Journal of Hepatology 34 (2001) 603±605
www.elsevier.com/locate/jhep
Editorial
Alphafetoprotein: an obituary
Morris Sherman
University of Toronto, Toronto, ON, Canada
Toronto General Hospital, EN9-223200 Elizabeth Street, Toronto, Canada, ON, MSG 2C4
See Article, pages 570±575
The use of alphafetoprotein (AFP) serum concentration as
a diagnostic test for hepatocellular carcinoma (HCC) has a
long and venerable history. This use arose from the ®nding
that some HCC's secreted massive amounts of AFP. In
some instances the serum concentration exceeded 1 mg/ml
(reviewed in [1]). This was in an era before the availability
ultrasonography and CT scanning. When a patient presented
with jaundice or a mass in the right upper quadrant a posi-
tive AFP test, particularly when the concentration was more
than about 500 ng/l, was diagnostic, and obviated the need
for further invasive investigations, such as hepatic angiogra-
phy or diagnostic laparotomy.
The advent of sophisticated abdominal imaging techni-
ques directly in¯uenced the usefulness of AFP as a diagnos-
tic test in two ways. First, it was recognized that a signi®cant
proportion of HCC's identi®ed by imaging did not secrete
diagnostic levels of AFP. Second, the use of imaging and the
emergence of programs for early detection of HCC meant
that AFP levels in the range of mg/ml were now seldom
seen. These changes have made the use of AFP controver-
sial, whether AFP was used as a diagnostic test or for HCC
screening. In this issue of the Journal Dr Trevisani and
colleagues [2] address the issue of the value of AFP as a
diagnostic test for HCC.
There are several measures which can be used to gauge
the ef®ciency of a test such as the AFP. The simplest
measures are the sensitivity, speci®city, and positive and
negative predictive values. To remind readers, the sensitiv-
ity is a measure of the proportion of positive tests in patients
with the disease, whereas speci®city measures the propor-
tion of negative tests in patients without the disease. These
measurements are independent of prevalence of the disease,
and are inversely related to each other. As sensitivity
increases, speci®city decreases and vice versa. However,
the true-positive or true-negative rate of a test is also depen-
dent on the prevalence of the disease it purports to detect. If
a disease is infrequent in a population even a test with a high
degree of speci®city will produce a high proportion of false
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positives. The effect of disease prevalence on sensitivity and
speci®city is captured by the positive and negative predic-
tive values. The positive predictive value (PPV) is a
measurement of the frequency with which a positive result
is a true positive. Conversely, the negative predictive value
is a measure of the proportion of all negative results that are
true negatives. Although sensitivity and speci®city are
inversely related, the ratios are different for different tests
and in different diseases. This variation can be expressed by
the Youden Index, which is [sensitivity 1 speci®city]-1.
Thus a test which is highly speci®c and highly sensitive
will have a high Youden index. One study [3], for example,
found that the Youden index for an AFP .20 ng/ml in HCC
was only about 0.45, which is low.
Finally the test being evaluated could provide its output
as a dichomotous variable (positive or negative), or as a
continuous variable (range of values), in which case it is
important to determine the test value which provides least
error, i.e. the fewest false negatives and false positives. This
is achieved by using the receiver operating characteristic
(ROC) curve. This is a graph of sensitivity vs. 1-speci®city,
plotted over the whole range of values of the test.
Dr Trevisani and his colleagues have studied patients
with HCC and cirrhosis due to chronic viral hepatitis to
determine the performance characteristics of alphafetopro-
tein as a diagnostic/screening test for HCC. Although this is
a retrospective study it has three major strengths. First, the
study cohort was matched with a similar cohort with equiva-
lent severity of liver disease, but who did not develop HCC.
This is crucial to the proper evaluation of AFP as a diag-
nostic test. Second, the performance characteristics of AFP
were studied over the whole range of values obtained, and
third, the results were analyzed using proper tools, such as
those described above, both for their experimental popula-
tions, and for hypothetical populations more representative
of those seen in most liver clinics. Their unequivocal
conclusion is that AFP is not a good diagnostic test to detect
HCC.
604 M. Sherman / Journal of Hepatology 34 (2001) 603±605
Dr Trevisani and colleagues [2] have constructed an
ROC for AFP as a diagnostic test in their population.
From their data, the point at which fewest classi®cation
errors occurred was an AFP of 16±20 ng/l. However at
this level the sensitivity was only 0.6, although the speci-
®city was about 0.9. This means that if 16±20 ng/l is used
as the cut-off for diagnosis 40% of all HCC's in a similar
population (e.g. cirrhotic patients) will not detected. This is
in a population with known HCC. In a population not
known to have HCC (e.g. a surveillance population) the
performance characteristics of AFP will likely be worse.
Clearly then, AFP is not an adequate diagnostic test. As
their Fig. 1 shows, if a higher cut-off is used a progres-
sively smaller proportion of HCC's will be detected.
Conversely, reducing the cut-off means that more HCC's
would be identi®ed, but at the cost of a progressive
increase in the false-positive rate.
This analysis was performed in a cohort of patients in
whom the prevalence of HCC was arti®cially set at 50%
(equal sizes of experimental and control populations).
Data are also provided for lower HCC prevalence rates,
more like those seen in most liver clinics. We should note
however, that in following patients with chronic liver
disease we are more interested in incidence rates than preva-
lence rates. In clinics the incidence of HCC in cirrhotic
patients may range from about 1±5%/year. Since Dr Trevi-
sani's study was retrospective we cannot accurately infer
how well AFP will perform when the HCC incidence is in
the range usually seen in clinics, but we can conclude that
the performance characteristics are likely to be similar or
worse. Furthermore, in cohorts undergoing surveillance for
HCC the incidence of HCC may be even lower than 1±5%,
depending on the criteria for entry into surveillance. For
example, in adult non-cirrhotic hepatitis B carriers infected
at birth the incidence of HCC is usually less than 1% [4,5].
Trevisani et al. [2] also show that the underlying cause of
the cirrhosis, whether hepatitis B or hepatitis C does not
in¯uence the performance characteristics of AFP.
If AFP is such a poor diagnostic test does it have any role
at all in the management of patients with chronic liver
disease? There remain two possible circumstances in
which one might consider the use of AFP. One is as a
surveillance test in asymptomatic patients with chronic
liver disease, and second, as a con®rmatory test in patients
who are already suspected of having HCC by virtue of a
mass found on ultrasonography. The value of AFP as a
surveillance test has been evaluated previously by ourselves
and many others [6±9]. Most investigators have documented
that the sensitivity and speci®city and PPV are similar to
that found by Dr Trevisani.
The case for the use of AFP as a surveillance tool has
been made by McMahon et al. [10] based on data from their
ongoing surveillance program in the Alaskan Native popu-
lation. This population does not have access to routine ultra-
sonography. In their cohort of hepatitis B carriers they found
that the sensitivity and speci®city of AFP as a surveillance
test were 94.1 and 99.9%, respectively [11]. The PPV was
5%. AFP surveillance is currently performed using a dried
spot of blood on a ®lter paper [12]. All positives are referred
to Anchorage for investigation. In the latest report from this
cohort the survival of patients in the screened cohort who
developed HCC was compared to a historical cohort, which
was not screened [12]. Survival in the screened cohort was
better than in the historical cohort. The authors have taken
these results to be evidence that AFP screening is useful.
Unfortunately, design ¯aws in this study preclude accepting
this notion. Comparison with a historical cohort is always
dubious, because of improvements in therapy over time.
Second, lead-time bias can account for all the apparent
improved survival. Essentially, the authors were comparing
survival of a cohort in whom the disease was discovered
early with a cohort in which the disease was discovered at a
later stage. The difference in timing of diagnosis alone
means that there will be an apparent prolongation of survi-
val, even if the intervention is completely ineffective.
Our experience of AFP as a surveillance tool [6] and that
of others [7±9] using ultrasound in addition to AFP has been
different. In at least three studies in which it was clear that
the AFP was being used as a screening test rather than a
diagnostic test, the sensitivity of AFP was between 39 and
64%, with a speci®city of 76±91% and the PPV was
between 9 and 32% [6±8].
Over the last 10 years of our program we have identi®ed
more than 70 HCC's in a cohort of hepatitis B carriers. In
only one instance were we alerted to HCC by a progres-
sively rising AFP while the ultrasound and CT scan were
negative. This was 10 years ago, before spiral CT scanning,
and before the current generation of ultrasound equipment.
The diagnosis was made by angiography. Since then, AFP
testing has not identi®ed any cases that did not also have a
mass on ultrasound (unpublished data).
Even the combined use of AFP and US is dubious. Yang
et al. [9] compared the use of AFP and ultrasound (US)
alone and in combination in a large screening study, invol-
ving nearly 20 000 subjects. This study has been running for
about 5 years now. Adding the two tests together paradoxi-
cally increases the false-positive rate from about 3% with
US alone to 7.5% [13]. The gain in sensitivity is about 8%.
The PPV is worst when both tests are used (3.0%) compared
to US (6.6%) or AFP (3.3%) used alone. This is also the
most expensive regimen, expressed as cost/tumour found.
Whether the increase in sensitivity is worth the deterioration
which occurs in all other aspects of testing is not clear.
There are two circumstances were AFP might be elevated
due to HCC, yet imaging might be negative. This can occur
when the lesion is too small to be detected on US or CT, or
because the lesion is diffusely in®ltrating, with no clear
margins between normal liver and tumour. If the lesion is
too small to be seen on imaging, it also is too small to be
treated. If the lesion is diffusely in®ltrating it is not suitable
for curative therapy. When you also consider that there is no
de®nite evidence that outcome is different if the lesion is
 M. Sherman / Journal of Hepatology 34 (2001) 603±605
treated when it is e.g. 1 cm in diameter vs. 2 cm the value of
early detection by AFP becomes harder to see.
Therefore, I conclude that the use of AFP as a surveil-
lance test can no longer be justi®ed, and it should be
dropped from surveillance protocols, except where ultraso-
nography is either not available, or of such poor quality that
lesions less than e.g. 2 cm will not be detected.
Trevisani et al. [2] suggest that in cirrhotic patients in
whom a liver mass has been discovered an AFP of more
than about 100 ng/ml is highly speci®c for HCC. They
appropriately caution that their study did not have the
correct controls to be certain of this conclusion. However,
if con®rmed, these results indicate that the correct use of
AFP is as a con®rmatory test. Under these circumstances
AFP could be a very useful test, since imaging techniques
don't always distinguish between cirrhotic macronodules,
dysplastic nodules and HCC.
In summary, I believe that time has come to bid a fond
adieu to AFP as a test for HCC diagnosis and particularly for
HCC surveillance. AFP will hopefully still be with us, but in
another guise, as a con®rmatory test in patients in whom
HCC is already suspected.
References
[1] Kew MC. Alpha-fetoprotein. In: Read AE, editor. Modern trends in
gastroenterology, vol. 5. London: Butterworths, 1975. p. 91.
[2] Trevisani F, D'Intino PE, Morselli-Labate AM, Mazzella G, Accogli
E, Caraceni P, et al. Serum a-fetoprotein for diagnosis of hepatocel-
lular carcinoma in patients with chronic liver disease: in¯uence of
HBsAg and anti-HCV status. J Hepatol 2001;34:570±575.
[3] Ishii M, Gama H, Chida N, Ueno Y, Shinzawa H, Takagi T, et al.
Simultaneous measurements of serum alpha-fetoprotein and protein
605
induced by vitamin K absence for detecting hepatocellular carcinoma.
Am J Gastroenterol 2000;95:1036±1040.
[4] Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carci-
noma and hepatitis B virus: a prospective study of 22 700 men in
Taiwan. Lancet 1981;2:1129±1133.
[5] Liaw YF, Tai DI, Chu CM, Lin DY, Sheen IS, Chen TJ, et al. Early
detection of hepatocellular carcinoma in patients with chronic type B
hepatitis. Gastroenterology 1986;90:263±266.
[6] 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;22:432±438.
[7] 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 Hepatology 1994;20:65±71.
[8] Oka H, Tamori A, Kuroki T, Kobayashi K, Yamamoto S. Prospective
study of alpha-fetoprotein in cirrhotic patients monitored for devel-
opment of hepatocellular carcinoma. Hepatology 1994;19:61±66.
[9] Yang B, Zhan B, Xu Y, Wang W, Wu M, Yu LY, et al. Prospective
study of early detection for primary liver cancer. J Cancer Res Clin
Oncol 1997;123:357±360.
[10] McMahon BJ, Alberts SR, Wainwright RB, Bulkow L, Lanier AP.
Hepatitis B-related sequelae. Prospective study of 1400 hepatitis B
surface antigen-positive Alaska native carriers. Arch Intern Med
1990;150:1051±1054.
[11] McMahon BJ, Wainwright RW, Lanier AP. The Alaska Native HCC
Screening Program: a population-based screening program for hepa-
tocellular carcinoma. In: Tabor E, Di Bisceglie AM, Purcell RH,
editors. Etiology, pathology and treatment of hepatocellular carci-
noma in North America, Houston: Gulf Publishing Company, 1990.
pp. 231±242.
[12] McMahon BJ, Bulkow L, Harpster A, Snowball M, Lanier A, Sacco
F, et al. Screening for hepatocellular carcinoma in Alaska natives
infected with chronic hepatitis B: a 16-year population-based study.
Hepatology 2000;32:842±846.
[13] Zhang B, Yang B. Combined alpha fetoprotein testing and ultrasono-
graphy as a screening test for primary liver cancer. J Med Screen
1999;6:108±110.