Obesity and Hepatocellular Carcinoma:
Hype and Reality
See Article on Page 858
I
t has been suggested that the rising prevalence of
obesity and its associated metabolic consequences,
including diabetes mellitus, have contributed con-
siderably to the overall as well the increasing burden
of hepatocellular carcinoma (HCC) in several Western
societies. This statement depends on interpretation of
the association between obesity and HCC, the burden
(measured by attributable fraction) of obesity-related
HCC, and the temporal trends of obesity-related
HCC. We will review the veracity of this statement
based on the available epidemiological and mechanistic
evidence, and place the findings of the study by Alek-
sandrova et al. in context.1
The association between obesity and HCC has been
examined in several epidemiological studies. Most—but
not all—of these studies are suggestive of a modest
increase in the relative risk of HCC in obese persons.
For example, a systematic review2 of 10 cohort studies
found a positive association between obesity, measured
as body mass index (BMI), and risk of HCC in seven
studies (relative risks ranging from 1.4 to 4.1), no asso-
ciation in two, and an inverse association in one study.
Many of these studies were limited by a small number
of cases with HCC, possibility of misclassification, and
inconsistent adjustment for potential confounders.
The contribution of obesity to the overall HCC
burden is driven to a large extent by the prevalence of
obesity in the general population. However, the inter-
pretation of available data is limited by the relative
risk estimates as well as overreliance on BMI as a mea-
Abbreviations: BMI, body mass index; EPIC, European Prospective Investi-
gation into Cancer and Nutrition; HCC, hepatocellular carcinoma; IGF-1,
insulin-like growth factor 1; NASH, nonalcoholic steatohepatitis; PAF, popula-
tion attributable fraction.
Address reprint requests to: Hashem B. El-Serag, M.D., MPH, Section of
Gastroenterology and Hepatology, Michael E DeBakey VA Medical Center and
Baylor College of Medicine, and Houston VA HSR&D Center for Innovations
in Quality, Effectiveness and Safety, Houston TX 77030. E-mail: hasheme@
bcm.edu; fax: 713-748-7359.
Published 2014. This article is a US Government work and is in the public
domain in the USA.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep.27172
Potential conflict of interest: Nothing to report.
sure of obesity in most published studies. In contrast
to the relative risk ratios (as described in the systematic
review and meta-analysis described above), population
attributable fraction (PAF) accounts for both an esti-
mate of prevalence as well as the relative risk, and thus
describes the proportional reduction in disease that
would occur if exposure to a risk factor were to be
eliminated. Using this parameter, obesity is likely to
have the greatest PAF of any HCC risk factors in the
U.S. and several other regions in Europe and North
America. For example, a report based on the European
Prospective Investigation into Cancer and Nutrition
(EPIC) indicated that obesity might account for
16% of HCC3 cases in Europe (EPIC is a
population-based cohort from several European coun-
tries). Similarly, data from U.S. SEER Medicare esti-
mated that diabetes and/or obesity may be attributed
to 36.6% of HCC in the U.S. Medicare population.4
However, these studies make certain assumptions in
calculating attributable risk that may not be true. First,
there are differences between excess fraction (differen-
ces between HCC risk in obese and nonobese irrespec-
tive of the presence of other cofactors such as viral
hepatitis or alcoholic liver disease) which is used in the
PAF calculation, and etiological fraction (differences
between the groups limited to cases caused solely by
obesity) which may be much smaller.5 The magnitude
of the difference between excess fraction and etiologi-
cal fraction related to obesity is unknown. Second, the
PAF calculations do not account for the considerable
time lag between acquiring the risk factor (obesity)
and developing the disease (HCC), and therefore the
applicability of PAF to current HCC burden is very
doubtful. In the available cross-sectional studies of
HCC, viral hepatitis still accounts for most cases and
there have been no convincing studies of temporal
trends of obesity-related HCC. Thus, the available
obesity-related PAF data may represent, if at all, the
upper bound of the HCC risk associated with obesity
(i.e., the worst-case scenario). Lastly, the factors that
increase or attenuate the risk of HCC among obese
persons are only partly understood. We believe that
thoughtful modeling studies that incorporate natural
history estimates of disease progression are needed for
a better understanding of the burden of obesity-related
HCC.
779
780 EL-SERAG AND KANWAL
Most studies used BMI to classify patients as obese
versus nonobese. BMI is a rather gross and likely dis-
tal operator in explaining the link between obesity
and HCC. Moving beyond BMI and into more prox-
imal features in the association between BMI and
HCC, a previous publication from the EPIC cohort
found that a high waist-to-hip ratio conferred a 3-
fold higher HCC risk to subjects in the upper tertile
of waist hip ratio6 than those in the lowest tertile.
These findings suggest a role for abdominal visceral
fat as a source of imbalance for cytokines and adipo-
kines.7 There is a clear need for studies to examine
more proximal—and likely mechanistic—links that
either jointly or independently explain the association
between obesity and HCC.
Examining these mechanistic associations is particu-
larly important in obesity-related HCC. This is because
the conventional assumption that most HCC develops
in patients with underlying cirrhosis may be violated in
the case of obesity-related HCC. While nonalcoholic
steatohepatitis (NASH) arising from fatty liver disease
seems to be an underlying lesion for some HCC cases,8
the extent to which the presence or the severity of
NASH explains obesity-related HCC remains unclear.
For example, HCC was reported in a French surgical
series to have developed in a background liver without
significant fibrosis in approximately two-thirds of 31
cases with metabolic syndrome (a strong correlate of
obesity) as the only risk factor for liver disease, com-
pared with less than one-third in 97 with an overt cause
of liver disease.9 Another Japanese study reported that
approximately half of the 87 cases of HCC occurring in
patients with histologically confirmed NASH had no
established cirrhosis.10 These findings are supportive of
the possibility that HCC arises in these traditionally
nonhigh-risk groups by completely bypassing cirrhosis
and possibly through mechanisms other than NASH.
There are several potential mediators of obesity-
related HCC that were discussed in previous
reviews11,12; these include lipotoxicity, changes in the
gut microbiome,13 an imbalance in proinflammatory/
antiinflammatory cytokines, stimulation of the insulin-
like growth factor 1 (IGF-1) axis by hyperinsulinemia,
reduced adiponectin secretion, and increased leptin.14
These biomarkers may also explain the joint effect of
obesity with traditional risk factors toward further
increasing the risk of HCC. However, only a few pro-
spective epidemiological studies examined the associa-
tion between inflammatory or metabolic biomarkers
and risk of HCC in a general population. Having this
information is important because evidence of the rela-
tion between obesity-related biomarkers and risk of
HEPATOLOGY, September 2014
liver cancer may provide clues for understanding the
underlying etiological mechanisms.
In this issue of HEPATOLOGY, Aleksandrova et al.
reported the findings of a nested case-control study in
the EPIC cohort. A total of 125 HCC cases were com-
pared to controls matched on the recruitment center,
age, sex, fasting serum status, and time of specimen
collection. Higher baseline serum levels of C-reactive
protein, interleukin 6, C peptide, and high molecular
weight adiponectin were associated with an increased
risk of developing HCC in the general population.
The risk ratios were modest and ranged between 1.22
and 2.25 for doubling of each of the significant bio-
markers. Other biomarkers of interest that were not
significantly associated with HCC included leptin. The
study has multiple strengths, including a population-
based cohort, longitudinal design, and careful charac-
terization of study subjects. Some of the limitations
include the relatively small number of HCC cases and
the absence of main risk factors among HCC cases
(only 30% had either hepatitis C virus [HCV] or
HBV), which, while possible, invokes likely misclassifi-
cation bias. Lastly, the finding that high adiponectin
was associated with higher HCC risk goes against the
proposed biological rationale (adiponectin, a protective
factor, is reduced in obesity).
Despite these limitations, as the authors mention,
there are two broad potential implications for their
findings. First, the study provides a mechanistic link
between obesity and HCC by demonstrating an associ-
ation with obesity using measures that are more
“proximal” than BMI and anthropometric measures.
Second, the study provides potential biomarkers for
HCC. With regard to the first implication, we believe
that the study findings represent a significant advance.
However, this may not be the case with the latter
implication. There the potential use of proposed bio-
markers is considerably limited by biological (the
markers have been implicated with several other condi-
tions including nonliver cancer) and test performance
(although the relative risk of HCC was elevated mod-
estly with some of the markers, the absolute risk of
HCC in this mostly low-risk population is exceedingly
small, and hence increasing this risk by 2 to 3-fold is
still not meaningful personal predictive value) factors.
In summary, the relative risk of HCC is modestly
elevated in obese persons but the absolute risk is likely
very low. The factors that influence HCC risk among
obese person are unclear. Obesity-related inflammatory
mechanisms are possibly operative in mediating
obesity-related HCC (as shown in this longitudinal
study), but the factors that further increase or
HEPATOLOGY, Vol. 60, No. 3, 2014
attenuate HCC risk among obese persons are unclear.
The obesity-related increase in HCC risk has not
translated yet into a large burden, but its future impact
is possible and needs to be studied. The possibility of
obesity-related HCC developing in noncirrhotic liver
is real and needs to be further examined because of its
potential to disrupt the current algorithms for defining
high-risk groups (with implications for prevention and
surveillance).
HASHEM B. EL-SERAG, M.D., MPH
FASIHA KANWAL, M.D., MSHS
Section of Gastroenterology and Hepatology
Michael E DeBakey VA Medical
Center and Baylor College of Medicine
Houston VA HSR&D Center for Innovations in
Quality, Effectiveness and Safety
Houston, TX
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