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Am J Gastroenterol 2012; 107:53-55; doi:10.1038/ajg.2011.390
Editorial: Hepatocellular Carcinoma in Type 2 Diabetes: More Than Meets the
Eye György Baffy MD, PhD1
1VA Boston Healthcare System and Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts, USA Correspondence: György Baffy,
MD, PhD, VA Boston Healthcare System, Section of Gastroenterology, 150 S.
Huntington Avenue, Room 6A-46, Boston, Massachusetts 02130, USA. E-mail:
[email protected] Received 12 September 2011; Accepted 26 September 2011
Top of page Abstract Abstract: Hepatocellular carcinoma (HCC), a disease
with poor survival rates unless recognized and treated early, ranks as the
fifth most common cancer worldwide and has a rising incidence in the United
States. Recent data indicate that the growing epidemic of type 2 diabetes
mellitus may contribute to this alarming trend. In this issue, Lai et al.
utilize a large Taiwanese insurance claims database to demonstrate that
diabetes is associated with an increased risk of HCC. Moreover, this risk
escalates if diabetes coincides with chronic hepatitis C and cirrhosis. Lai
et al. also show that treatment with metformin or thiazolidinediones may
reduce the risk of HCC. The findings may prompt risk stratification for HCC
surveillance and improved disease control in diabetes as measures of
cancer prevention. Hepatocellular carcinoma (HCC) accounts for 70-85% of
primary liver cancers, ranking fifth among the most common malignancies
worldwide and third as a cause of cancer death. Dominant etiological
factors of HCC show great variations according to different geographic
areas. In Asia, vertically transmitted hepatitis B infection is a major
contributor to HCC, which may emerge in non-cirrhotic livers due to direct
oncogenic properties of the hepatitis B virus. In sub-Saharan Africa,
dietary exposure to aflatoxin may synergize with the carcinogenic effects
of chronic hepatitis B infection. In the Western world, HCC most often
complicates cirrhosis evolving from chronic viral hepatitis B and C,
alcoholic injury, or inherited disorders such as hemochromatosis (1,2). HCC
is increasingly common in the United States, with an age-adjusted incidence
rising from 1.5 to 4.9 per 100,000 individuals between 1975 and 2005 (3).
This trend is alarming since HCC remains a disease with poor outcomes
despite recent advances in its diagnosis and treatment. The rising
incidence has been primarily attributed to the high prevalence of chronic
hepatitis C in the US population and is predicted to reach its peak by 2020
(4). However, the underlying cause of HCC remains unknown in as many as 50%
of all cases and additional risk factors need to be identified to
facilitate disease prevention and timely recognition (1,2). Evidence shows
that the rapidly growing obesity epidemic and its ill effects may
contribute to the rising incidence of HCC. A recent epidemiological
analysis conducted on 900,000 American adults found that higher body mass
indices are linked to increased relative risk of cancer death (5). Thus,
obesity confers higher risk of dying from various cancers (primarily
affecting the digestive system), with a relative risk of 4.52 for liver
cancer death topping the list among men with a body mass index of 35?kg/m2
or above (5). Reports indicate that individuals with type 2 diabetes, an
increasingly common disease complicating and overlapping with obesity, also
are at higher risk for many forms of cancer, including the liver (6,7). In
a population-based US study on patients aged 65 years and older, the
proportion of diabetes among HCC patients (43%) was significantly greater
than in non-cancer controls (19%) and multiple logistic regression analysis
indicated a threefold increase in the risk of HCC among diabetics (8).
Co-existing diabetes and chronic hepatitis C infection conferred a 37-fold
increase in HCC risk, while 57% of HCC patients with diabetes did not have
any specific major risk factor for liver cancer (8). Subsequent studies
found that longer duration of diabetes increases the risk of HCC (9). In
this issue of the American Journal of Gastroenterology, Lai et al. (10) use
population-based insurance claims data to examine the risk of HCC in
Taiwanese individuals with diabetes. Their retrospective analysis of the
Taiwan National Health Insurance Research Database between 2000 and 2005
identified a cohort of 19,349 patients at least 20 years of age when
diagnosed with diabetes. The incidence of subsequently (within 8 years)
recognized HCC was compared with a non-diabetic group matched for age and
gender. Authors found that HCC incidence rates classified by age, gender,
and length of follow-up were all higher in the diabetes group. Male gender
and longer duration of diabetes carried higher HCC incidence.
Co-morbidities associated with increased risk of HCC, including chronic
hepatitis B and C, alcoholic liver damage, cirrhosis, obesity, and
non-alcoholic fatty liver disease (NAFLD), were all more prevalent in the
diabetes group. The hazard ratio of HCC associated with diabetes was 1.73
(95% confidence interval (CI)=1.47-2.03) when adjusted for these
co-morbidities and it reached 72.4 (95% CI=42.9-122) for subjects having
diabetes, chronic hepatitis C, and cirrhosis. These findings identify a
segment of the diabetic population where HCC surveillance may be critically
important. The pathogenesis of HCC complicating diabetes in the absence of
major HCC risk factors is not well understood. Oncogenic pathways in
diabetes may be activated due to hyperinsulinemia, pro-inflammatory
adipokine imbalance, oxidative stress, and lipotoxicity (11,12). Diabetes
is commonly associated with NAFLD, the major hepatic manifestation of
obesity that presents as steatosis or steatohepatitis and may progress to
cirrhosis in up to 5% of patients (13,14). Diabetes has been identified as
an independent risk factor in this progression (15). The findings of Lai et
al. (10) indicate that this interaction perseveres and diabetes may
synergize with cirrhosis in promoting the development of HCC. Current HCC
surveillance guidelines propose bi-annual liver ultrasound for patients
diagnosed with cirrhosis (16). These guidelines apply to diabetic patients
with cirrhosis, who may increasingly benefit from this surveillance as
suggested by the Taiwanese group (10). It is more difficult to determine
the need for HCC surveillance in diabetic patients with non-cirrhotic liver
or with no established liver disease. Importantly, up to half of all HCC
cases may develop in non-cirrhotic livers (17,18). Evidence is accumulating
that NAFLD, the most prevalent liver condition in the United States
affecting diabetic patients, may contribute to non-cirrhotic HCC. A recent
analysis of a large US health care claims database found that only 46% of
patients with NAFLD and HCC were reported to have cirrhosis (19). However,
the extent to which NAFLD, and its advanced form of steatohepatitis, may be
responsible for promoting HCC among diabetics with no cirrhosis and no
major HCC risk factors remains currently unknown. NAFLD has also been
associated with cryptogenic cirrhosis (20), which may account for as much
as 40% of all HCC cases (2). Since the index of suspicion for HCC is
generally low in the absence of viral or alcoholic injury, HCC in
cryptogenic cirrhosis often remains undiagnosed until reaching clinically
advanced stages. In a recent study, patients with cryptogenic cirrhosis
were less likely to be enrolled in HCC surveillance (23%), leading to
delayed diagnosis, larger tumor size, and diminished likelihood for
successful therapy (21). To avoid these pitfalls, increased awareness of
risk factors for advanced background liver disease and HCC in diabetic
patients may be warranted (e.g., male gender, older age, morbid obesity,
poorly controlled and long-standing disease, co-existing hepatitis C),
perhaps by developing an "HCC risk score," to prompt HCC surveillance when
appropriate. Further studies may be required before such an approach is
considered for 26 million diabetic Americans. Of note, the Taiwanese
findings may not be directly extrapolated to the US population. While a
recent US study found that 74% of diabetic patients had biopsy-proven NAFLD
of which 22% were steatohepatitis (22), Lai et al. (10) found unusually low
rates of NAFLD reported among Taiwanese diabetics (3.6%), which may
indicate underreporting, variation in disease criteria, or biological
differences. Lai et al. (10) also investigated the effect of anti-diabetic
therapy on the risk of HCC. Hazard ratios of HCC were determined for each
of five different treatment modalities (insulin, metformin, sulfonylureas,
thiazolidinediones, and ?-glucosidase inhibitors) and compared by Cox
proportional hazard analysis, which could not account for the effect of
combined use of medications. Patients who were prescribed metformin for an
average of 2.5 years (n=16,282) had the lowest hazard ratio of HCC at 0.49
(95% CI=0.37-0.66), while patients taking thiazolidinediones for an average
of 2.1 years (n=3,835) had a similarly low hazard ratio at 0.56 (95%
CI=0.37-0.84). Somewhat at variance with earlier data in the literature
(reviewed in ref. 23), Lai et al. (10) found that other anti-diabetic
agents also reduced the risk of HCC, albeit the effects did not reach
statistical significance. Moreover, medication compliance and the extent of
diabetes control (HgbA1c) is unknown from the study, although compliance
was likely less than optimal (e.g., the rate of alcohol consumption in the
diabetes group was almost threefold higher compared with non-diabetic
controls), making perhaps the observed impact on HCC hazard ratios even
more important. Experimental and clinical observations on the ability of
anti-diabetic medications to alter cancer risk by improving insulin
resistance are accumulating (23). Metformin, an activator of AMP-activated
protein kinase, and thiazolidinediones, agonists of peroxisome
proliferator-activated receptor ?, may effectively reduce circulating
glucose and insulin levels and limit their systemic effects on oncogenic
pathways (23). In addition, metformin and thiazolidinediones reduce the
extent of hepatic lipid accumulation, further limiting the organ-specific
molecular events that may contribute to hepatocarcinogenesis (24). The
observations of Lai et al. (10) provide valuable additional evidence that
properly controlled glucose and lipid homeostasis may help avoid or delay
diabetes-associated complications, an unfortunately long list that now
includes HCC.
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发表于 2012-1-20 04:00