Open Journal of Gastroenterology, 2013, 3, 49-54 OJGas Published Online February 2013 (
Alpha-fetoprotein testing for hepatocellular carcinoma
may not be helpful in nonalcoholic steatohepatitis
Linda L. Wong1,2*, Christopher J. Kim2, Sandi A. Kwee3,4, Brenda Y. Hernandez3
1University of Hawaii Cancer Center, Honolulu, USA
3Department of Surgery, University of Hawaii, John A. Burns School of Medicine, Honolulu, USA
2Department of Medicine, University of Hawaii, John A. Burns School of Medicine, Honolulu, USA
4PET Imaging Research, University of Hawaii, Honolulu, USA
Email: *
Received 21 October 2012; revised 22 November 2012; accepted 30 November 2012
Background & Objectives: Diagnosing hepatocellular
carcinoma (HCC) often utilizes serum tumor markers.
Although the most commonly used tumor marker in
clinical practice, alpha-fetoprotein (AFP) is not in-
cluded in recent guidelines for diagnosing HCC. The
overall performance characteristics of AFP as a tu-
mor marker is viewed as insufficiently sensitive or
specific. The diagnostic value of AFP specifically in
nonalcoholic steatohepatitis (NASH) related HCC is
unknown. We aimed to determine the utility of AFP
testing in NASH-related HCC. Methods: Retrospec-
tive review of 737 HCC patients referred from 1993-
2011 to a single facility treating the majority of chronic
liver disease in Hawaii. HCC was diagnosed histologi-
cally by percutaneous biopsy, liver biopsy at the time
of surgery, or examination of the resected liver. Pa-
tients were classified according to HCC risk factors
including NASH, hepatitis B and C infection, and
alcohol-related. Other data collected included: demo-
graphics, ethnicity, presence of cirrhosis, tumor char-
acteristics (size, number, vascular invasion), diabetes,
hyperlipidemia, body mass index (BMI) and blood
testing to calculate Model for End-Stage Liver Dis-
ease (MELD) score. Elevated AFP was defined as >20
ng/mL. Sensitivity of AFP was determined and com-
pared between various subgroups. Results: Elevated
AFP levels were detected in 64.3% of patients. AFP
sensitivity was 47% for NASH-related HCC (n = 100),
and 67.2% for HCC with viral or alcoholic risk fac-
tors (n = 637) (OR 0.43, 95% CI 0.28 - 0.66, p =
0.0001). Elevated AFP had higher sensitivity in fe-
males (71.9% vs. 61.8%, OR 1.58, 95% CI 1.1 - 2.27,
p = 0.013), non-diabetics (67.4% vs. 57.2%, OR 0.65,
95% CI 0.47 - 0.89, p = 0.0093), and cirrhotics (67.1%
vs. 56.8%, OR 1.55, 95% CI 1.10 - 2.19, p = 0.0012).
AFP did not vary significantly with regard to hyper-
lipidemia or BMI. AFP was more sensitive in advanced
disease including tumors > 5 cm, multiple tumors, or
vascular invasion (all with p < 0.05). AFP did not
vary with MELD score. Conclusions: Normal AFP is
common in NASH-related HCC. Better tumor mark-
ers may be needed to optimally screen and diagnose
NASH-related HCC. Without more effective tumor
markers, HCC detection relies heavily upon imaging
and liver biopsy.
Keywords: Hepatocellular Cancer; Nonalcoholic
Steatohepatitis; Alpha-Fetoprotein
Primary liver cancer is the fifth most common cancer
worldwide, and the third leading cause of cancer death.
HCC is the major histologic subtype among primary
liver cancers. Endemic areas of HCC include Southeast
Asia and sub-Saharan Africa [1]. In areas of low preva-
lence including North America and Europe, HCC inci-
dence is rising [2,3]. In the United States, HCC had the
highest increase in mortality, and second highest increase
in incidence, of all cancers between 1995 and 2004 [4].
Chronic liver disease and cirrhosis are primary risk
factors for HCC. Chronic viral infection with hepatitis B
(HBV), hepatitis C (HCV), and alcoholic injury, are the
predominant causes of liver disease [5]. In the United
States, HBV rates are lower, whereas HCV is associated
with 70% of HCC [6,7]. However, 15% - 50% of HCC
cases are non-viral and non-alcohol related and classified
as cryptogenic [7-9].
Metabolic disease including obesity, diabetes mellitus,
and hyperlipidemia, are associated with non-viral and
non-alcohol related HCC [7]. Perhaps a hepatic manifes-
tation of metabolic disease, non-alcoholic fatty liver dis-
ease (NAFLD) is the most common liver disease in the
*Corresponding author.
L. L. Wong et al. / Open Journal of Gastroenterology 3 (2013) 49-54
United States [10]. Characterizing a disease spectrum
including simple steatosis, NASH, cirrhosis, and end-
stage liver disease (ESLD), NAFLD may progress to
HCC, and account for a substantial portion of crypto-
genic HCC [11,12].
Diagnosing HCC utilizes liver imaging, histopathol-
ogic evaluation, and tumor markers. Screening for HCC
commonly uses liver ultrasound (US) and measuring
AFP. Abnormal screening findings prompt diagnostic
imaging with contrast-enhanced computed tomography
(CT) and/or magnetic resonance imaging (MRI). Liver
biopsy is used in scenarios with diagnostic ambiguity.
AFP is a glycoprotein which is normally produced by
the fetal liver, yolk sac, and the gastrointestinal tract.
Although it is most commonly elevated in HCC, eleva-
tions in serum AFP can be seen in various malignancies
including testicular, bile duct, pancreatic, stomach, and
colon cancer. Elevated AFP can also seen with non-ma-
lignant conditions including hepatitis and cirrhosis [13].
AFP is the most commonly used tumor marker for
HCC in clinical practice. It is easily obtainable and rela-
tively inexpensive. However, recent guidelines do not
include AFP in the diagnostic algorithm because of its
overall sensitivity or specificity for HCC [14]. Defining
an elevated AFP level > 20 ng/mL, confers a sensitivity
of 60% and specificity of 80%. At a cut-off AFP level >
200 ng/mL, specificity approaches 100%, but sensitivity
falls to 20% [15]. Yet, these performance characteristics
for AFP are based largely upon studies of patients with
chronic viral hepatitis developing HCC. Adding to the
uncertain diagnostic utility of AFP has been the observa-
tion that a significant number of small HCCs do not se-
crete AFP.
Although AFP has long been used as tumor marker for
HCC, it is increasingly viewed to be unnecessary in a
contemporary role for diagnosis. Part of the reason for
this change is likely due to improvements in diagnostic
imaging. Another possibility may be the changing preva-
lence of chronic viral disease to fatty liver disease as the
cause of chronic liver disease and HCC development.
However, it is unclear whether there is a significant cor-
relation between AFP and the development of HCC spe-
cifically in the setting of NASH. The purpose of this
study is to compare the frequency of elevated AFP with
various risk factors, and estimate the relative diagnostic
utility of AFP in NASH-related HCC.
This is a retrospective analysis of 737 HCC cases re-
ferred to a Liver Center affiliated surgical group (LW) at
Hawaii Medical Center-East (formerly St. Francis Medi-
cal Center) from 1993-2011. This medical center was a
tertiary center and sole clinic dedicated to liver diseases
in Hawaii, the only liver transplant center in the State,
and the primary referral center for hepatobiliary surgery
for American territories of the Pacific Basin (including
American Samoa, Guam, Saipan, and the Marshall Is-
lands). Additionally, a number of patients were foreign
nationals from Asian countries, including China, Japan,
Korea, and the Philippines, who sought medical care in
the United States. This center managed approximately
60% - 70% of HCC cases in the State of Hawaii.
HCC was diagnosed histologically by percutaneous
biopsy, liver biopsy at the time of surgery, or examina-
tion of the resected liver. Consistent with the United
Network for Organ Sharing (UNOS) policy regarding
transplant for HCC, patients without histologic confir-
mation were diagnosed with HCC if they had chronic
liver disease and a liver lesion 2 cm in size on two im-
aging studies (US, CT, or MRI) and one of the following:
1) vascular blush on CT or MRI 2) AFP > 200 ng/ml, or
3) arteriogram confirming the tumor [16].
The clinical presentation (i.e. reasons for referral and
clinical workup leading to the diagnosis of HCC) for
each patient were categorized as 1) symptomatic (i.e.
abdominal pain or mass, weight loss, liver decompensa-
tion, jaundice), 2) asymptomatic (e.g. workup prompted
by incidental finding on a prior imaging test), and 3)
asymptomatic—abnormal finding on screening.
Although the Liver Center at our institution recom-
mended that patients with viral hepatitis and chronic
liver disease undergo HCC screening with AFP testing
and US every six months, there was no uniform practice
within our community that lead to this cohort. However,
patients referred based on screening results, were identi-
fied by AFP testing and/or imaging (either US, CT, or
MRI) at various intervals, ranging from three to twelve
months, consistent with National Comprehensive Cancer
Network guidelines [17].
Demographic information, medical history, laboratory
results, tumor characteristics, treatment, and survival data
were collected via clinical interview by a single physi-
cian without structured questionnaire and entered into a
prospective database. Information on diabetes mellitus,
hyperlipidemia, smoking, family history of HCC, and
risk factors for HCC including viral hepatitis, alcohol
abuse (defined as greater than two alcoholic beverages
daily for at least ten years), and other chronic liver dis-
eases, were included. Patients who had elevated lipid
levels or took a lipid-lowering agent were classified as
having hyperlipidemia. Measured height and weight were
used to determine body mass index (BMI), with obesity
defined as BMI 30. NASH was diagnosed based on
liver biopsy, absence of significant alcohol use, negative
hepatitis serologies, and no established etiology for liver
disease after clinical work-up by a gastroenterologist
and/or hepatologist.
Laboratory data collected included bilirubin level, al-
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L. L. Wong et al. / Open Journal of Gastroenterology 3 (2013) 49-54
Copyright © 2013 SciRes.
bumin level, prothrombin time, creatinine, alanine ami-
notransferase (ALT), aspartate aminotranferase (AST),
platelet count, and serum AFP level. Laboratory data
used for the study were obtained on, or within 2 weeks,
of the patient’s initial visit. Bilirubin, prothrombin time
with international normalized ratio (INR), and creatinine,
were used to calculate the MELD score. Tumor size,
number, and location, were used to determine the Tumor
Node Metastases stage according to the American Joint
Commission on Cancer (AJCC) staging manual [18]. Mi-
lan criteria was defined as having a single tumor 5 cm
in size, or 3 tumors each 3 cm in size, no macrovascu-
lar involvement, and no radiographic evidence of extra-
hepatic disease [19].
AFP levels were determined as normal (20 ng/mL) or
elevated (>20 ng/mL). The proportion of elevated AFP
was compared by ethnicity, race, hepatitis B and C status,
and presence of NASH. Normal vs. elevated AFP were
also analyzed by presence of cirrhosis, tumor size, vas-
cular invasion, MELD score 10 vs. MELD < 10 and
MELD 15 vs. MELD < 15.
Analyses were performed using Excel, and JMP 9.0
(SAS Institute). Group characteristics were compared
using analysis of variance (continuous variables) and chi-
squared analysis (categorical variables) with calculation
of odds-ratios and 95% confidence intervals. Two-tailed
p-values < 0.05 were considered significant.
In this cohort of 737 patients, 551 patients (74.8%) were
male, and the mean age was 61.7 years. Ethnic distribu-
tion was: Asian—478 (64.9%), White—136 (18.5%) and
Pacific Islander—103 (14.0%). 20 patients were classi-
fied “Other” and were Afro-American, Hispanic, or mixed
ethnicity (see Table 1).
One hundred patients were diagnosed with NASH-re-
lated HCC. Their mean age was 67.2 ± 11.0 years, and
the male: female ratio was 58:42. Compared to the 637
non-NASH patients, NASH-related HCC patients con-
sisted of fewer males (58.0% vs. 77.6%, p < 0.0001),
more diabetics (56.1% vs. 26.1%, p < 0.0001), large tu-
mors >5 cm in size (62.0% vs. 46.8%, p < 0.01), and
single tumors (74.0% vs. 63.6%, p < 0.05). There was no
difference in age, BMI, or MELD score between NASH
and non-NASH patients. There was also no difference in
the proportion of patients meeting the Milan Criteria.
The percentage of symptomatic patients at referral did
not differ significantly between NASH and non-NASH
patients (49% vs. 40.5%, p = 0.127). However, patients
with NASH-related HCC were less frequently identified
through screening compared to non-NASH patients (11.0%
vs. 21.4%, p < 0.05). Notably, a significantly lower per-
centage of NASH patients presented with elevated AFP
levels compared to patients with diseases other than
NASH (47% vs. 67.2%, p = 0.0001). While the mean
AFP level did not differ significantly between NASH
and non-NASH patients (12593 vs. 19721 ng/mL, p =
0.15), the median AFP value in NASH was 14 ng/mL vs.
70 ng/mL in non-NASH patients.
With respect to metabolic disease, the frequency of
elevated AFP did not differ in various groups categorized
by BMI or the presence of hyperlipidemia. However,
elevated AFP was less common in diabetics with HCC as
compared to nondiabetics (57.2% vs. 67.4%, p = 0.0093)
(see Tables 2 and 3).
Elevated AFP were more frequent in patients with
greater disease burden, including large tumors (>5 cm),
Table 1. AFP differences by gender and ethnicity.
Elevated AFP > 20 ng/mL (n = 474) Normal AFP 20 ng/mL (n = 263)Odds-ratio (95% conf interval) p-value
Gender p = 0.013
Males 341 (61.8%) 211 (38.2%) Ref
Females 133 (71.9%) 52 (28.1%) 1.58 (1.10 - 2.27)
White 82 (60.3%) 54 (39.7%) Ref
Pacific Islander 76 (73.8%) 27 (26.2%) 1.85 (1.05 - 3.23)
Asian 305 (63.8%) 173 (36.2%) 1.16 (0.78 - 1.71)
Chinese 59 (61.5%) 37 (38.5%) 1.05 (0.61 - 1.79)
Filipino 76 (69.7%) 33 (30.3%) 1.52 (0.89 - 2.59)
Japanese 115 (59.6%) 78 (40.4%) 0.97 (0.62 - 1.52)
Korean 30 (66.7%) 15 (33.3%) 1.32 (0.64 - 2.68)
Southeast Asian 20 (71.4%) 8 (28.6%) 1.65 (0.68 - 4.00)
Age < 65 years 297 (66.9%) 147 (33.1%) 1.32 (0.97 - 1.80) NS (p = 0.08)
Age 65 years 177 (60.4%) 116 (39.6%) Ref
Age < 50 years 78 (71.6%) 31 (28.4%) 1.47 (0.94 - 2.30) NS (p = 0.10)
Age 50 years 396 (63.1%) 232 (36.9%) Ref
*20 patients with “other ethnicity” not included in analysis.
L. L. Wong et al. / Open Journal of Gastroenterology 3 (2013) 49-54
Table 2. AFP by risk factors.
Elevated AFP > 20 ng/mL Normal AFP 20 ng/mL Odds-ratio p-value
Hepatitis B NS (p = 0.94)
Negative 259 (60.7%) 168 (39.3%) Ref
Positive 145 (61.8%) 92 (38.8%) 1.02 (0.74 - 1.41)
Hepatitis C p < 0.0001
Negative 278 (61.1%) 177 (38.9%) Ref
Positive 231 (83.7%) 45 (16.3%) 3.27 (2.25 - 4.74)
Alcohol 207 (65.7%) 108 (34.3%) 1.11 (0.82 - 1.51) NS (p = 0.53)
No Alcohol 267 (66.4%) 155 (33.6%) Ref
NASH 47 (47%) 53 (53%) 0.43 (0.28 - 0.66) p = 0.0001
Non-NASH 428 (67.2%) 209 (32.8%) Ref
Table 3. AFP by metabolic factors.
Elevated AFP > 20 ng/mL Normal AFP 20 ng/mL Odds-ratio p-value
Diabetic 127 (57.2%) 95 (42.8%) 0.65 (0.47 - 0.89) p = 0.0093
Nondiabetic 346 (67.4%) 167 (32.6%) Ref
Hyperlipidemia 75 (57.7%) 55 (42.3%) 0.70 (0.48 - 1.05) NS (p = 0.09)
No hyperlipidemia 381 (65.8%) 198 (34.2%) Ref
BMI < 20 31 (66%) 16 (34%) Ref NS (p = 0.066)
BMI 20 331 (61.1%) 211 (38.9%) 0.81 (0.43 - 1.52)
BMI < 25 147 (65%) 79 (35%) Ref NS (p = 0.34)
BMI 25 215 (59.2%) 148 (40.8%) 0.78 (0.55 - 1.10)
BMI < 30 290 (61.5%) 179 (38.5%) Ref NS (p = 0.75)
BMI 30 72 (60%) 48 (40.0%) 0.93 (0.61 - 1.39)
BMI < 35 339 (61.5%) 212 (38.5%) Ref NS (p = 1.00)
BMI 35 23 (60.5%) 15 (39.5%) 0.96 (0.49 - 1.88)
multiple tumors, and vascular invasion (see Table 4).
The frequency of elevated AFP did not differ with re-
gards to MELD score or cirrhotic disease.
Overall, 263 patients (35.7%) had a normal AFP. The
percentage of patients with an elevated AFP did not dif-
fer significantly with age as listed in Table 1, but was
higher in females compared to males (71.9% vs. 61.8%,
p = 0.018). An elevated AFP was also more common in
Pacific Islanders (73.8%) compared to Whites (60.3%),
although Asians and Asian subgroups did not differ
compared to Whites (see Table 1 for odds-ratios). Ele-
vated AFP did not differ with regard to HBV status, but
was more frequently elevated in HCV-related HCC com-
pared to HCV negative HCC (83.7% vs. 61.1%). When
patients were both HBV and HCV positive, 73.4% had
elevated AFP. The frequency of elevated AFP did not
differ depending on alcohol use.
Favorable outcomes in HCC are more likely when de-
tected at an early stage. Thus, effective screening aims at
detecting preclinical HCC. For this purpose, various
combinations of AFP testing, imaging with US, CT and/or
MRI, are recommended. The role of chronic viral hepati-
tis in hepatocarcinogenesis is established. Screening pa-
tients with chronic viral hepatitis has been shown to re-
sult in earlier HCC detection, and reduced cancer mortal-
ity [20]. Guidelines for screening and diagnosing HCC
by the American Association for the Study of Liver Dis-
eases (AASLD), and the European Association for the
Study of the Liver (EASL), are largely based on studies
involving viral-related HCC [14,21,22].
Non-viral related HCC is estimated to account for
15% - 50% of all HCC cases [7]. NAFLD progressing to
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L. L. Wong et al. / Open Journal of Gastroenterology 3 (2013) 49-54 53
Table 4. AFP by tumor characteristics and underlying liver function.
Elevated AFP > 20 ng/mL Normal AFP 20 ng/mL Odds-ratio p-value
Single tumor 286 (60%) 191 (40%) Ref p = 0.0012
Multiple tumors 184 (72.2%) 71 (27.8%) 1.73 (1.24 - 2.41)
Largest tumor < 5 cm 218 (58%) 158 (42%) Ref p = 0.0002
Largest tumor 5 cm 256 (70.8%) 104 (29.2%) 1.78 (1.31 - 2.42)
No vascular invasion 405 (61.6%) 253 (38.4%) Ref p = 0.001
Vascular invasion 69 (87.3%) 10 (12.7%) 4.31 (2.18 - 8.52)
MELD < 15 389 (65.2%) 207 (34.8%) Ref NS (p = 0.39)
MELD 15 67 (59.1%) 43 (40.9%) 0.83 (0.55 - 1.26)
MELD < 10 264 (64.9%) 142 (35.1%) Ref NS (p = 0.81)
MELD 10 192 (64%) 108 (36%) 0.96 (0.70 - 1.31)
Non-cirrhotics 105 (56.8%) 80 (43.2%) Ref p = 0.012
Cirrhotics 365 (67.1%) 179 (32.9%) 1.55 (1.10 - 2.19)
NASH-related HCC may contribute a significant portion
of non-viral related HCC cases. NASH is estimated to
effect 3% to 6% of the general population, and 30% of
the morbidly obese [23]. However, it is clinically diffi-
cult to identify the population at risk with NASH, as
many patients remain undiagnosed. Further, the degree to
which NASH contributes to HCC risk is currently un-
known. Those diagnosed with NASH may be followed
by a primary care physician and not by a hepatologist or
gastroenterologist expected to be more adherent to
screening recommendations [24].
In the United States, a minority of patients undergo
screening or surveillance before HCC is diagnosed. In
one population based study, only 17% of HCC patients
underwent surveillance before diagnosis [25]. In our
study, screening was also infrequent, occurring in 11.0%
of NASH patients, and 21.4% of non-NASH patients.
Rather, our patients were commonly found to have HCC
due to symptoms (NASH 49% and non-NASH patients
40.5%), or by imaging performed for unrelated reason.
Not surprisingly, data regarding HCC screening in NASH
patients is lacking. There is less data regarding AFP
testing in NASH-related HCC.
The primary finding of this study is the relative infre-
quency of an elevated AFP level in patients diagnosed
with HCC with NASH as the only identified risk factor
for their cancer. Indeed, the median AFP level of NASH
patients diagnosed with HCC fell within the normal
range in this study. This is somewhat surprising since the
patients with NASH-related HCC were more likely in
this study to have tumors > 5 cm in diameter, and were
equally likely to have presented with symptoms, as com-
pared to patients with HCC associated with other risk
factors. In our patient population the majority of patients
were not screened, and many presented with clinical
symptoms, whether or not they had NASH. Thus, our
data mainly reflects the efficacy of AFP as a confirma-
tory diagnostic test.
A primary limitation of this study was that it was a
retrospective review of patients referred to a single cen-
ter for HCC management. Although relative diagnostic
sensitivities of elevated AFP levels for detecting HCC
can be estimated based on the tables in this study, ab-
sence of a complete dataset that includes patients without
HCC including those with NASH (i.e. those not referred
for surgical consultation), limits formal estimations of
diagnostic sensitivity, specificity, or overall accuracy. Fur-
thermore, potential referral bias exists for any case series,
although in this study, the geographic isolation of our
patient population and our institution’s status as the sur-
gical referral center for the majority of HCC cases in our
region, limit such potential sources of bias.
Our study cautions against reliance upon AFP as a scre-
ening tumor marker in patients suspected of having HCC,
especially in those with NASH as the only risk factor.
Without adequate tumor markers for HCC in NASH,
other strategies are needed to enhance early detection.
US and other imaging will likely remain the primary
screening modalities for patients at risk. Our clinical
practice continues to rely heavily upon increasing com-
munity awareness, imaging-based surveillance measures,
and selective liver biopsy for early detection of HCC.
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