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Diabetes Is Leading Cause of Attributable Cases of Hepatocellular Carcinoma
I was surprised by this article - and rather dismayed. I hate posting negative news but I always think it is better to know. Of course, I happen to be a diabetic.....wouldn't you just know?
Diabetes Is Leading Cause of Attributable Cases of Hepatocellular Carcinoma
Nick Mulcahy
April 28, 2010 (Washington, DC) — Which risk factor for hepatocellular carcinoma (HCC) is associated with the largest proportion of cases of the disease in the United States?
If you answered hepatitis C (HCV), hepatitis B (HBV), or alcohol-related disease, you would be wrong.
The mistake is understandable. These risk factors have the highest odds ratios for HCC, and therefore put an affected individual at relatively higher risk of developing the disease than other factors, said Katherine McGlynn, PhD, from the National Cancer Institute (NCI), here at the American Association for Cancer Research (AACR) 101st Annual Meeting.
However, more cases of HCC overall are attributable to diabetes than any other risk factor, she said during a meeting press conference, where the results of the study were highlighted.
The impact of well known risk factors for HCC, such as hepatitis, "tends to be misinterpreted" because information on their incidence is not presented, Dr. McGlynn told reporters.
Also, "there is a perception that the majority of cases of the disease are not associated with a known risk factor," she said.
But the new study from Dr. McGlynn and colleagues from the NCI and Baylor College of Medicine in Houston, Texas, sheds light on the risk factors for HCC and their incidence.
They found that diabetes was associated with the greatest percentage of cases (33.5%), followed by alcohol-related disorders (23.9%), HCV infection (20.7%), HBV infection (5.7%), rare metabolic disorders (3.1%), and obesity (2.7%).
The findings conflict with conventional wisdom about HCC and its associated risks, said Dr. McGlynn.
Much of the hepatocellular carcinoma literature now states that HCV is 'the major risk factor.'
"Much of the hepatocellular carcinoma literature now states that HCV is 'the major risk factor for hepatocellular carcinoma in the United States'," she told Medscape Oncology.
Overall, approximately 63% of HCC was associated with 1 or more of these risk factors, indicating that 37% of cases are not explainable by the known risk factors.
Still, the new findings point to an important direction in the prevention of HCC.
"Overall, controlling diabetes might have a greater impact than any other single factor on reducing the incidence of hepatocellular carcinoma in the United States," the study authors conclude in their abstract.
The incidence of HCC has been steadily increasing in the United States, said Dr. McGlynn. The total incidence was about 1.59 per 100,000 person-years in 1975; by 2006, the total incidence reached 4.82 per 100,000 person-years, according to a graphic presented by Dr. McGlynn.
Mining the SEER–Medicare Database
In the study, the investigators reviewed data from the NCI Surveillance, Epidemiology and End Results Program (SEER)–Medicare linked database.
The case population consisted of 5607 people diagnosed with HCC who had at least 3 prediagnostic years of Medicare coverage between 1994 and 2005. The control population was a 5% random sample of people residing in SEER–Medicare locations.
For each HCC risk factor, odds ratios of an individual developing HCC were calculated.
They found that HCV infection was the risk factor with the highest odds ratio (44.26; 95% confidence interval [CI], 39.52 - 49.56). The odds ratio (95% CI) for HBV infection was 13.37 (10.53 - 16.97); for alcohol-related disease was 4.43 (4.14 - 4.74); for rare metabolic disorder was 3.51 (2.96 - 4.15); for diabetes was 2.37 (2.23 - 2.52); and for obesity was 1.53 (1.37 - 1.72).
The risk-factor percentages also varied by racial/ethnic group.
In terms of explainable risk factors, the investigators found that 67.9% of Asians with HCC had 1 or more of the identified risk factors, whereas only 53.5% of blacks had an identifiable risk factor. These 2 groups had the highest and lowest percentages, respectively; Hispanics (64.9%) and whites (62.9%) were in between.
The investigators also used the SEER–Medicare data to calculate the proportion of HCC cases attributable to the risk factors. As noted above, the order of risk factors was very different, with diabetes at the top of the list of attributable cases.
Are clinicians acutely aware that diabetes causes HCC?
"I think so," said Ernest T. Hawk, MD, MPH, vice president of the Division of Cancer Prevention and Population Sciences at the University of Texas M.D. Anderson Cancer Center in Houston. Dr. Hawk moderated the AACR press conference at which Dr. McGlynn spoke.
I suspect that primary care physicians may not know that persons with diabetes are at increased risk.
"It's well known that diabetes and overweight can cause hepatocellular carcinoma. They are in the list of causes in all medical textbooks. But they may be under a name like metabolic syndrome," he told Medscape Oncology.
However, Dr. McGlynn said that, compared with the other causes, diabetes and overweight have been associated with HCC only "more recently."
"I suspect that primary care physicians may not know that persons with diabetes are at increased risk of hepatocellular carcinoma," she said.
The authors have disclosed no relevant financial relationships.
American Association for Cancer Research (AACR) 101st Annual Meeting: Abstract 1816. Presented April 19, 2010.
Mike
Diabetes Is Leading Cause of Attributable Cases of Hepatocellular Carcinoma
Nick Mulcahy
April 28, 2010 (Washington, DC) — Which risk factor for hepatocellular carcinoma (HCC) is associated with the largest proportion of cases of the disease in the United States?
If you answered hepatitis C (HCV), hepatitis B (HBV), or alcohol-related disease, you would be wrong.
The mistake is understandable. These risk factors have the highest odds ratios for HCC, and therefore put an affected individual at relatively higher risk of developing the disease than other factors, said Katherine McGlynn, PhD, from the National Cancer Institute (NCI), here at the American Association for Cancer Research (AACR) 101st Annual Meeting.
However, more cases of HCC overall are attributable to diabetes than any other risk factor, she said during a meeting press conference, where the results of the study were highlighted.
The impact of well known risk factors for HCC, such as hepatitis, "tends to be misinterpreted" because information on their incidence is not presented, Dr. McGlynn told reporters.
Also, "there is a perception that the majority of cases of the disease are not associated with a known risk factor," she said.
But the new study from Dr. McGlynn and colleagues from the NCI and Baylor College of Medicine in Houston, Texas, sheds light on the risk factors for HCC and their incidence.
They found that diabetes was associated with the greatest percentage of cases (33.5%), followed by alcohol-related disorders (23.9%), HCV infection (20.7%), HBV infection (5.7%), rare metabolic disorders (3.1%), and obesity (2.7%).
The findings conflict with conventional wisdom about HCC and its associated risks, said Dr. McGlynn.
Much of the hepatocellular carcinoma literature now states that HCV is 'the major risk factor.'
"Much of the hepatocellular carcinoma literature now states that HCV is 'the major risk factor for hepatocellular carcinoma in the United States'," she told Medscape Oncology.
Overall, approximately 63% of HCC was associated with 1 or more of these risk factors, indicating that 37% of cases are not explainable by the known risk factors.
Still, the new findings point to an important direction in the prevention of HCC.
"Overall, controlling diabetes might have a greater impact than any other single factor on reducing the incidence of hepatocellular carcinoma in the United States," the study authors conclude in their abstract.
The incidence of HCC has been steadily increasing in the United States, said Dr. McGlynn. The total incidence was about 1.59 per 100,000 person-years in 1975; by 2006, the total incidence reached 4.82 per 100,000 person-years, according to a graphic presented by Dr. McGlynn.
Mining the SEER–Medicare Database
In the study, the investigators reviewed data from the NCI Surveillance, Epidemiology and End Results Program (SEER)–Medicare linked database.
The case population consisted of 5607 people diagnosed with HCC who had at least 3 prediagnostic years of Medicare coverage between 1994 and 2005. The control population was a 5% random sample of people residing in SEER–Medicare locations.
For each HCC risk factor, odds ratios of an individual developing HCC were calculated.
They found that HCV infection was the risk factor with the highest odds ratio (44.26; 95% confidence interval [CI], 39.52 - 49.56). The odds ratio (95% CI) for HBV infection was 13.37 (10.53 - 16.97); for alcohol-related disease was 4.43 (4.14 - 4.74); for rare metabolic disorder was 3.51 (2.96 - 4.15); for diabetes was 2.37 (2.23 - 2.52); and for obesity was 1.53 (1.37 - 1.72).
The risk-factor percentages also varied by racial/ethnic group.
In terms of explainable risk factors, the investigators found that 67.9% of Asians with HCC had 1 or more of the identified risk factors, whereas only 53.5% of blacks had an identifiable risk factor. These 2 groups had the highest and lowest percentages, respectively; Hispanics (64.9%) and whites (62.9%) were in between.
The investigators also used the SEER–Medicare data to calculate the proportion of HCC cases attributable to the risk factors. As noted above, the order of risk factors was very different, with diabetes at the top of the list of attributable cases.
Are clinicians acutely aware that diabetes causes HCC?
"I think so," said Ernest T. Hawk, MD, MPH, vice president of the Division of Cancer Prevention and Population Sciences at the University of Texas M.D. Anderson Cancer Center in Houston. Dr. Hawk moderated the AACR press conference at which Dr. McGlynn spoke.
I suspect that primary care physicians may not know that persons with diabetes are at increased risk.
"It's well known that diabetes and overweight can cause hepatocellular carcinoma. They are in the list of causes in all medical textbooks. But they may be under a name like metabolic syndrome," he told Medscape Oncology.
However, Dr. McGlynn said that, compared with the other causes, diabetes and overweight have been associated with HCC only "more recently."
"I suspect that primary care physicians may not know that persons with diabetes are at increased risk of hepatocellular carcinoma," she said.
The authors have disclosed no relevant financial relationships.
American Association for Cancer Research (AACR) 101st Annual Meeting: Abstract 1816. Presented April 19, 2010.
Mike
and adding a (hopefully) positive note to this gloomy topic for all SVRs :
"Drs. Zhong and Yang also raise the question whether the carcinogenic effect of hepatitis C virus (HCV) might be partly explained by metabolic abnormalities induced by HCV. Indeed, we think that it is possible that part of the carcinogenic effect of HCV is mediated by metabolic abnormalities induced by the virus.2,3 If this hypothesis is true, improving insulin sensitivity by exercise, weight loss, or insulin-sensitizing agents might help to protect against the development of hepatocellular carcinoma. These potential effects should be investigated in prospective studies. Because sustained virologic response has been shown to be associated with a decreased risk of developing diabetes mellitus, achieving sustained virologic response may be the best way for patients infected with HCV to prevent insulin resistance."
from the author's reply to a comment by Zhong and Yang to the Veldt'08 paper linked above.
"Drs. Zhong and Yang also raise the question whether the carcinogenic effect of hepatitis C virus (HCV) might be partly explained by metabolic abnormalities induced by HCV. Indeed, we think that it is possible that part of the carcinogenic effect of HCV is mediated by metabolic abnormalities induced by the virus.2,3 If this hypothesis is true, improving insulin sensitivity by exercise, weight loss, or insulin-sensitizing agents might help to protect against the development of hepatocellular carcinoma. These potential effects should be investigated in prospective studies. Because sustained virologic response has been shown to be associated with a decreased risk of developing diabetes mellitus, achieving sustained virologic response may be the best way for patients infected with HCV to prevent insulin resistance."
from the author's reply to a comment by Zhong and Yang to the Veldt'08 paper linked above.
Here's a couple more reports, along these lines:
http://www.ncbi.nlm.nih.gov/pubmed/18506898
which reports that "For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC." with more than a doubled 5-year HCC incidence rate (11 vs 5) when DB was coupled with advanced fibrosis. However, they have no control data for HCC rates in the presence DB but without HCV nor, more relevant to this thread, how that risk changes in the presence of DB after SVR.
A recent meta-analysis of published data (free access) doesn't answer the question either but seems skeptical of a "true" causal DB-HCC link.
http://www.ncbi.nlm.nih.gov/pubmed/19822488
In fairness to Dr. McGlynn, she's an epidemiologist, not an MD, so her area of expertise would be associations rather than mechanism. Personally I have no clue what interpretation accompanies an AR vs OR difference - they look like they should be pointing in the same direction..
http://www.ncbi.nlm.nih.gov/pubmed/18506898
which reports that "For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC." with more than a doubled 5-year HCC incidence rate (11 vs 5) when DB was coupled with advanced fibrosis. However, they have no control data for HCC rates in the presence DB but without HCV nor, more relevant to this thread, how that risk changes in the presence of DB after SVR.
A recent meta-analysis of published data (free access) doesn't answer the question either but seems skeptical of a "true" causal DB-HCC link.
http://www.ncbi.nlm.nih.gov/pubmed/19822488
In fairness to Dr. McGlynn, she's an epidemiologist, not an MD, so her area of expertise would be associations rather than mechanism. Personally I have no clue what interpretation accompanies an AR vs OR difference - they look like they should be pointing in the same direction..
"Interesting news but I think Nick Mulcahy may sensationalizing McGlynn's findings a bit "
An accurate observation from my view point. I'm not dismissing the positive contributions of any reporters or authors also but I will admit that I also scrutinize articles like this when they come from Liz Highleyman or Jules Levin also. And I agree with you on the analysis of establishing solid connections. - ML
mike- An interesting read, thanks for posting. maybe I'm missing alot of info but from what you posted I cannot see one firm finding that is supported sufficiently to put any credence to it. And I question the credibilty of those who involved. To wit, one expert from the study answered this question: Are clinicians acutely aware that diabetes causes HCC?
"I think so," said Ernest T. Hawk, MD, MPH, vice president of the Division of Cancer Prevention and Population Sciences at the University of Texas M.D. Anderson Cancer Center in Houston. Dr. Hawk moderated the AACR press conference at which Dr. McGlynn spoke. He went on to say.....
"It's well known that diabetes and overweight can cause hepatocellular carcinoma. They are in the list of causes in all medical textbooks. But they may be under a name like metabolic syndrome," he told Medscape Oncology."
Then the other 'expert' ,Dr McGlynn, who obviously needs to stand behind her findings or should I say lack thereof , went on to say right after this:
""I suspect that primary care physicians may not know that persons with diabetes are at increased risk of hepatocellular carcinoma," she said.
Perhaps she needs to look under 'metabolic disorders' to find that it is indeed covered at doctor school.
all- How can someone find anything 'scary' in this is really beyond me. There is nothing proven as far as HCC connections are concerned, The diabetes issue is still unclear still locked in a chicken or egg theory as it relates to HCV and HCC. Does HCV cause the diabetes ? Then the causal effect would be from HCV, not diabetes. Does diabetes negatively affect liver function in those with HCV creating a synergistic effect leading to worsening of disease and poorer clinical outcomes ? In this setting it could be a multi-factorial causal effect. Further clouding the picture is their association of alcohol as a seperate risk factor for HCC. This in light of the well known association of alcohol abuse and HCV, alcohol abuse and diabetes, and alcohol abuse and HCC. I just didn't see any hint of statistical analysis beyond basic percentages for AR,OR and CI . All in all a study that produced no new findings---at least ones that made sense, while succeeding in muddying the waters for many who won't look any further than this article and will be undoubtedly repeating whatever numbers and percentages that struck their fancy as a fact. - ML
An accurate observation from my view point. I'm not dismissing the positive contributions of any reporters or authors also but I will admit that I also scrutinize articles like this when they come from Liz Highleyman or Jules Levin also. And I agree with you on the analysis of establishing solid connections. - ML
mike- An interesting read, thanks for posting. maybe I'm missing alot of info but from what you posted I cannot see one firm finding that is supported sufficiently to put any credence to it. And I question the credibilty of those who involved. To wit, one expert from the study answered this question: Are clinicians acutely aware that diabetes causes HCC?
"I think so," said Ernest T. Hawk, MD, MPH, vice president of the Division of Cancer Prevention and Population Sciences at the University of Texas M.D. Anderson Cancer Center in Houston. Dr. Hawk moderated the AACR press conference at which Dr. McGlynn spoke. He went on to say.....
"It's well known that diabetes and overweight can cause hepatocellular carcinoma. They are in the list of causes in all medical textbooks. But they may be under a name like metabolic syndrome," he told Medscape Oncology."
Then the other 'expert' ,Dr McGlynn, who obviously needs to stand behind her findings or should I say lack thereof , went on to say right after this:
""I suspect that primary care physicians may not know that persons with diabetes are at increased risk of hepatocellular carcinoma," she said.
Perhaps she needs to look under 'metabolic disorders' to find that it is indeed covered at doctor school.
all- How can someone find anything 'scary' in this is really beyond me. There is nothing proven as far as HCC connections are concerned, The diabetes issue is still unclear still locked in a chicken or egg theory as it relates to HCV and HCC. Does HCV cause the diabetes ? Then the causal effect would be from HCV, not diabetes. Does diabetes negatively affect liver function in those with HCV creating a synergistic effect leading to worsening of disease and poorer clinical outcomes ? In this setting it could be a multi-factorial causal effect. Further clouding the picture is their association of alcohol as a seperate risk factor for HCC. This in light of the well known association of alcohol abuse and HCV, alcohol abuse and diabetes, and alcohol abuse and HCC. I just didn't see any hint of statistical analysis beyond basic percentages for AR,OR and CI . All in all a study that produced no new findings---at least ones that made sense, while succeeding in muddying the waters for many who won't look any further than this article and will be undoubtedly repeating whatever numbers and percentages that struck their fancy as a fact. - ML
Causes of Diabetes
Diabetes mellitus occurs when the pancreas doesn't make enough or any of the hormone insulin, or when the insulin produced doesn't work effectively. In diabetes, this causes the level of glucose in the blood to be too high.
Although millions of people undergo problems with diabetes, they are not generally aware that their problems could greatly be relieved by adjusting their diet. Diabetes is the 8th leading cause of death in the United States, because diabetics are extremely vulnerable to arteriosclerosis and are highly prone to heart attacks and stroke. Most diabetics eat the standard diet that most other people eat. As a result most of them, during a seventeen year period which follows discovery of their diabetic condition, undergo major health problems, including heart attack, kidney failure, strokes, and blindness. In Lancet, the British medical publication, Dr.Inder Singh reported a study in which 80 diabetic patients were restricted to very low fat diets - 20 to 30 grams per day - and forbidden any sugar. By the time six weeks had elapsed, more than 60% of the patients no longer required insulin. The figure eventually rose to 70%, and those who were left only required a small fraction of the insulin formerly needed. All 80 cases were monitored for periods ranging from six months to over five years, and the success of the dietary change was confirmed over time. [1]
http://www.karlloren.com/diet/p42.htm
Diabetes mellitus occurs when the pancreas doesn't make enough or any of the hormone insulin, or when the insulin produced doesn't work effectively. In diabetes, this causes the level of glucose in the blood to be too high.
Although millions of people undergo problems with diabetes, they are not generally aware that their problems could greatly be relieved by adjusting their diet. Diabetes is the 8th leading cause of death in the United States, because diabetics are extremely vulnerable to arteriosclerosis and are highly prone to heart attacks and stroke. Most diabetics eat the standard diet that most other people eat. As a result most of them, during a seventeen year period which follows discovery of their diabetic condition, undergo major health problems, including heart attack, kidney failure, strokes, and blindness. In Lancet, the British medical publication, Dr.Inder Singh reported a study in which 80 diabetic patients were restricted to very low fat diets - 20 to 30 grams per day - and forbidden any sugar. By the time six weeks had elapsed, more than 60% of the patients no longer required insulin. The figure eventually rose to 70%, and those who were left only required a small fraction of the insulin formerly needed. All 80 cases were monitored for periods ranging from six months to over five years, and the success of the dietary change was confirmed over time. [1]
http://www.karlloren.com/diet/p42.htm
No diabetes, here... No matter how many times my doctor has checked my A1C over the past couple of years, he's never found it to be outside of the normal limits. My blood sugar has jumped over the cuttoff a few times, but by only 1-5 points, like for example 105 as opposed to under 100. So, not considered a diabetic with a consistently normal A1C. ALso, considering that I have a huge sweet tooth and do indulge myself with that, so the over 100 is more than likely only because of that.
Susan400
Susan400
I was wondering the same thing, if control over it makes a difference. Similarly, if the absence of HCV (meaning achieved SVR) has significance and if an improving liver (post SVR and healthy living) makes a difference. As the article reads, it's kinda scary. (p.s. I had a first last week, dizzy and shakey from low B.S.). I guess I'm not so well controlled yet.
Your control is great. My A1c was also in that range - 5.4 or 5.5.
"Overall, controlling diabetes might have a greater impact than any other single factor on reducing the incidence of hepatocellular carcinoma in the United States," the study authors conclude in their abstract.
I am not sure how to read that. Is he talking about controlling the incidence of diabetes or controlling the diabetes itself - blood sugar? The recent material I have seen doesn't show a great benefit is derived from tight control but I still like it and strive for it. So, I would like to believe that he's talking about glucose but I suspect he may be referencing the number of diabetics.
Thanks for your thoughts Bill and congratulations on your numbers.
Mike
"Overall, controlling diabetes might have a greater impact than any other single factor on reducing the incidence of hepatocellular carcinoma in the United States," the study authors conclude in their abstract.
I am not sure how to read that. Is he talking about controlling the incidence of diabetes or controlling the diabetes itself - blood sugar? The recent material I have seen doesn't show a great benefit is derived from tight control but I still like it and strive for it. So, I would like to believe that he's talking about glucose but I suspect he may be referencing the number of diabetics.
Thanks for your thoughts Bill and congratulations on your numbers.
Mike
i would imagine well regulated diabetics would not be affected so badly, as the balance is the same, only a wild guess of course
Wow, Mike; very interesting. I’m diabetic as well; I’ll try to discuss this with my hepatologist next month when I go in for HCC monitoring. One thing that wasn’t mentioned in this read was how much/if tight blood sugar control changes this picture; I’ve been doing very well in that department now that I’m finished with IFN treatment. My last A1c result was 5.5%, and my fingerstick average has been around 85-90 mg/dL. I imagine my doc will have seen this and had time to digest it in time for my next appointment. As always, great to see you post, Michael—
Bill
Bill
Wow I had no idea - and IR being a negative predictor isn't that having to do with the same sort of issues? It's scary stuff I certainly would have said it was been HCV - and we consider ourselves the educated 'experts' well WRONG!!!!!!!!!!!!!!!
I too always think it's better to know and be prepared rather than live in blissful ignorance (which is why I'm such a basket case I guess).
Thank you quite interesting information.
I too always think it's better to know and be prepared rather than live in blissful ignorance (which is why I'm such a basket case I guess).
Thank you quite interesting information.
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Interesting news but I think Nick Mulcahy may sensationalizing McGlynn's findings a bit (which often happens in reporting conference reports). The actual abstract, from poster presentation 1826 at the recent AACR, is below (available from their website by searching conference program). Odds Ratio (OR) and Attributable Risk (AR) are competing stats for measuring the association between an effect and a condition (defn of AR given on wikipedia page).
McGlynn applied both stats to what seems to be a good sized sample. For HCC, HCV has the highest overall OR (44.26), which is pretty darn high. In assessing the effect via the AR statistic, the HCV effect dropped to 3rd place (20.7%) behind diabetes (34%) and alcohol (24%) - but only when averaging across all patients. When blacks, whites, asians and hispanics were broken out, only among whites did the diabetes AR come out on top. (OR by group not given)
This seems an interesting contribution but to interpret it as indicating that diabetes is a cause of hcc independent of hcv seems like stretching what McGlynn reported. We know there's a very strong diabetes/hcv link and it's not clear (to me at least) that anything in that report explains to what extent diabetes "causes" hcc simply by correlation with the fact that many diabetics with hcc also had (resolved or unresolved?) hcv.
-----------------abstract text
In the United States, known risk factors for hepatocellular carcinoma (HCC) include infection with the hepatitis B virus (HBV), infection with the hepatitis C virus (HCV), excess alcohol consumption, diabetes, obesity and several rare metabolic disorders (hemochromatosis, α-1 antitrypsin deficiency, porphyrias). The proportion of risk in the U.S. attributable to each factor separately, and to all factors together, however, is not well understood. To better quantify the risk attributable to these factors, logistic regression analysis was conducted using data from the SEER-Medicare linked database. All persons diagnosed with HCC (n=5,607), with at least 3 pre-diagnostic years of Medicare coverage between 1994 and 2005, were included as cases. A 5% random sample of persons residing in SEER locations (n=190,782) were included as controls. For each risk factor, odds ratios (OR) with their 95% confidence intervals (95%CI), and attributable risks (AR) with their 95%CI were calculated. In addition to calculating overall risks, risks were calculated after stratifying on race/ethnicity, gender and time period of HCC diagnosis. Among all individuals, the AR of all factors together was 63.3%. The AR among males, however, was higher than the AR among females (64.6% vs. 60.7%, respectively). By race/ethnicity, the AR of all factors together was highest among Asians (67.9%). This AR was followed by that among Hispanics (64.9%), then whites (63.3%) and finally, blacks (53.0%). Among specific factors, diabetes had the greatest AR at 34%, followed by alcohol-related conditions at 24.0%, HCV at 20.7%, HBV at 5.7%, metabolic disorders at 3.1% and obesity at 2.0%. These findings differed by gender and race/ethnicity, however. While diabetes had the highest AR among both males and females, the factor with the second highest AR among males was alcohol-related diseases, while among females; the factor with the second highest AR was HCV. The factors with the highest AR among each race/ethnic group were: whites - diabetes (36.4%) and alcohol-related disease (23.5%), blacks - HCV (31.9%) and alcohol-related disease (20.3%), Hispanics - alcohol-related disease (29.9%) and diabetes (28.0%), and Asians - HCV (31.7%) and diabetes (26.5%). These findings indicate that the current increase in incidence of HCC in the U.S. may be fueled by different factors in different racial/ethnic and gender groups. Overall, controlling diabetes might have a greater impact than any other single factor on reducing the incidence of HCC in the U.S.