SPECIAL ARTICLE

Is Higher BMI Associated with Worse Overall Mortality in
Hepatocellular Carcinoma Patients? An Evidence Based
Case Report
Alessa Fahira1, Ratu S. Hanifah1, Mohamad P. Wardoyo1, Amirah D. Diba1,
Rahadian Ramadhan1, Julie D. Barliana2, Chyntia O. M. Jasirwan3
Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
Department of Ophthalmology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.
3
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine Universitas
Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
1
2

Corresponding Author:
Chyntia Olivia Maurine Jasirwan, MD. Division of Gastroenterology and Hepatology, Department of Internal
Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital. Jalan Diponegoro no. 71,
Jakarta 10430, Indonesia. email: fahiraalessa@gmail.com.
ABSTRAK
Latar belakang: saat ini kanker hati adalah kanker paling mematikan kedua di dunia yang umumnya dengan
karsinoma hepatocelullar (HCC) - terhitung 90% dari semua kasusnya. Dengan peningkatan obesitas global
yang cukup mengkhawatirkan, maka ada peningkatan kasus penyakit hati berlemak, yang merupakan salah satu
etiologi utama sirosis virus di dunia. Tujuan dari penelitian ini adalah untuk mengevaluasi apakah pasien HCC
obesitas memiliki hasil kelangsungan hidup yang lebih buruk. Metode: PubMed, Cochrane, Scopus, ProQuest, dan
EBSCOhost secara komprehensif mencari ulasan sistematis dan penelitian prognostik kohort dengan mempelajari
kelangsungan hidup keseluruhan pasien HCC yang kekurangan berat badan dan obesitas menurut indeks massa
tubuh (IMT) mereka. Tiga studi dipilih dan dinilai secara kritis. Data kemudian dirangkum secara deskriptif.
Hasil: tiga studi terdiri dari satu meta-analisis dan dua studi kohort. Studi meta-analisis menyatakan tidak ada
hubungan antara kelebihan berat badan dan status obesitas dengan tingkat kematian yang lebih tinggi pada
pasien HCC ras Asia (aHR, 1,10; 95% CI, 0,63-1,92). Sebuah studi kohort dari Jepang melaporkan sementara ada
perbedaan yang signifikan dari tingkat kematian pada pasien HCC obesitas dalam analisis bivariat, penyesuaian
dengan faktor prognostik penting lainnya berdasarkan analisis multivariat tidak ditemukan korelasi signifikan
antara obesitas dan tingkat kematian terkait HCC (aHR, 1,00; 95 % CI, 0,83-1,22). Studi kohort lain dari Cina
melaporkan bahwa tingkat kematian terkait HCC pada pasien dengan IMT tinggi, lebih rendah daripada pasien
dengan IMT rendah (aHR, 0,347; 95% CI, 0,239-0,302). Kesimpulan: tidak ada hubungan antara BMI yang lebih
tinggi dengan mortalitas terkait HCC pada pasien ras Asia.
Kata kunci: karsinoma hepatoselular (HCC), mortalitas, indeks massa tubuh (IMT), overweight, obesitas,
prognosis.
ABSTRACT
Background: liver cancer is currently the second deadliest cancer in the world with hepatocelullar carcinoma
(HCC) being the commonest form—accounting 90% of all its cases. With the current global alarming increase
of obesity, there is hence an increase of fatty liver disease cases, which is one of the major non-viral etiology of
cirrhosis in the world. The objective of this study is to evaluate whether obese HCC patients have worse survival

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Is higher BMI associated with worse overall mortality in HCC patients?

outcome. Methods: PubMed, Cochrane, Scopus, ProQuest, and EBSCOhost were comprehensively searched for
systematic review and cohort prognostic researches studying overall survival of HCC patients who are underweight
and obesity according to their BMI. Three studies were selected and critically appraised. Data were then summarized
descriptively. Results: the three studies included consist of one meta-analysis and two cohort studies. Meta-analysis
study stated no association between overweight and obesity status with higher mortality rate in Asian race HCC
patients (aHR, 1.10; 95% CI, 0.63-1.92). A cohort study from Japan reported while there was a significant difference
of mortality rate in obese HCC patients in bivariate analysis, adjustment with other important prognostic factors
with multivariate analysis found no significant correlation between obesity and HCC-related mortality rate (aHR,
1.00; 95% CI, 0.83-1.22). Another cohort study from China reported that HCC-related mortality rate in patients
with higher BMI was lower than in patients with lower BMI (aHR, 0.347; 95% CI, 0.239-0.302). Conclusion:
there is no association between higher BMI with HCC-related mortality in Asian race patients.
Keywords: hepatocellular carcinoma (HCC), Mortality, body mass index (BMI), overweight, obesity,
prognosis.
INTRODUCTION

Liver cancer, the fifth most common occurring
cancer in the world, is currently the second
deadliest cancer—weighing more than 800.000
per year globally.1 Hepatocellular carcinoma
(HCC), the most common histological form of
liver cancer, accounts 90% of all liver cancer cases
in the world.2 In Indonesia, HCC is the fourth most
common occurring cancer with a grave prognosis,
where the average life expectancy would usually
not reach a period of three months.3 Of all cases
of HCC, 80-90% patients had an underlying
condition of cirrhosis.4 In many low and middle
income countries, hepatitis B acts as the most
common etiologies and is a major risk factor for
liver cirrhosis due to the low coverage of hepatitis
B vaccination in newborn babies as one of its
major cause, followed by chronic hepatitis C,
alcoholic liver disease, and non-alcoholic fatty
liver disease.5,6
The alarming increase of obesity which
currently happening across many parts of the
world including in developing countries, has
been regarded to be one of the major cause
of the increase of non-alcoholic fatty liver
disease incidence in recent years. The known
pathophysiology of which is through the
accumulation of triglycerides in the liver that
leads to the inflammation and the forming of
fibrosis that may later develop into cirrhosis
and HCC.7 This situation is becoming more
common in patients and have been considered
to negatively impact the prognosis of cirrhosis

and at the same time complicate the judgement
of performing liver transplantation—particularly
in the setting of living donor liver transplantation
where the negative ratio of low graft to recipient
may affects survival. On the other hand,
treatment of obesity tends to be more arduous in
these patients due to difficulty in implementing
lifestyle measures, safety of orally consumed
anti-obesity drugs and high risk of surgery.8
Obesity epidemic had emerged as a major
factor underlying the increasing burden of liver
disease in the United States and many other
countries—yet there is no evidence based case
report which studied the prognosis of HCC
patients who are underweight and obesity. 9
This evidence-based case report is meant to
comprehensively review the overall survival rate
of HCC patients with an underlying condition of
overweight and obesity from available studies.
CASE ILLUSTRATION

A 52 years old woman suffering from fatigue,
swelling in the legs, and loss of appetite who had
previously been diagnosed with hepatocellular
carcinoma (HCC) with the etiology of fatty liver
disease went to the doctor as a part of her routine
check-up. The woman is currently obese and is
wondering whether her weight could contribute
to a higher mortality rate in the upcoming years.
Therefore, the doctor is curious if the condition
of overweight and obesity in people with HCC
could worsen their survival rate.

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CLINICAL QUESTION

Based on the case illustration, the clinical
question is “Is higher BMI associated with
worsened overall survival rate in hepatocellular
carcinoma patients?”

exclusion criteria. Searching strategy, searching
results, inclusion and exclusion criteria are
shown in Figure 1. Exclusion criteria of subjects
with age under 50 years old were made to study
the natural history of obesity.10

Table 1. Clinical question formulation

RESULTS

Population

Patients with HCC

Exposure

Overweight and obesity

Comparison

-

Outcome

Death

Type of question

Prognosis

Type of relevant
studies

Systematic Review-Meta Analysis of
Cohort Studies and Cohort Studies

Based on the process of article selection, 3
relevant studies were collected to be analyzed
further in our evidence-based case report. The
studies consist of two cohort studies and one
meta-analysis study.

METHODS

Literature searching was conducted using the
keywords shown in Table 2 from five different
journal databases of which are Pubmed, ProQuest,
Cochrane, Scopus, and EBSCOhost. The studies
obtained from the search were screened by title
and abstract. They were filtered through the
inclusion criteria which are in accordance with
prognostic studies design (cohort, systematic
review, and meta-analysis). Relevant articles
were then further studied by reading their full
article. Articles not in accordance with the
objective of this study are separated by the

Critical Appraisal

We divided the critical appraisal process
and results into two tables based on the studies’
design. Critical appraisal of the studies conducted
by Li Q, et al.11 and Fujiwara N, et al.12 which are
both retrospective cohort studies, is evaluated in
Table 4. Study conducted by Gupta A, et al.13 is
a meta-analysis study and therefore evaluated
in Table 5.
Cohort Studies

HCC patients analyzed in the study of
Fujiwara, et al.12 were included in the study after
being diagnosed with hepatocellular carcinoma
(HCC). Based from Table 4, weaknesses were
found on each aspect of validity, importance, and

Table 2. Searching strategy
Database

Searching Strategy

Hits

Selected

Pubmed

((((((((Obesity[Title/Abstract]) OR Obesity[MeSH Terms]) OR Obese[Title/Abstract])
OR Obese[MeSH Terms]) OR Overweight[Title/Abstract]) OR Overweight[MeSH
Terms])) AND ((((Hepatocellular carcinoma[Title/Abstract]) OR Hepatocellular
carcinoma[MeSH Terms]) OR HCC[Title/Abstract]) OR HCC[MeSH Terms])) AND
((((((mortality[Title/Abstract]) OR mortality[MeSH Terms]) OR death[Title/Abstract]) OR
death[MeSH Terms]) OR survival rate[Title/Abstract]) OR survival rate[MeSH Terms])

316

3

ProQuest

(TI(hepatocellular carcinoma OR liver cancer OR cancer of liver OR hepatoma) OR
AB(hepatocellular carcinoma OR liver cancer OR cancer of liver OR hepatoma))
AND (TI(obesity OR (obese OR overweight)) OR AB(obesity OR (obese OR
overweight))) AND (TI(mortality OR death) OR AB(mortality OR death)) AND stype.
exact("Conference Papers & Proceedings" OR "Scholarly Journals" OR "Dissertations
& Theses") AND at.exact("Dissertation/Thesis" OR "Conference Proceeding" OR
"Conference Paper" OR "Conference" OR "Article") AND la.exact("English") AND
subt.exact("humans" NOT ("animals" OR "mice"))

296

8

Cochrane

"hepatocellular carcinoma" OR "liver cancer" OR hepatoma in Title Abstract Keyword
AND obesity OR (obese OR overweight) in Title Abstract Keyword AND mortality OR
death in Title Abstract Keyword - (Word variations have been searched)

4

0

Scopus

(TITLE-ABS-KEY (hepatocellular AND carcinoma OR hcc ) AND TITLE-ABS-KEY (
obesity OR overweight OR obese ) AND TITLE-ABS-KEY ( mortality OR death OR
survival AND rate))

186

1

EBSCOhost

("hepatocellular carcinoma" OR "liver cancer" OR hepatoma) AND (obesity OR
(obese OR overweight)) AND (mortality OR death) Human; Human

285

9

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Is higher BMI associated with worse overall mortality in HCC patients?

Figure 1. Literature searching procedure
Table 3. Summary of studies
Study
Type

Fujiwara N, et al.

Li Q, et al.

Gupta A, et al.
Systematic Review and MetaAnalysis

Retrospective cohort

Retrospective cohort

Subject

1257 patients with different stages
of Hepatocellular Carcinoma in the
Department of Gastroenterology, University
of Tokyo Hospital.

379 patients who were
diagnosed with HCC
at the First Affiliated
Hospital of Harbin
Medical University
between June 2012 and
August 2014

Control

No control was used

No control was used

No control was used

Results

BMI did not have significant effect on HCC
mortality

Higher BMI has
significant correlation
with lower HCC-related
mortality rate after
adjustment with other
prognostic factors (aHR,
0.347; 95% CI, 0.2390.502). The absolute
reduction risk (ARR) is
37,9%.

Obese HCC patients have higher
rate of mortality compared to
HCC patients with normal BMI in
Caucasian patients, while there’s no
difference in mortality rate of Asian
obese and non-obese patients

HR = 1.00 [95% CI 0.83-1.22, p= 0.97]

Other
results

Factors such as low SMI (called
sarcopenia), low MA (called intramuscular
fat [IMF] deposition), and high VSR (called
visceral adiposity) were significantly
associated with mortality, independently of
cancer stage or Child-Pugh classification.
A multivariate analysis revealed that
sarcopenia (hazard ratio [HR], 1.52; 95%
confidence interval [CI], 1.18–1.96; p =
0.001), IMF deposition (HR, 1.34; 95% CI,
1.05–1.71; p = 0.020), and visceral adiposity
(HR, 1.35; 95% CI, 1.09–1.66; p = 0.005)
were significant predictors of survival

Multivariate analysis
found, that besides BMI,
Child-Pugh staging,
treatment strategy, and
extrahepatic metastases
has significant
correlation with HCCrelated mortality rate

HCC patients with Obesity, 9 studies
in pooled analysis
Systematic review from 6 databases;
Medline In Process, MEDLINE,
EMBASE, Cochrane Central
Register of Controlled Trials, Ovid
Cochrane Database of Systematic
Reviews, dan Cochrane Database of
Reviews of Effect

On subgroup analysis, magnitude
of increased mortality was higher in
obese men (aHR, 2.50;
95% CI, 2.02-3.09; 3 studies) as
compared with obese women (aHR,
1.45; 95% CI, 1.08-1.97; 2 studies).
The impact of premorbid obesity
on HCC-related mortality was
observed only in western
populations
(aHR, 2.10; 95% CI, 1.77-2.48; 4
studies), but not Asian populations
(aHR, 1.10; 95% CI, 0.63-1.92; 1
study)

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Table 4. Critical appraisal for cohort studies
Studies

Appraised Aspects
Validity

Importance
Applicability

Fujiwara, et al.

Li Q, et al.

A defined, representative sample of patients was assembled at
a common point in the course of the disease

+

+

Patient follow-up was sufficiently long and complete

+

+

Objective outcome criteria were applied in a “blind” fashion

-

-

There was adjustment for important prognostic factors, if
subgroups with different prognoses are identified

+

+

Likely outcome

-

-

Precise prognostic estimation

+

+

Patients of the study were similar

+

+

This evidence will make a clinically important impact

-

+

+ = stated in the article; - = not stated in the article

applicability of a critical appraisal. By evaluating
the validity, we found no blinding of researchers
in both studies—although this is not an issue
due to the objective outcome of mortality. Even
though blinding was not performed, to minimize
selection bias and potential finding, Fujiwara,
et al.12 utilized propensity score. Propensity
score is a statistical matching technique using
logistic regression which attempt to estimate
the conditional probability of exposed subjects
by accounting for their confounding factors.
Moreover, in the study conducted by Fujiwara,
et al.12 the subjects of research were assembled
in the same timeline point of the disease. All
patients were followed up for 3 to 8 years. This
study also conducted adjustments for significant
factors i.e. patients’ tumor stage and liver
functional status.
The study by Fujiwara, et al.12 showed a
non-statistically significant correlation between
BMI and HCC-related mortality with the hazard
ratio (HR) of 1.00 [95% confidence interval [CI]
0.83-1.22; p = 0.97]. However, the study found
a higher prevalence of poor prognosis in HCC
patients with obese and underweight compared
to patients with normal BMI. This study also
highlighted variety of other body composition
measurement such as sarcopenia, IMF deposition
and visceral obesity as better predictors of
survival. Hazard ratio and confidence interval
of each body composition measurement are;
Sarcopenia, HR 1.52 [95% CI 1.18-1.96; p =
0.001]; visceral adiposity, HR 1.35 [95% CI 1.091.66; p = 0.005], and IMF deposition, HR 1.34

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Table 5. Critical appraisal for meta-analysis study

Validity

Importance

Appraised Aspects

Study
Gupta, et al.

Clear clinical question in
the study

+

Good study selection

+

Appropriate criteria for
inclusion

+

Sufficient validity of
included studies

+

Similarity of results from
study to study

-

Clinically important HR/
OR/RR

HR: 1.95

Precise study result
Applicability

95% CI:
1.46-2.46

Patients of the study were
similar

+

This evidence will make a
clinically important impact

+

+ = stated in the article; - = not stated in the article

[95% CI 1.05-1.71; p = 0.020]. By utilizing the
BMI Guideline for Asia Pacific populations—of
which include Indonesia—the patients enrolled
in the study conducted by Fujiwara, et al.12 is
identical to our patient in the terms of BMI,
although there is no significant effect of BMI
found on HCC-related mortality (HR = 1.01)
in patients with higher BMI (obesity patients)
compared to those who had normal BMI (nonobese patients).
The study conducted by Li Q, et al. 11
included representative subjects from patients
with HCC in Harbin Medical School Hospital.
The diagnosis for HCC was also made in the

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Is higher BMI associated with worse overall mortality in HCC patients?

same hospital, enabling all the patients in the
cohort study to be followed simultaneously. This
cohort study was conducted with the median
follow-up period of 296 days (with a range of
15 until 720 days). The follow-up in this study
is considered sufficient because of the mean life
expectancy of HCC patients is around 134 days.3
In the study, Li Q, et al.11 did not specify whether
the outcome was blinded or not. However,
considering the outcome of the study is the
number of patients with HCC-related mortality,
which is an objective outcome, we deem that
outcome blinding in this study is unnecessary.
Li Q, et al.11 had also adjusted other important
prognostic factors by performing a multivariate
analysis which included said factors.
Meta-Analysis Study

The systematic review conducted by Gupta,
et al.13 included 9 different cohort studies from
5 databases which discusses the relationship
between premorbid obesity and HCC-related
mortality. The systematic review has fulfilled
almost all of the validity, importance, and
applicability criteria in this case report. However,
several weaknesses were found in this review
such as a moderate degree of heterogeneity in the
review which can be explained due to difference
in the population studied by the cohorts included
(1 cohort studied Asian population while 4
cohorts studied Western population). While the
review did state an existing relationship between
premorbid obesity and HCC-related mortality
(i.e. premorbid obesity increases HCC-related
mortality rate), this relationship is only found
in Western population studies—hence the
results may not be fully applicable in the Asian
population.
DISCUSSION

The ceaseless increase of mortality rate
due to hepatocellular carcinoma have been a
continuous concern for health-care workers in
many parts of the world. In the year of 2012,
hepatocellular carcinoma rose to be the second
most common cause of death due to cancer
worldwide14—this is suspected due to the current
limited therapeutic options and the increase cases
of non-viral hepatocellular carcinoma etiologies

such as fatty liver disease with metabolic risk
factors of obesity and diabetes.15-17
Obesity is one of the major health problems
associated with the occurrence of non-alcoholic
fatty liver disease (NAFLD).15 Several studies
have shown that NAFLD is currently the most
influential factor in the increase of liver-health
problems including hepatocellular carcinoma.
Studies in the United States found that there are
as many as 59% of hepatocellular carcinoma
cases associated with NAFLD, while hepatitis
C virus infection and alcoholic liver disease
(ALD) were only associated with the incidence
of hepatocellular carcinoma in 22% and 12%
of cases.18 An increase in NAFLD-related cases
of hepatocellular carcinoma was also found
in various other studies.19,20 Meanwhile, other
studies found that the increase risk of death due
to cancer may be correlated with the value of
patients’ body mass index (BMI). In the study,
patients with a BMI of more than 35 kg/m2 had
a ratio of deaths due to cancer 4.52 times than
those who had normal BMI.21
In this evidence-based case report, we
included three studies that were in accordance
with the aforementioned clinical question.
The three studies provide different statements
regarding whether the condition of obesity may
predict mortality in hepatocellular carcinoma
patients. Stated in the meta-analysis conducted
by Gupta, et al.13 is that obese patients had
a higher mortality rate from hepatocellular
carcinoma (aHR, 1.95; 95% CI, 1.46-2.46)
compared to patients with normal body weight.
Different statement was made by Fujiwara,
et al.12, showing that neither overweight nor
underweight condition had a significant effect on
hepatocellular carcinoma related deaths. Li Q, et
al.,11 on the other hand, found a higher mortality
rate in hepatocellular carcinoma patients with
less weight (BMI <23 kg/m 2). With three
conflicting findings, the answer whether obesity
can predict death in hepatocellular carcinoma
patients may be inconclusive.
Of the three studies we analyzed, study
conducted by Gupta, et al.13 based on the results
of our critical appraisal, is considered to be the
most valid—with all aspects of validity were
well fulfilled. Both cohort studies included

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Alessa Fahira

did not assess output with the blinding, but
considering the outcome of interest being the
mortality, blinding was eventually not required.
In terms of applicability, Gupta, et al.13 found
that the predictive ability of obesity in cancer
deaths was only found in Caucasian race patients.
Meanwhile, Asian race patients who were obese
are found to have no difference in death due to
HCC compared to those who are not obese. This
finding was confirmed by Fujiwara, et al.,12 who
found no difference in HCC deaths in obese
patients compared with non-obese patients in
patients at Tokyo University Hospital. However,
study of Li Q, et al.,11 conducted at the Harbin
Medical School Hospital, found that BMI
levels can predict deaths from hepatocellular
carcinoma, although worse outcomes were found
in patients with less weight.
CONCLUSION

This evidence-based case report concluded
that according to included studies, there are
stronger evidence that there is no association
between higher BMI with HCC-related mortality
in Asian race patients.
RECOMMENDATION

Although BMI is the most common body
measurement in assessing patients’ body weight,
existing literature recommended to use different
body composition measurement in predicting
HCC-related death due to obesity. These body
composition measurements may include IMF
deposition and visceral adiposity status.
Despite the inconclusive statement between
studies, obese patients with HCC should still
control their diet to improve overall health
condition. Medications targeted to reduce obesity
must be given by considering its metabolism
pathway and liver function.
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