi-
were simultaneously checked in the logistic regression tivity. However, attention should be paid to predictive
values which help the physician in clinical practice more
Table 3
Sensitivity and specicity of serum AFP of .20 ng/ml for the diagnosis than the specicity and sensitivity. In our population, the
of HCC according to the virological status of patients a NPV of AFP (indicating the probability that an individual
with a normal serum AFP is free from HCC) was unsatis-
Patients (n) Sensitivity (%) Specicity (%)
factory. It should be pointed out that predictive values are
HBsAg1/anti-HCV2 (27) 59.3 85.2 critically inuenced by the prevalence of the disease [31]
HBsAg2/anti-HCV1 (103) 67.0* 89.3 and in our case-control study the HCC prevalence was much
HBsAg1/anti-HCV1 (17) 58.8 94.1 greater (50%) than that expected in a clinical setting. We
HBsAg2/anti-HCV2 (23) 30.4** 100.0 therefore calculated the predictive values for cancer
a
AFP, a-fetoprotein; HCC, hepatocellular carcinoma; HBsAg, hepatitis frequencies matching those found in clinical practice
B surface antigen; anti-HCV, antibody to hepatitis C virus. *P 0:025 and [22,23,3236]. With a HCC prevalence of 5% the NPV
**P 0:011 vs. the overall sensitivity (hierarchical log-linear models). became very high (about 98%), suggesting that most
574 F. Trevisani et al. / Journal of Hepatology 34 (2001) 570575
patients with normal AFP are correctly allocated to the
group without cancer. Unfortunately, the clinical usefulness
of this prediction is diminished by the low sensitivity of
AFP. In fact, although false negative cases were a minimal
percentage of the patients with normal AFP, they accounted
for 40% of all HCC cases (Table 1). This conrms the poor
efciency as a `screening test' demonstrated by AFP in
prospective studies [8,19,32,36,39].
Another important pitfall of this AFP cut-off was the
unacceptably low PPV (that is, the probability that a patient
with an abnormal AFP has HCC), which fell to 25% at the
lowest cancer prevalence. This gure is close to that
reported in a prospective study on cirrhotic patients by
using the cut-off value of 15 ng/ml [8]. Therefore, AFP
monitoring alone in patients with CLD would lead to suspi-
cion of malignancy in a high proportion of individuals with-
out cancer, inappropriately eliciting stressful and expensive
investigations in three out of four cases with elevated AFP.
In this respect, 200 ng/ml was the best cut-off value, yield-
ing a correct allocation into the neoplastic group of two-
thirds of patients with an elevated AFP. However, the use
of this cut-off value as a screening test cannot be recom-
mended because almost 80% of HCC would be missed. Our
ndings strengthen the suggestion that the use of AFP as a
screening test for HCC in CLD patients should be aban-
doned [19].
Serum AFP is also utilized as a `conrmatory test' to
discriminate HCC from other solid lesions of the liver.
The levels of 200 [8,21] and 400 ng/ml [22,23] are
commonly utilized for this purpose. In our population, not
only these values but also 100 ng/ml showed a very high
specicity, indicating that even 100 ng/ml could be conr-
matory for HCC. However, this assumption needs to be
veried through studies in which the control group is
formed by CLD patients with hepatic nodules other than
HCC.
Previous studies have suggested that the etiology of liver
disease inuences the probability of nding an abnormal
AFP in HCC patients, but they did not analyze the impact
of these ndings in HCC diagnosis [9,14,15,40]. Moreover,
data denying the inuence of etiology in AFP utility have
also been produced [1618]. The distribution of the different
etiologic groups found in our study was similar to that
reported by a recent large multicentric Italian study [15].
We found that the sensitivity of an elevated AFP (.20
ng/ml) reached the lowest value in patients without viral
infection, owing to the very low proportion (30%) of secret-
ing HCCs. Similar ndings have been obtained in serone-
gative non-Caucasian patients [14,16] and Italian alcoholic
patients [40], who frequently have normal AFP at the time
of HCC detection. A precise explanation for this phenom-
enon is not available. It is worth noting, however, that the
only independent predictor of an AFP elevation in our study
was the ALT level, and seronegative individuals showed
signicantly lower ALT values than the remaining groups
taken together (43.6 ^ 30.1 vs. 81.4 ^ 58.8 IU/l,
P , 0:001). Since ALT levels are surrogate markers of
CLD activity, which can stimulate the `non-tumoral' secre-
tion of AFP [10,11,19,20], it is conceivable that a feeble
extratumoral production contributed to abate the sensitivity
of AFP in seronegative patients. This may also explain the
absence of false positive cases, which rose to 100% both
specicity and PPV. Such gures would indicate that an
AFP rise in non-viral CLD patients may be considered
highly indicative of HCC occurrence. However, owing to
the low number of seronegative individuals, our results need
to be conrmed in a larger series.
The best sensitivity of AFP found in anti-HCV1/
HBsAg2 supports the association between HCV infection
and AFP elevation previously reported in HCC patients
[14,15]. The greater propensity to produce AFP by these
patients does not have an explanation. It cannot be attributed
to a higher activity of the underlying CLD since ALT levels
did not differ among the three groups of infected patients
(KruskalWallis test: P 0:293, data not shown).
Lastly, the kind of viral infection did not greatly affect the
predictive values at any HCC prevalence, and the PPV
became unacceptably low in all infected patients when a
clinical setting was simulated. We may conclude that
among patients with viral CLD, the type of infection does
not inuence the clinical usefulness of AFP.
In conclusion, our study showed that in patients with CLD
(1) the AFP value of 20 ng/ml, above which investigations for
HCC are currently recommended, has a discriminating
power almost equivalent to the best cut-off (16 ng/ml), (2)
the diagnostic efciency of AFP is poor, dampening its use as
a screening test for HCC detection in fact, AFP monitoring
alone allows many tumors to escape identication and
arouses the suspicion of malignancy in too many patients
without cancer, unnecessarily increasing medical costs and
patient anxiety, (3) the specicity of 100 ng/ml AFP is high,
making it advisable to assess the role of this cut-off value as a
conrmatory test for HCC, (4) the predictive values, which
are the most helpful parameters in clinical practice, are barely
affected by the kind of viral infection responsible for the
underlying liver disease, and (5) an elevated AFP could be
more indicative of HCC in non-infected than infected
patients.
References
[1] World Health Organization. 1994 World Health Statistics Annual.
Geneva: WHO, 1995.
[2] Bruix J. Treatment of hepatocellular carcinoma. Hepatology
1997;25:5962.
[3] Collier J, Sherman M. Screening for hepatocellular carcinoma. Hepa-
tology 1998;27:273278.
[4] Kuromatsu R, Tanaka M, Tanikawa K. Serum alpha-fetoprotein and
lens culinaris agglutinin-reactive fraction of alpha-fetoprotein in
patients with hepatocellular carcinoma. Liver 1993;13:177182.
[5] Sato Y, Nakata K, Kato Y, Shima M, Ishii N, Koji T, et al. Early
recognition of hepatocellular carcinoma based on altered proles of
alpha-fetoprotein. N Engl J Med 1993;328:18021806.
 F. Trevisani et al. / Journal of Hepatology 34 (2001) 570575
[6] Takahashi H, Saibara T, Iwamura S, Tomita A, Maeda T, Onishi S, et
al. Serum alpha-l-fucosidase activity and tumor size in hepatocellular
carcinoma. Hepatology 1994;19:14141417.
[7] Giardina MG, Matarazzo M, Morante R, Lucariello A, Varriale A,
Guardasole V, et al. Serum a-l-fucosidase activity and early detec-
tion of hepatocellular carcinoma. A prospective study of patients with
cirrhosis. Cancer 1998;83:24682474.
[8] Pateron D, Ganne N, Trinchet JC, Aurousseau MH, Mal F, Meicler C,
et al. Prospective study of screening for hepatocellular carcinoma in
Caucasian patients with cirrhosis. J Hepatol 1994;20:6571.
[9] Lee HS, Chung YH, Kim CY. Specicities of serum a-fetoprotein in
HBsAg1 and HBsAg2 patients in the diagnosis of hepatocellular
carcinoma. Hepatology 1991;14:6872.
[10] Liaw YF, Tai DI, Chen TJ, Chu CM, Huang MJ. Alpha-fetoprotein
changes in the course of chronic hepatitis: relation to bridging hepatic
necrosis and hepatocellular carcinoma. Liver 1986;6:133137.
[11] Chen DS, Sung JL. Relationship of hepatitis B surface antigen to
serum alpha-fetoprotein in nonmalignant diseases of the liver. Cancer
1979;44:984992.
[12] Okuda K, Peters RL, Simson IW. Gross anatomic features of hepato-
cellular carcinoma from three disparate geographic areas. Proposal of
new classication. Cancer 1984;54:21652173.
[13] Tiribelli C, Melato M, Croce LS, Giarelli L, Okuda K, Ohnishi K.
Prevalence of hepatocellular carcinoma and relation to cirrhosis:
comparison of two different cities of the world Trieste, Italy, and
Chiba, Japan. Hepatology 1989;10:9981002.
[14] Tsai JF, Chang WY, Jeng JE, Ho MS, Lin ZY, Tsai JH. Frequency of
raised a-fetoprotein level among Chinese patients with hepatocellular
carcinoma related to hepatitis B and C. Br J Cancer 1994;69:1157
1159.
[15] Stroffolini T, Andreone P, Andriulli A, Ascione A, CraxI A, Chiar-
amonte M, et al. Characteristics of hepatocellular carcinoma in Italy. J
Hepatol 1998;29:944952.
[16] Kew MC, Houghton M, Choo QL, Kuo G. Hepatitis C virus antibo-
dies in southern African blacks with hepatocellular carcinoma. Lancet
1990;335:873874.
[17] Saitoh S, Ikeda K, Koida I, Tsubota A, Arase Y, Chayama K, et al.
Serum des-gamma-carboxyprothrombin concentration determined by
avidin-biotin complex method in small hepatocellular carcinomas.
Cancer 1994;74:29182923.
[18] Hwang SJ, Tong MJ, Lai PPC, Ko ES, Co RL, Chien D, et al. Evalua-
tion of hepatitis B and C viral markers: clinical signicance in Asian
and Caucasian patients with hepatocellular carcinoma in the United
States of America. J Gastroenterol Hepatol 1996;11:949954.
[19] Sherman M, Peltekian KM, Lee C. Screening for hepatocellular carci-
noma in chronic carriers of hepatitis B virus: incidence and preva-
lence of hepatocellular carcinoma in a north American urban
population. Hepatology 1995;22:432438.
[20] Trevisani F, D'Intino PE, Caraceni P, Pizzo M, Stefanini GF,
Mazziotti A, et al. Etiologic factors and clinical presentation of hepa-
tocellular carcinoma. Difference between cirrhotic and noncirrhotic
Italian patients. Cancer 1995;75:22202232.
[21] Associazione Italiana per lo Studio del Fegato. Epatocarcinoma.
Linee guida per la diagnosi e la terapia. Bologna: Tipograa Moderna,
1998.
[22] Colombo M, De Franchis R, Del Ninno E, Sangiovanni A, De Fazio
C, Tommasini M, et al. Hepatocellular carcinoma in Italian patients
with cirrhosis. N Engl J Med 1991;325:675680.
[23] Borzio M, Bruno S, Roncalli M, Colloredo Mels G, Ramella G,
575
Borzio F, et al. Liver cell dysplasia is a major risk factor for hepato-
cellular carcinoma in cirrhosis: a prospective study. Gastroenterology
1995;108:812817.
[24] Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R.
Transection of the oesophagus for bleeding oesophageal varices. Br J
Surg 1973;60:646649.
[25] Trevisani F, Caraceni P, Bernardi M, D'Intino PE, Arienti V, Amorati
P, et al. Gross pathologic types of hepatocellular carcinoma in Italian
patients. Relationship with demographic, environmental and clinical
factors. Cancer 1993;72:15571563.
[26] Edmondson HA, Steiner PE. Primary carcinoma of the liver. A study
of 100 cases among 48,900 necropsies. Cancer 1954;7:462503.
[27] Siegel S. Non-parametric statistics for the behavioral sciences. New
York: McGraw-Hill, 1956.
[28] Zweig MH, Campbell G. Receiver-operating characteristic (ROC)
plots: a fundamental evaluation tool in clinical medicine. Clin
Chem 1993;39:561577.
[29] Hanley JA, McNeil BJ. The meaning and use of the area under a
receiver operating characteristic (ROC) curve. Radiology
1982;143:2936.
[30] Pezzilli R, Morselli-Labate AM, Miniero R, Barakat B, Fiocchi M,
Cappelletti O. Simultaneous serum assays of lipase and interleukin-6
for early diagnosis and prognosis of acute pancreatitis. Clin Chem
1999;45:17621767.
[31] Komaroff AL, Berwick DM. Decision theory and medical practice.
In: Isselbacher KJ, Adams RD, Braunwald E, Pedersdorf RG, Wilson
JD, editors. Principles of internal medicine. Update IV, New York:
McGraw-Hill, 1983. pp. 243254.
[32] Cottone M, Turri M, Caltagirone M, Maringhini A, Sciarrino E,
Virdone R, et al. Early detection of hepatocellular carcinoma asso-
ciated with cirrhosis by ultrasound and alfafetoprotein: a prospective
study. Hepatogastroenterology 1988;35:101103.
[33] Imberti D, Fornari F, Sbolli G, Buscarini E, Squassante L, Buscarini
L. Hepatocellular carcinoma in liver cirrhosis. A prospective study.
Scand J Gastroenterol 1993;28:540544.
[34] Propst T, Propst A, Dietze O, Judmaier G, Braunsteiner H, Vogel W.
Prevalence of hepatocellular carcinoma in alpha-1-antitrypsin de-
ciency. J Hepatol 1994;21:10061011.
[35] Curley SA, Izzo F, Gallipoli A, de Bellis M, Cremona F, Parisi V.
Identication and screening of 416 patients with chronic hepatitis at
high risk to develop hepatocellular carcinoma. Ann Surg
1995;222:375383.
[36] Zoli M, Malagotti D, Bianchi G, Gueli C, Marchesini G, Pisi E.
Efcacy of surveillance program for early detection of hepatocellular
carcinoma. Cancer 1996;78:977985.
[37] Norusis MJ. SPSS Inc. SPSS/PC1. Base system and advanced statis-
tics, version 5.0. Chicago, IL: SPSS, 1992.
[38] Bayati N, Silverman AL, Gordon ST. Serum alpha-fetoprotein levels
and liver histology in patients with chronic hepatitis C. Am J Gastro-
enterol 1998;93:24522456.
[39] Shinagawa T, Ohto M, Kimura K, Tsunetomi S, Morita M, Saisho H,
et al. Diagnosis and clinical features of small hepatocellular carci-
noma with emphasis on the utility of real-time ultrasonography. A
study in 51 patients. Gastroenterology 1984;86:495502.
[40] Fasani P, Sangiovanni A, De Fazio C, Borzio M, Bruno S, Rochi G, et
al. High prevalence of multinodular hepatocellular carcinoma in
patients with cirrhosis attributable to multiple risk factors. Hepatol-
ogy 1999;29:17041707.