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Sunday, 19 May 2013

Does Aspirin Prevent Liver Cancer, and, Does Ginkgo Extract Cause It?

Aspirin (acetylsalicyclic acid) is one of those drugs that blurs the distinction between the natural world and the products of human ingenuity, being a barely-tweaked analogue of salicylic acid. Salicylic acid is not only prevalent in the diet, it appears to be synthesised endogenously in fasting states.
(music: Seven Fishes by Jigsaw)

Aspirin has long been regarded ambivalently in medicine. On the one hand it kills pain and reduces fever, on the other hand excess can make the gut bleed and damage the kidneys, and even cause hepatitis. Low-dose, buffered aspirin is commonly used as a preventive of heart attacks and strokes, but its overall effectiveness in this role is questioned:

Meta-Analysis of Multiple Primary Prevention Trials of Cardiovascular Events Using Aspirin

The meta-analysis suggested superiority of aspirin for total CV events and nonfatal MI, with nonsignificant results for decreased risk for stroke, CV mortality, and all-cause mortality. There was no evidence of a statistical bias. In conclusion, aspirin decreased the risk for CV events and nonfatal MI in this large sample. Thus, primary prevention with aspirin decreased the risk for total CV events and nonfatal MI, but there were no significant differences in the incidences of stroke, CV mortality, all-cause mortality and total coronary heart disease.

So the findings in this survey were unexpected:

Nonsteroidal Anti-inflammatory Drug Use, Chronic Liver Disease, and Hepatocellular Carcinoma

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated.
Methods We analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health–AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided.
Results Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users.
Conclusions Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.

Now, these are huge correlations, especially when you consider that the use of NSAIDs is considered to put one at risk of leaky gut syndromes, and that SIBO and endotoxaemia are proving to be significant factors in the development of chronic liver disease. When epidemiology goes so strongly against the grain of one's expectations, one really should sit up and take notice. There's an extra convincing feature here - the differential correlations of aspirin (less CLD, less HCC) and other NSAIDs (less CLD but no reduction in cancers). If the result was co-incidental (people with better liver function more able to use NSAIDs, for instance) this difference shouldn't exist. Non-aspirin NSAIDs lumped together by the methodology include (are mainly) ibuprofen and paracetamol (acetaminophen) and the latter can cause liver damage by depleting reduced glutathione. This has cancelled out the anti-cancer benefit (we might hypothesise) but the aspirin-like anti-inflammatory effects of ibuprofen still show.

Of course if you already have low platelets and poor blood clotting due to cirrhosis it might be a bit late to take any advantage you might see in this research. However, there is an alternative theory; that Aspirin should be considered as a salicylate supplement, and that fruits and vegetables, which are naturally rich in salicylate, can supply the same benefit. Wiki lists the sources thus:
Unripe fruits and vegetables are natural sources of salicylic acid, particularly 
blackberriesblueberriescantaloupesdatesraisinskiwi fruitsguavasapricotsgreen pepperolivestomatoesradish and chicory; also mushrooms. Some herbs and spices contain quite high amounts, although meat, poultry, fish, eggs and dairy products all have little to no salicylates. Of the legumesseedsnuts, and cereals, only almondswater chestnuts and peanuts
 have significant amounts.

Almonds just got interesting again...
Some people are intolerant of salicylates. These people may have little need for aspirin anyway if blood salicylate levels are naturally high. Removing 75% of salicylate from the body involves conjugation with glycine (requiring pantothenic acid - vitamin B5 - plus sulfur, as acetyl CoA), and clearance of salicylate might improve on a paleo diet with bone broth to supply glycine, and low carbohydrate intakes to stimulate trans-sulfation and acetyl-CoA synthesis.

Anyway the take home message from the Aspirin study as I see it - if you're concerned about the health of your liver, and your platelets are still in the normal range, you needn't be afraid to use aspirin. Though it might be a good idea to also ensure you're getting enough vitamin K.

Ginkgo Biloba Extract and Cancer

It's a common enough fallacy that natural medicines, especially ones in common use, can't be as harmful as pharmaceuticals. The appeal to nature, the appeal to antiquity, and all that. The fact is that the supplement industry is very poorly regulated in most countries, and no-one has yet worked out how to regulate it in a way that consumers, long used to experimenting freely with often cheap and sometimes effective natural medicines, will tolerate. It doesn't help that regulation is usually the business of government agencies that are seen, with some reason, as being in the pocket of Big Pharma. A few weeks ago Stephan Guyenet tweeted about this study (PDF) which shows commercial ginkgo extract is highly carcinogenic in rats and mice. 
Liver: The incidences of multiple hepatocellular 
adenoma, hepatocellular carcinoma, and hepatoblastoma 
were increased in all dosed groups of males; multiple 
hepatocellular adenoma incidences were increased in all 
dosed groups of females, and multiple hepatocellular 
carcinoma and hepatoblastoma incidences were 
increased in 600 and 2,000 mg/kg females. When single and multiple neoplasm 
incidences were combined, significant increases were 
seen in the incidences of hepatocellular adenoma in 
200 mg/kg males and all dosed groups of females, 
hepatocellular carcinoma in all dosed groups of males 
and 2,000 mg/kg females, and hepatoblastoma in all 
dosed groups of males and 600 and 2,000 mg/kg 
females. These significantly 
increased incidences also exceeded the historical control 
ranges for these neoplasms from corn oil gavage studies 
and all routes of administration (except for hepatocellular adenoma in 200 mg/kg females) 
(Cancers were also found to be significantly increased at a number of other sites including the nose and thyroid).

One could take this with a grain of salt, rats being rats, and the doses being a little higher than human doses, but the paper does refer to human trials, and these results too give cause for concern.

Two epidemiological studies explored carcinogenicity 
associated with use of Ginkgo biloba supplements. In a
population-based, case-control study reported by Ye 
et al. (2007), in which the case group included 668
women in Massachusetts and New Hampshire 
diagnosed with epithelial ovarian cancer matched to 
721 women in the control group, an inverse association
(OR=0.41; 95% confidence interval, 0.20-0.84; P=0.01)
was found between Ginkgo biloba use and risk for 
ovarian cancer. A more recent study by Biggs et al. 
(2010) used data from the largest epidemiological study
of Ginkgo biloba efficacy (Ginkgo Evaluation of 
Memory Study) conducted to date to analyze cancer as a 
secondary endpoint. The study population consisted of 
3,069 participants, age 75 years or greater, that were 
randomly assigned to receive twice daily doses of either 
a placebo or Ginkgo biloba extract (120 mg EGb 761®) 
and were followed for approximately 6 years. 
Researchers found an increased risk of breast (hazard 
ratio, 2.15; 95% confidence interval, 0.97-4.80; P=0.06) 
and colorectal (hazard ratio, 1.62; 95% confidence 
interval, 0.92-2.87; P=0.10) cancers and a decreased 
risk of prostate cancer (hazard ratio, 0.71; 
95% confidence interval, 0.43-1.17; P=0.18) in the 
population receiving Ginkgo biloba extract.

It seems to me that a more than doubled incidence of breast cancer in a randomized controlled study is the kind of result that should have been more widely discussed than it was. If this happened in a study of statins or aspartame, the whole internet would be abuzz with it. Why does Ginkgo get a pass?
Ginkgo Biloba leaf extract is not a traditional Chinese medicine. There is some mention of monks at some time making tea of the leaves, but they do not appear in any TCM formulary that I have perused. The seeds appear occasionally but are recognized as toxic and their use is rare. Ginkgo leaf extract contains many worthwhile compounds (I could fill another post with these), and it's the best treatment I know to give someone who has memory impairment from chronic marijuana use. It has a potent antifibrotic effect and has been used in modern Chinese hepatitis therapies. It will inhibit many cancers in vitro (the difference can be small between what might cause cancers, and what might treat them; some chemo drugs, as well as radiation, are carcinogenic). I used to take Ginkgo regularly every now and then. I'll still take it when I have to drive long distances, on the principle that the increased alertness will reduce risk in the short term without exposing me to longer term risk.
 is a mixture of many different types of phytochemical, and some might be more effective once isolated. It seems likely that the carcinogenic component will be identified and removed from extracts, hopefully sooner than later. The uncritical acceptance of the idea that whole herbal extracts are intrinsically more effective and safer than isolated compounds may have been mistaken in the case of Ginkgo.
Well, here we have a drug that might be better for us than was previously thought, and a popular herbal product that might actually be harmful in its present form.

What is the world coming to?


Bill said...

I'm not surprised aspirin fared differently from other NSAIDs, but I'm hugely intrigued about the role of 'dietary' salicylates - they've shown promise in inflammation-induced IR (PMIDs: 22357964 & 11533494).

Puddleg said...

The second link relates to 1KK2 -
"IKK's activity causes activation of a transcription factor known as Nuclear Transcription factor kappa-B or NF-κB. Activated IKK-β phosphorylates a protein called the inhibitor of NF-κB, IκB (IκBα), which binds NF-κB to inhibit its function. Phosphorylated IκB is degraded via the ubiquitination pathway, freeing NF-κB, and allowing its entry into the nucleus of the cell where it activates various genes involved in inflammation and other immune responses."
Immunology regulating physiology?

Puddleg said...

Here it is:

Uncoupling of Inflammation and Insulin Resistance by NF-κB in Transgenic Mice through Elevated Energy Expenditure

Innate immunity protects against IR and obesity in rodent HF overfeeding models; we're back to the Th2 dominance concept.

Puddleg said...

Here's a review of those salicylate effects

Bill said...

I'm so accustomed to reading about the dissociation of obesity and insulin resistance via [insert any pro-inflammatory gene] deletion, that I almost entirely missed the point of that NFkB overexpressing mouse paper. Increased inflammation with no effect on insulin sensitivity - interesting.

Puddleg said...

Of course if that mad scientist is still sneaking up on us with his syringe full of insulin these mice might not be so lucky.
But a little bird tells me that certain aspects of what we currently lump together as inflammation might be beneficial metabolically.

Bill said...


There are far too many things "lumped together as inflammation," imo, especially regarding IR (eg, glucocorticoids??)... the PI I worked with at UCSD never made the distinction. Come to think of it, he never even referenced the whole rubor, tumor, d, c, fl aspects at all.

Puddleg said...

I like using the calor, dolor, rubor, and tumor reality check when inflammation is claimed.

There are a few sites I googled that say "don't take echinacea if you have..." and then list all the main autoimmune diseases.
You have an autoimmune disease, obviously you don't want to stimulate immunity.
"There are concerns that by stimulating immune function, Echinacea could potentially exacerbate autoimmune disease and/or decrease the effectiveness of immunosuppressive drugs, but this warning is based on theoretical considerations rather than human data." - wikipedia

What would happen IRL?
Echinacea might make some of these conditions worse in some people (but which?) but I am willing to bet that (if it did anything, I am just using it as an example everyone knows) it would improve others.

Switching on NFkB in one type of immune cell might have a very different effect from activating it in a different type of immune cell, and activating NFkB in non-immune cells...NFkB is maybe like an amplifier and it depends what station you're tuned to when you turn it on, what sound comes out.

majkinetor said...

Aspirin is good only for acute usage.

Regarding CVD if U skip it few days there is rebound effect and your chance of infarction is increased by up to 30%. So if you take it, be regular, although fish oil beat it anytime IMO.

Ibuprofen was the (good) result of the effort to reduce its GI damage. If you take aspirin every day, make sure it goes down with C as it induces C deficiency.

Its beyond understanding why would you take plant stress hormone every day. Xenohormesis doesn't work like that.

About Ginko, the study was probably preset for results. The dose was massive for first. The mices were highly engineered and it may very well be relevant for that type of (cancer-prone) mices. I don't say results are not valid, they might very well be but the relevance to humans is dubious. That said, many people report problems even with small dose Ginko (like headaches or upset stomach).

Puddleg said...

Thanks Majkinetor,
Aspirin and fish oil share a common pathway, resolvins. The benefit in the HCC study, if I read it right, wasn't dependent on constant dosing:
"The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users."

The ginkgo study was the standard safety test, and the results were unusual. The doses were high but didn't produce any other obvious toxicity. Humans can also have genetic predisposition to cancers.
The results are perhaps not directly comparable but then improving the safety of ginkgo extract will probably be an easy and profitable business.

Bill said...


Reducing NFkB decreases inflammation and cures IR but not obesity.

Increasing NFkB increases inflammation and cures obesity but not IR.

And now "Amlexanox" reduces NFkB and cures both obesity *and* IR.


Puddleg said...

Down the rabbithole, through the looking glass - the only thing I'm ever sure about when I'm trying to understand immunology is, that "opposites day" will soon come round again. Turn down one tiny cytokine, or one nutrient-derived factor like all-trans retinoic acid, or something that's not even being measured at all, and everything flips on its head.

Edward Edmonds said...

Effect of chronic aspirin administration on an experimental model of metabolic syndrome

Lymphocyte Adherence in Multiple Sclerosis

Unknown said...

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