CLINICAL RESEARCH STUDY

Independent of Cirrhosis, Hepatocellular

Carcinoma Risk Is Increased with Diabetes and
Metabolic Syndrome
Allison J. Kasmari, MD,a Amy Welch, MD, MSN, MSc,b Guodong Liu, PhD,c Doug Leslie, PhD,c
Thomas McGarrity, MD,b Thomas Riley, MDb
a
Department of Internal Medicine, bDivision of Gastroenterology and Hepatology, and cDepartment of Public Health Sciences, Penn State
Hershey Medical Center, College of Medicine, Pa.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma is the most common primary liver malignancy, commonly a
sequelae of hepatitis C infection, but can complicate cirrhosis of any cause. Whether metabolic syndrome
and its components, type II diabetes, hypertension, and hyperlipidemia increase the risk of hepatocellular
carcinoma independent of cirrhosis is unknown.
METHODS: A retrospective cohort study was conducted using the MarketScan insurance claims database
from 2008-2012. Individuals with hepatocellular carcinoma aged 19-64 years and age and sex-matched
controls were included. Multivariate analysis of hepatocellular carcinoma risk factors was performed.
RESULTS: Hepatitis C (odds ratio [OR] 2.102) was the largest risk factor for hepatocellular carcinoma. Other
independent risk factors were type II diabetes (OR 1.353) and hypertension (OR 1.229). Hyperlipidemia
was protective against hepatocellular carcinoma (OR 0.885). The largest risk increase occurred with hy-
pertension with type II diabetes and hepatitis C (OR 4.580), although hypertension and type II diabetes
without hepatitis C still incurred additional risk (OR 3.399). Type II diabetes and hyperlipidemia had a
similar risk if hepatitis C was present (OR 2.319) or not (OR 2.395). Metformin (OR 0.706) and cholesterol
medications (OR 0.645) were protective in diabetics. Insulin (OR 1.640) increased the risk of hepatocellular
carcinoma compared with the general type II diabetes population.
CONCLUSION: In the absence of cirrhosis, type II diabetes and hypertension were independent risk factors
for hepatocellular carcinoma. Hyperlipidemia and medical management of type II diabetes with metformin
and cholesterol medication appeared to reduce the incidence of hepatocellular carcinoma. In contrast,
insulin was associated with a higher risk of hepatocellular carcinoma.
Ó 2017 Elsevier Inc. All rights reserved.
The American Journal of Medicine (2017) 130, 745.e1-745.e7

KEYWORDS: Diabetes; Hepatocellular carcinoma; Metabolic syndrome

Hepatocellular carcinoma is the most common primary

Funding: This study was funded by the Department of Gastroenter-
ology and Hepatology at Penn State Hershey Medical Center.
Conflict of Interest: The authors have no financial interests or affilia-
tions with organizations that may have financial interest influenced by this
study.
Authorship: All listed authors had access to the data presented and had
a role in writing this manuscript.
Requests for reprints should be addressed to Allison J. Kasmari, MD,
Department of Internal Medicine, Penn State Hershey Medical Center,
College of Medicine, 500 University Drive, PO Box 850, Mail Code H039,
Hershey, PA 17033.
E-mail address: akasmari@pennstatehealth.psu.edu
liver malignancy. Although relatively uncommon, the
incidence is increasing and prognosis is poor. It has nearly
tripled in the US since the 1980s1 and is projected to sur-
pass breast and colorectal cancer by 2030.2 Surgical
resection and liver transplantation are the only curative
therapies.3 However, these modalities often cannot be used,
as hepatocellular carcinoma is often diagnosed when
lesions are large in size, bilobar, or multifocal.2,3 To
improve survival and opportunities for curative therapy,
early detection is required.3
To improve early detection, risk factors for hepatocellular
carcinoma must be understood. Currently, one-third of

0002-9343/$ -see front matter Ó 2017 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjmed.2016.12.029
745.e2 The American Journal of Medicine, Vol 130, No 6, June 2017

hepatocellular carcinoma cases in the US are attributed to from 2008 to 2012 were used, which include information on
hepatitis C.4 The Centers for Disease Control and Preven- over 56 million covered lives annually.
tion estimates that 3.5 million people in the US are infected The study population included adults >18 years of age
with hepatitis C.5 The increase in hepatocellular carcinoma represented in the MarketScan Database between 2008 and
has been paralleled by increasing incidence of type II dia- 2012 who had an outpatient visit with a primary or sec-
betes obesity, and metabolic syndrome.6,7 Some recent ondary diagnosis code of hepatocellular carcinoma (Inter-
studies indicated that type II dia- national Classification of
betes may increase the risk of Diseases, Ninth Revision [ICD-9]
developing hepatocellular carci- CLINICAL SIGNIFICANCE code: 155.0). In order to mini-
4
noma. A Taiwanese population
Independent of cirrhosis, type II dia- mize the error that can occur with
study indicated that patients with betes and metabolic syndrome increase insurance coding, the diagnosis
cirrhosis and diabetes were twice had to be present on 2 separate
the risk of hepatocellular carcinoma.
as likely to develop hepatocellular occasions to be included. The total
carcinoma as cirrhotics without
Metformin and statin therapy decrease number of patients with hepato-
diabetes.8 Another study from the the risk of hepatocellular carcinoma. cellular carcinoma was 17,446.
Department of Veterans Affairs Patients with concomitant di-

Hepatocellular carcinoma screening in
(VA) showed that diabetes served agnoses of hepatitis B (ICD-9:
as a risk factor only in the setting
type II diabetes and metabolic syndrome 070.2, 070.22, 070.3, 070.32),
of other well-established risk fac- without cirrhosis may be indicated after alcoholic liver damage (ICD-9:
tors for hepatocellular carcinoma further research. 571.0, 571.1, 571.3), hereditary
(ie, alcoholic cirrhosis or hepatitis hemochromatosis (ICD-9: 275.0),
B or C).9 nonalcoholic fatty liver disease
Type II diabetes is often associated with metabolic syn- (ICD-9: 571.8), nonalcoholic steatohepatitis (ICD-9: 571.8),
drome. Current data suggest that nearly 25% of the US cirrhosis (ICD-9: 571.2, 571.5, 571.6), alpha-1 antitrypsin
population meets criteria for metabolic syndrome.6 Meta- deficiency (ICD-9: 273.4), autoimmune hepatitis (ICD-9:
bolic syndrome includes a combination of type II diabetes, 571.42), and Wilson disease (ICD-9: 275.1) were excluded.
obesity, hypertension, and hyperlipidemia. The suggestion Because hepatitis C is the largest known risk factor for
of type II diabetes as a potential risk factor for hepatocellular hepatocellular carcinoma in the US, these patients were
carcinoma raises the question of whether other metabolic included in the analysis to evaluate the contribution of
syndrome components, for example, hypertension, hyper- hepatitis C with and without type II diabetes or metabolic
lipidemia, and obesity, may also increase hepatocellular syndrome. There were 7473 patients remaining after ex-
carcinoma risk. clusions were applied. Controls were age and sex matched
Recently, hepatocellular carcinoma has been associated in a 1:3 fashion, creating a control group of 22,110 in-
with components of metabolic syndrome in the setting of dividuals that complied with the same exclusion criteria.
cirrhosis. However, with the magnitude of hepatocellular The Figure describes how the study sample was
carcinoma and its projected increase in the US, meaningful constructed. The mean age was 57.7 years (SD  9.08
prevention and screening may need to begin prior to the years), with a range of 19-64 years (Table 1). There was
detection of cirrhosis. For this reason, we set out to deter- an equal distribution of males and females between cases
mine if type II diabetes, metabolic syndrome, or its com- and controls; confirming age and sex match at a rate of
ponents are risk factors for hepatocellular carcinoma 1:3 (99%) was effective. Cases were categorized based on
independent of cirrhosis. geographic region of health care consumption. Most cases
were from the South at 39.72%, with the Northeast,
North-central, and West regions being nearly equal in dis-
MATERIALS AND METHODS tribution (19.4%, 20.62%, and 19.19%). The geographic
region was unknown in 1.06% of cases.
Population
The MarketScan Commercial Claims and Encounters
Database (Truven Health Analytics, Bethesda, Md) captures Methods
clinical utilization, expenditures, and prescription drug A univariate analysis was performed with type II diabetes
claims data from a selection of large employers and health (ICD-9: 250.xx), hypertension (ICD-9: 401.0, 401.1,
plans, including commercial insurance companies, Blue 401.9), and hyperlipidemia (ICD-9: 272.4), as well as with
Cross and Blue Shield plans, and third-party administrators. hepatitis C (ICD-9: 070.54, 070.70, 070.71). The first 3
The database includes data from approximately 100 payers, variables were chosen as they represent significant com-
and represents insured employees and their dependents, ponents of the metabolic syndrome. Hepatitis C was
early retirees, Consolidated Omnibus Budget Reconciliation analyzed as a variable, as it currently represents the largest
Act (COBRA) individuals, and Medicare-eligible retirees known risk factor for hepatocellular carcinoma. A condi-
with employer-provided Medicare Supplemental plans. Data tional multivariable logistic regression analysis was then
Kasmari et al Diabetes and Metabolic Syndrome Increase Hepatocellular Carcinoma Risk 745.e3

Figure Study flow diagram. DM ¼ diabetes mellitus; HCC ¼ hepatocellular carcinoma; HCV ¼ hepatitis
C virus.

performed to determine the association of type II diabetes whether there were multiple medications used in the same
hypertension, hyperlipidemia, and hepatitis C with the patient. Hyperlipidemia medications included: lovastatin,
development of hepatocellular carcinoma. In addition, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvas-
medications used to treat diabetes and hyperlipidemia were tatin, pitavastatin, gemfibrozil, fenofibrate, nicotinic acid,
included in the primary multivariable analysis. Diabetes cholestyramine, colestipol, colesevelam, and ezetimibe.
medications included: insulin, metformin, thiazolidine- These medications were consolidated into one category,
diones, and sulfonylureas (glipizide, glyburide, glime- “cholesterol medications,” for analysis and were designated
piride). They were identified in the analysis as being present as being present or not. The medication analysis was con-
or not. There were no data included on length of use or structed as described based on prior studies’ identification
of medication group impact on metabolic syndrome and
hepatocellular carcinoma risk rather than individual
Table 1 Sociodemographic Data and Study Group Description
medications.
In an effort to evaluate metabolic syndrome and type II
Cases (N ¼ 7473) Controls (N ¼ 22,110) diabetes independent impact on hepatocellular carcinoma
risk, a sub-analysis was performed, which separately eval-
n (%) n (%)
uated patients with and without hepatitis C. Cases and
Age controls were divided into 2 groups: type II diabetes with
Mean hepatitis C and type II diabetes without hepatitis C. A
(SD  8.09) 57.7
conditional multivariable logistic regression analysis was
Median
(SD  8.09) 57
performed with hypertension and hyperlipidemia as co-
Range 19-64 y variants to create groups that met criteria for metabolic
Sex syndrome. Obesity is an important factor in metabolic
Male 4563 (61.01) 13,371 (60.47) syndrome; however, it is seldom coded as a diagnosis on
Female 2916 (38.99) 8793 (39.53) insurance claims. Therefore, the metabolic syndrome sub-
Geographic region analysis was used as a surrogate for the lack of obesity
Northeast 1452 (19.4) 2514 (11.34) data. Attempts to evaluate the diagnosis of metabolic syn-
North-central 1542 (20.62) 5136 (23.23) drome by diagnosis code (ICD-9: 277.7) were met with
South 2971 (39.72) 10,008 (45.26) similar difficulty to that of obesity, as it is seldom coded on
West 1435 (19.19) 4432 (20.05) insurance claims.
Unknown 79 (1.06) 20 (0.09)
This study was funded by the Department of Gastroen-
terology and Hepatology at Penn State Hershey Medical
745.e4
Center. There were no external funding sources. The study
was approved by the Institutional Review Board at Penn
State Hershey Medical Center.
RESULTS
A univariate analysis was performed to evaluate risk factors
for hepatocellular carcinoma individually (Table 2). There
were 2451 patients with hepatocellular carcinoma who
had type II diabetes, 4764 had hypertension, 2931 had
hyperlipidemia, and 2303 had hepatitis C. Type II
diabetes, hypertension, and hepatitis C all had a P value
of <.001, indicating a significant association with
hepatocellular carcinoma. Interestingly, when analyzed in
a univariate fashion, hyperlipidemia was found not to
have a significant association with hepatocellular
carcinoma (P value ¼ .6421).
Analysis of patients with hepatocellular carcinoma in a
multivariable analysis demonstrates that patients with type II
diabetes are 1.353 times more likely to develop hepatocel-
lular carcinoma than those without type II diabetes (95%
confidence interval [CI], 1.249-1.465) (Table 3). Hepatitis
C represented the largest individual risk factor, with a
2.102-increased risk of developing hepatocellular carci-
noma (95% CI, 1.964-2.250). Hypertension was associated
with an increased risk of 1.229 (95% CI, 1.155-1.308).
Conversely, hyperlipidemia was associated with a 12% he-
patocellular carcinoma risk reduction (odds ratio [OR]
0.885; 95% CI, 0.831-0.942).
Our data suggests increased risk of hepatocellular carci-
noma (OR 1.640; 95% CI, 1.482-1.814) in diabetic patients
using insulin. Metformin was associated with a 33% lower
risk of hepatocellular carcinoma (OR 0.706; 95% CI, 0.632-
0.788) (Table 3). There was no significant change in risk
associated with sulfonylureas. Cholesterol medications
were associated with a lower risk than metformin, with
44% hepatocellular carcinoma risk reduction (OR 0.645;
95% CI, 0.601-0.692).
To evaluate metabolic syndrome, we looked at hyper-
tension and hyperlipidemia in the setting of type II diabetes
with and without hepatitis C. Hypertension had a significant
impact on hepatocellular carcinoma risk, compounding the
established risk of hepatitis C and type II diabetes (Table 4).
Hypertension patients with both type II diabetes and
hepatitis C were associated with a 4.580-increased risk of
Table 2 Univariate Analysis of Risk Factors for Hepatocellular Carcinoma
Cases (N ¼ 7473)
Without Condition With Condition
Diabetes 4932 2541
Hypertension 2709 4764
Hyperlipidemia 4542 2931
Hepatitis C 5171 2303
The American Journal of Medicine, Vol 130, No 6, June 2017
hepatocellular carcinoma (95% CI, 3.705-5.662), whereas
those with hypertension and type II diabetes without hepa-
titis C had a 3.399 risk (95% CI, 3.11-3.708). Patients with
hyperlipidemia and type II diabetes had a similar risk,
whether hepatitis C was present or not. Hyperlipidemia with
type II diabetes and hepatitis C carried a 2.319 risk (95% CI,
1.978-2.718), while those with hyperlipidemia and type II
diabetes without hepatitis C had a 2.395 risk (95% CI,
2.215-2.590).
DISCUSSION
In the US, hepatitis C is the leading risk factor for
hepatocellular carcinoma.10 Hepatitis C cirrhosis carries a
39.89-fold (95% CI, 36.29-43.84) increased risk of hepa-
tocellular carcinoma. Hepatocellular carcinoma occurs in
these individuals secondary to hepatic inflammation and
fibrosis, as well as malignant transformation of hepatitis
C-infected cells.11 A meta-analysis showed that hepatitis
C-positive patients had 17 times the risk of hepatocellular
carcinoma when compared with a hepatitis C-negative
cohort.10,11 In patients with cirrhosis, the risk of developing
hepatocellular carcinoma is 1%-4% per year.12 There are
limited data evaluating the risk of hepatocellular carcinoma
associated with type II diabetes and metabolic syndrome
independent of cirrhosis. Type II diabetes or obesity, or
both, had a 2.47-fold (95% CI, 2.34-2.61) increased risk of
hepatocellular carcinoma in the setting of cirrhosis accord-
ing to a SEER-Medicare database study conducted in 1991
to 2007.13 Our aim was to clarify the risk of hepatocellular
carcinoma, without cirrhosis, associated with type II dia-
betes and metabolic syndrome.
In the VA, diabetes was found to increase the risk of
hepatocellular carcinoma in the presence of hepatitis C,
hepatitis B, or alcoholic cirrhosis (OR 1.57; 95% CI, 1.08-
2.28).9 Further, a recent VA study showed that 13% of
patients with hepatocellular carcinoma had no evidence of
cirrhosis. Of those without cirrhosis that had hepatocellular
carcinoma, a higher proportion had metabolic syndrome.14
These studies are less generalizable to the US population
due to male predominance and inclusion of other causes of
cirrhosis in the first mentioned study. Another VA pro-
spective study identified a 1.5 hazard ratio [HR] (95% CI,
0.9-2.5) for hepatocellular carcinoma with type II diabetes,
which was not statistically significant.15 A meta-analysis of
Controls (N ¼ 22,110)
Without Condition With Condition P Value
16,696 5414 <.0001
10,703 11,407 <.0001
13,371 8739 .6421
19,133 2977 <.0001
Kasmari et al Diabetes and Metabolic Syndrome Increase Hepatocellular Carcinoma Risk 745.e5

differences in findings.19 In addition, a study from northern

Table 3 Primary Conditional Multivariable Logistic Regression
Analysis: Factors Associated with HCC Europe showed a 2.08 relative hepatocellular carcinoma risk
with hypertension (95% CI, 0.95-4.73), which was not
OR 95% CI statistically significant.18,20 Viral hepatitis status was un-
DM 1.353 1.249-1.465 known in that study, which could account for the difference
Insulin 1.640 1.482-1.814 in findings.20
Metformin 0.706 0.632-0.788 Hyperlipidemia has been associated with decreased he-
Rosiglitazone 1.020 0.750-1.385 patocellular carcinoma, mortality with HRs of 0.38 and 0.5,
Pioglitazone 0.913 0.772-1.080 respectively (95% CI, 0.26-0.55 and 0.37-0.69).16 Consis-
Sulfonylureas 1.044 0.885-1.233 tent with these data, we demonstrated that hyperlipidemia
Cholesterol medication 0.645 0.601-0.692
was associated with decreased hepatocellular carcinoma risk
HTN 1.229 1.155-1.308
HLP 0.885 0.831-0.942
without cirrhosis (OR 0.885; 95% CI, 0.831-0.942). In the
HCV 2.102 1.964-2.250 Medicare population, the adjusted OR of hepatocellular
carcinoma risk with hyperlipidemia in the setting of
CI ¼ confidence interval; DM ¼ diabetes mellitus; HCC ¼ hepato-
cellular carcinoma; HCV ¼ hepatitis C virus; HLP ¼ hyperlipidemia;
cirrhosis was 1.35 (95% CI, 1.26-2.45).18,20 On the other
HTN ¼ hypertension; OR ¼ odds ratio. hand, a study from Eastern Europe found risk in cirrhotic
patients similar to our study, but it was not statistically
significant.18,20
studies that have looked at type II diabetes and hepatocel- The incidence of metabolic syndrome and hepatocellular
lular carcinoma showed a summary relative risk of 1.56 carcinoma continues to increase in the US population.20
(95% CI, 1.30-1.87) for type II diabetes associated with There is a link between the increase in hepatocellular car-
hepatocellular carcinoma.7 This analysis looked at 25 cinoma and metabolic syndrome.21 One-third of the US
studies, and only 2 were conducted in the US, at the VA.7 In population now meets criteria for metabolic syndrome.22
our study, the risk of hepatocellular carcinoma in type II Metabolic syndrome promotes hepatocellular carcinoma
diabetes was 1.353 (95% CI, 1.249-1.465). Unlike the VA development in multiple ways. It creates insulin resistance
study, we had equal sex and age distribution. Our study that leads to an increase in insulin-like growth factor-1, the
differed in design from those previously reported because most powerful activator of cellular proliferation.23 It
we controlled for all causes of cirrhosis except hepatitis C. increases the signaling of several cancer development
Our study population, however, did not include subjects pathways, and creates an environment ideal for developing
over the age of 64 years, whereas the VA had a mean age of hepatic inflammation and steatosis.6,19,23 Hepatitis C in-
62 years and included older subjects. creases the risk of diabetes.24 Hepatitis C core protein re-
Hypertension and its association with hepatocellular duces insulin receptor substrates 1 and 2, leading to insulin
carcinoma risk has not been well studied. However, resistance.24 A Welzel et al17 study using a Medicare claims
hypertension has been associated with an increased hepa- database demonstrated that metabolic syndrome occurred
tocellular carcinoma mortality.16 Our study shows an inde- more commonly in patients with hepatocellular carcinoma
pendent risk association between hypertension and (37.1%) compared with those without hepatocellular carci-
hepatocellular carcinoma (OR 1.229; 95% CI, 1.155-1.308). noma (17.1%), and metabolic syndrome was associated with
One Medicare database study showed a 2.22-adjusted OR increased risk of hepatocellular carcinoma (OR 2.13; 95%
for hepatocellular carcinoma risk with hypertension (95% CI, 1.96-2.31). Although this population is older than the
CI, 2.04-2.42).17,18 Unlike our study, causes of cirrhosis one analyzed in our study, a relationship still exists between
were not excluded and the population was older. Hepato- hepatocellular carcinoma and metabolic syndrome.
cellular carcinoma occurring with metabolic syndrome has There is limited data about hepatocellular carcinoma
been thought to occur at an older age than hepatocellular associated with metabolic syndrome in noncirrhotic patients.
carcinoma from other causes, which could explain the A case series by Perumpail et al6 evaluated a cohort of
patients with nonalcoholic fatty liver disease and nonalco-
holic steatohepatitis that developed hepatocellular carci-
noma in the absence of cirrhosis.25 In this cohort of 44
Table 4 Secondary Conditional Multivariable Sub-analysis for
patients, 6 patients developed hepatocellular carcinoma
HCC
with either nonalcoholic steatohepatitis, nonalcoholic fatty
HTN HLP liver disease, or with 2 components of metabolic syndrome
and no underlying liver disease. All 6 patients had at least 2
OR 95% CI OR 95% CI
components of metabolic syndrome; all 6 had hypertension,
DM with HCV 4.580 3.705-5.662 2.319 1.978-2.718 and type II diabetes or insulin resistance, and 5 had
DM without HCV 3.399 3.11-3.708 2.395 2.215-2.590 hyperlipidemia. All of these patients had both hypertension
CI ¼ confidence interval; DM ¼ diabetes mellitus; HCC ¼ hepato- and type II diabetes, which is the combination in our
cellular carcinoma; HCV ¼ hepatitis C virus; HLP ¼ hyperlipidemia; analysis that represented the largest risk (OR 3.399; 95% CI,
HTN ¼ hypertension; OR ¼ odds ratio.
3.11-3.708).
745.e6
Our study suggests that diabetes, hypertension, and
metabolic syndrome are associated with hepatocellular car-
cinoma independent of cirrhosis. In order to combat these
risks, it is important to understand how the management of
these conditions influences hepatocellular carcinoma risk. A
Taiwanese study showed a protective effect with metformin
(HR 0.49; 95% CI, 0.37-0.84); likewise, metformin had an
OR of 0.706 (95% CI, 0.632-0.788) in our study.8 In the
Taiwanese study, thiazolidinediones were also protective
(hazard ratio 0.56; 95% CI, 0.37-0.84), while insulin and
sulfonylureas were not significant.8 In our analysis, sulfo-
nylureas and thiazolidinediones were not significant. Inter-
estingly, we found insulin to be associated with an increased
risk of hepatocellular carcinoma. This may serve as a marker
of disease severity rather than representing an association
with the medication itself, as patients with more severe
diabetes are typically treated with insulin. The differences
seen between the Taiwanese study and our results may be
caused by differences in underlying population risk factors.
In addition, the Taiwanese study was able to analyze the
duration of therapy and its effect on risk, which was not
available in our analysis.
Medications, such as statins, also seem to be associated
with lower hepatocellular carcinoma risk in prior studies,26-28
and lead to lower all-cause mortality in cirrhosis.29 A
population-based case-control Taiwanese study found that
statin use was associated with reduced risk of hepatocellular
carcinoma (OR 0.53; 95% CI, 0.41-0.69), which is similar to
the reduced risk suggested in our analysis with the use of
any cholesterol medication, including statins (OR 0.645,
95% CI, 0.601-0.692).26 Another Taiwanese cohort study
analyzed a doseeresponse relationship between statins and
hepatocellular carcinoma.28 This study found that statins
were protective against hepatocellular carcinoma, demon-
strating greater protection occurring in individuals that had
been treated with statins for longer periods of time. Our
study design did not include time course for medications,
but simply that the medication had been used, requiring
further analysis to evaluate a doseeresponse relationship
with statins.
Metformin has antitumoral properties through the acti-
vation of the 50 adenosine monophosphate-activated protein
kinase pathway. This inhibits mTOR, downregulates c-
Myc,23,30 inhibits cyclin D1 expression arresting the cell
cycle of hepatoma cells, and modulates the expression of
cytokines that suppress Wnt/B-catenin signaling.23,31
Similar to metformin, statin medications modify the same
3 pathways that promote hepatocellular carcinoma through
their 3-hydroxy-3-methylglutaryl coenzyme A inhibi-
tion,23,32 downregulating pathways that promote
apoptosis,23,32 and limiting destruction of the cyclin-
dependent kinase inhibitors that inhibit tumor growth.23
Based on several reported mechanistic and epidemiologic
studies, metformin and statins have been advocated as
chemoprotective agents for hepatocellular carcinoma.
Larger randomized clinical trials need to be performed to
help this become standard practice.
The American Journal of Medicine, Vol 130, No 6, June 2017
Limitations
Several limitations of this study must be acknowledged. The
patient population is relatively young, with ages ranging
from 19-64 years. The MarketScan Database includes
claims from private insurers and does not include the
Medicare population. Insurance claims data may under-
represent conditions when compared with other objective
research methods. Importantly, in this study there is the
chance that cirrhosis is not identified by insurance claim. A
recent study revealed that only 54% of patients with biopsy-
proven cirrhosis actually had an ICD-9 code for cirrhosis in
claims data.30 Additionally, conditions such as nonalcoholic
fatty liver disease may be present in these patients but not
coded for as a diagnosis. The time period analyzed during
our study is relatively short (2008-2012), making it difficult
to determine how the duration of risk-factor exposure in-
fluences the development of hepatocellular carcinoma.
Finally, a critical component of metabolic syndrome is
obesity. As the purpose of diagnosis codes is for billing,
obesity is not commonly documented as a diagnosis on
insurance claims. Therefore, obesity was not able to be
included as a variable. More prospective studies, including
obesity as a variable, are necessary to fully investigate this
critical component of metabolic syndrome. While associa-
tions between diabetes and metabolic syndrome with he-
patocellular carcinoma were seen in this study, further
analysis is required to determine the true association in the
absence of cirrhosis, as insurance claims data cannot guar-
antee that no undiagnosed cirrhosis or nonalcoholic fatty
liver disease was included in the study population.
CONCLUSION
Success in treatment of hepatocellular carcinoma is depen-
dent on early detection. Therefore, understanding the risk
factors is important for adequate treatment. Type II diabetes
and hypertension appear to be associated with hepatocellular
carcinoma, in the absence of cirrhosis. The medical man-
agement of diabetes and hyperlipidemia, particularly with
metformin and cholesterol medications, appears to be
associated with reduced risk of hepatocellular carcinoma.
On the contrary, insulin use was associated with increased
risk of hepatocellular carcinoma in diabetic patients without
cirrhosis. These findings may translate into targets for
screening and therapies to improve survival in patients with
hepatocellular carcinoma.
ACKNOWLEDGMENT
The study was approved by the Institutional Review Board
at Penn State Hershey Medical Center.
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