High Fructose Corn Syrup: the killer ingredient?

Fructose has been introduced into our diet as a substitute for sugar, but it is becoming apparent that it can have pretty serious medical effects in the long term. The BMJ this week (27 Nov 2012) has an article on the intake of high fructose corn syrups (HFCS) in different countries. These products contain about 30% more fructose than the same weight in sugar. I was a bit shocked to see a box of Special K on the picture, so I thought I should investigate further.

So what medical problems can be caused by HFCS?

The first is obesity. The figure opposite shows the sort of correlation between HFCS intake and obesity. In the BMJ article it is stated that the annual consumption of HFCS per person in the US is 25kg (55lb) compared to less than 0.5kg per year.

The second is diabetes. The epidemic of diabetes in the US parallels the graph of increasing body weight.

A couple of other associated conditions include fatty liver and gout. For the rheumatologist both of these are relevant. Have you ever wondered why your teetotal patient on Methotrexate keeps getting abnormal Liver Function Tests? Maybe we should be pointing the finger at their HFCS intake. And the prevalence of gout in the US has rocketed roughly in parallel to the obesity epidemic.

But what about our own intake of HFCS? For those of us who smugly assume that our diets are pretty healthy, are you surprised to see Kellogg’s All Bran and Kellogg’s Special K on the naughty list of products with high Fructose content? Now before Kellogg’s sues me, I personally have not read the small print on the packet (I would need reading glasses to do so). I think it is possible that the ingredients of Kellogg’s products are different in the US/Canada compared to the UK, and on the UK website I certainly can’t find HFCS on the list of ingredients. And I’m not going to throw out my favourite cereals until someone can show me that they are to blame!




Watch out for that Grapefruit juice!

The idea that drinking a glass of fruit juice could treble the drug levels of certain drugs is a bit disconcerting. To then find out that this effect can persist for over 24 hours should be enough to make us even more concerned. This startling effect of grapefruit juice was discovered quite by chance. I suppose we can only be surprised and thankful that most people seem to survive perfectly well when they take medication in spite of these hidden perils. Some readers may find some parts of this blog post a bit technical at times, but for professional readers the extra detail is important to understand what is going on.

This interaction was discovered quite by chance in 1989 in a small study into the effect of alcohol on the absorption of Felodipine. In this study, grapefruit juice was used as a supposedly neutral ingredient to obscure the taste of alcohol, but when greatly increased drug concentrations were observed it became apparent that the grapefruit juice and not the alcohol was to blame.  The significance of these results wasn’t widely publicised until several deaths were reported due to the interaction.  In humans, bergamottin and dihydroxybergamottin are thought to be responsible for the “grapefruit juice effect”, in which these furanocoumarins reduce CYP3A4 mediated  metabolism of certain drugs. Grapefruit juice tends to have maximum effect on orally administered drugs whose bioavailability is severely restricted by the action of this enzyme.

From a Rheumatology perspective, what should we be aware of? Of course we should be aware of the whole list of drugs (which has now grown to over 80) – but here is a list of drugs commonly encountered in the rheumatology clinic

The most important drugs to remember are those that cause a major interference  with cytochrome CYP3A4, the gut enzyme that metabolises a large number of drugs.

The first of these is Ciclosporin, a drug sometimes used for treating Rheumatoid or Psoriatic arthritis. It is clear that drinking grapefruit juice causes a major increase in drug levels which can lead to serious toxicity. All patients taking this drug should be warned to avoid grapefruit and possibly Seville oranges (a common ingredient of marmalade). Avoiding grapefruit juice is mentioned in most of the patient information leaflets but we should also warn patients verbally when we prescribe it.

The second group of drugs affected by grapefruit is the statins (for lowering cholesterol). Among these, Simvastatin and Atorvastatin seem to be the main culprits – the increased drug levels can lead to an increased risk of myopathy and rhabdomyolysis (muscle injury). Pravastatin and Rosuvastatin do not seem to be affected.

It is much more difficult to get information about a number of other drugs that may in theory have a minor interaction with grapefruit juice. Among the drugs we commonly encounter in rheumatology, the following list of possible interactions can be regarded as possible but not confirmed (as far as I can establish):

Analgesics: Codeine, Tramadol, Buprenorphine, Oxycodone, Paracetamol
Others: Amitriptyline, Colchicine,  Oral methylprednisolone

As far as I know, the following drugs are not significantly metabolised by CYP3A4: Methotrexate, Hydroxychloroquine, Sulfasalazine, Leflunomide, Morphine, Prednisolone. The absorption of these drugs will not be affected by grapefruit juice’s effect o CYP3A4, but that doesn’t necessarily mean that they’re in the clear…

There has been a suggestion recently that Methotrexate levels could be affected by grapefruit juice. I am not sure how much evidence there is for this, but it does not seem to be via a CYP3A4 effect.

Grapefruit juice also has been shown to reduce the plasma concentration of several drugs. This seems to be caused by the juice inhibiting the organic anion-transporting polypeptide (OATP), which assists in the uptake of drug molecules from the intestinal lumen into the enterocyte. The inhibition of OATP by grapefruit juice would reduce the absorption of drugs transported by this transporter. Orange juice and Apple juice have been found to have similar effects on the absorption of some drugs. Methotrexate levels are thought to be affected by OATP transporters, which are found in the gut, the kidneys, the liver and a few other places. The net effect of these transporters is hard to predict, as they can have competing actions – sometimes enhancing excretion and sometimes reducing it. I am not sure that there is clear evidence that fruit juices cause Methotrexate levels to go up or down significantly, but the safest thing to do would be to avoid drinking fruit juices the day or two before taking Methotrexate.

What you have read here is an over-simplification of what is actually going on – there are other transporters such as P-gp involved in drug metabolism, and we really don’t know enough about how they work and how they are affected by elements in our diet or ‘complementary’ medicines. Time for the scientists to help out – please!


Drug Interactions with Grapefruit Juice: An Evidence-Based Overview

Caffeine and the Rheumatologist

As a passionate fan of coffee, I feel like a real ‘killjoy’ when I advise people with arthritis not to drink too much coffee. So why all the fuss?

The problem is that caffeine has an effect on a chemical in the body called adenosine which is also the target of Methotrexate. In theory taking too much caffeine could stop Methotrexate working, and some studies (in rats, I have to admit) suggest that this  is a real effect. If you want to read about this in more detail, check out a recent article by Bruce Cronstein. Dr Cronstein and his co-workers have done much of the research so he knows what he is writing about. Methotrexate causes release of adenosine which may have an anti-inflammatory effect whereas  caffeine blocks the adenosine receptor (i.e. stops it working). Interestingly, he also says that adenosine helps put us to sleep and this may be why people taking Methotrexate often feel tired. From a practical point of view, if your Methotrexate is working well I wouldn’t worry too much about this, but if it hasn’t had the desired effect then cutting down on caffeine might just work! There are some pretty good decaff coffees so you mightn’t have to give up your favourite drink, after all.

Finally, a poem about coffee and the thinking man…

21st Century Rodin

The upper right-hand
corner of my desk blotter;
a fresh, stark canvas
this morning, now a sepia
montage of concentric
I sip,
I Think.
I sip,
I think.
I sip…
I think.
Colin Harmon, award winning barista, in Dublin brews concoctions here!Sip.
Big sip
sip sip sip
sip sip sippppp.
Final sip, cup down.
A caffeine-laced
still life of a Slinky.
was-I-ever productive

-Mark L. Lucker