My best friend was diagnosed with gout recently. I told him to stop ingesting fructose immediately.

Only twenty five years ago, when I was in training, gout looked like it was like a disease on its way to extinction, sort of like tuberculosis. We were taught it used to be common hundreds of years ago but that it was pretty rare. Sure, I had a few patients with gout in my clinic with gout but I would see a case once every couple of months at most.

Now, it’s exploded in frequency.

Gout is very, very bad. Not only because it is excruciatingly painful. (In some patients, you can’t even let a gouty big toe brush against tissue paper without unbearable pain. It’s one of the few things that may rival childbirth in the intensity of pain.) And not only because it is a major risk factor for heart disease. Not only because it causes heart disease. No, it’s very bad because your risk of dying goes up by 25% if you have gout.

What’s going on? Why has the incidence gone up so much? Weren’t those rich guys you see in paintings from the colonial days the only one who got gout?

Fructose.

There are certain foods, like meat and seafood, that can cause gout. So can alcohol. But the consumption of those things haven’t really gone up. Consumption of sugar, especially fructose has. And more fructose you eat (or more likely, drink), higher the risk of gout. And by feeding rats fructose, you can make their uric acid levels go up. (As an aside, those rats also develop diabetes too. This is consistent with the observation that if you take people off fructose for ten days, you can often resolve their diabetes. And if you take ten healthy college students and give them a lot of fructose for a few days, you can make then insulin resistant.

But why does that happen? Well, fructose is a fairly usual molecule, and rather rarely encountered in large quantities in nature. So our body is not designed to handle large quantities of it very well. In fact, it is a rather toxic molecule, all in all. And what processing does happen, it’s by a metabolic pathway shared by the alcohol metabolism pathway. So it stands to reason both fructose and alcohol can cause gout.

Fructose is a very bad actor. It doesn’t cause satiety, so you keep eating. And it increases fat stores. In fact, even on low calorie diet, you can make make rats become fat if you give then fructose instead of glucose. They get elevated blood pressure, abdominal obesity, hypertriglyceridemia, hyperuricemia and hyperinsulinemia. You can see a similar difference in people too between glucose and fructose.

The most worrisome thing about gout is that high levels of uric acid has been long recognized as a risk factor for cardiovascular disease. But it keeps being ignored. It was known as a risk factor hundreds of years ago. Then it was forgotten until the 50’s. And then the cholesterol hypothesis of heart disease became prevalent and then it was forgotten again.

To be frank, the evidence that high levels of uric acid (or even high normal levels) cause heart disease and metabolic syndrome is pretty convincing. For example, in the study I mention above, high uric acid levels caused matabolic syndrome in rats but if you lowered the uric acid levels, the metabolic syndrome disappeared. This is much better data than the data for hypertension of diabetes, or certainly cholesterol being causal. When you treat hypertension, diabetes doesn’t get better, nor does gout. If the reverse is true, then uric acid is much more important than hypertension.

An epidemiological study in Taiwan found that patients who had gout had 2.5X risk of cardiovascular death compared to patients without gout. However, if you treated those patients with uric acid lowering drug, then the risk dropped by 70%!

So… uric acid is a major driver for cardiovascular disease? How could that be?

Well, I’m glad you asked. It turns out that uric acid is a major DAMP–damage associated molecular pattern. It’s one of the important ways that your body senses that there is damage to cells. When there is damage to cells, inflammation pathway is turned on, because 1) it means that there might be a pathogen attacking us and killing cells, for example a virus and 2) inflammation is required to heal the body. When cells die, they release uric acid.

Why haven’t doctors widely accepted this hypothesis? I think it’s because the current belief is that cholesterol causes heart disease. This data on gout just doesn’t fit. Most doctors in the U.S. think it’s a weird hypothesis. I think once the cholesterol hypothesis is abandoned, which will take at least another ten years, uric acid hypothesis will find much wider purchase.

(One potential good news about gout: one paper suggests that the risk of Alzheimer’s disease is 24% lower in patients with gout. The problem with this study is that while they tried to adjust for people who died, I don’t think they did it right. (Specifically, the statistical technique they used censors the deaths, which is only appropriate if there is no association between risk of Alzheimer’s and deaths. In this case, there probably is). The reason it looked like the risk of Alzheimer’s was lower may have been because the people who would have developed Alzheimer’s instead died too early to develop it.)

Drug Development Aside

Gout, by the way, has a quite a storied history in the pharmaceutical industry. One of my favorite example of serendipity is drug develompent is the story of Ardea Bio. This San Diego company was born out of ashes of a another storied company, Intrabiotics, famous for missing the Phase III endpoint for a promising antibiotic when its CRO mixed up the randomization codes.

Ardea was developing an HIV drug, called RDEA806. It was an OK drug, but ended up being abandoned. But a sharp-eyed medical director at Ardea saw that it lowered uric acid levels. Ardea took the idea and ran. A metabolite of RDEA806, named Lesinurad, was developed for Gout and is on the market today.

On the opposite end, colchicine, which is a drug that’s about 2,000 years old, purified from the autumn crocus. It was used by Egyptians for gout, among other people. It is such an old drug that it had never been approved–it was older than the FDA. In 2009, URL Pharma got an official FDA approval, which forced other companies to stop making the drug. URL promptly raised the price from ten cents to five dollars. This was quite controversial, as you might imagine, and was a forerunner of the entire Martin Shkreli scandal.

Man and Animals

As an aside, gout is rare in animals. They have a much better ability to control uric acid than humans. That’s because we have a mutation in our uricase gene, which renders it inert. There is a hypothesis that this mutation makes us much more sensitive to fructose, and makes us much more prone to store up fat and go into the hibernation mode that fructose induces.

In dogs, however, there is one breed, Dalmatians, that get gout. They have high uric acid levels and get kidney stones. However, they don’t get cardiovascular disease, and they don’t seem to be at higher risk of metabolic syndrome. This natural experiment is inconsistent with the hypothesis laid out above. The mutation that those dogs have is in the transport of uric acid across cells, so it’s a different mutation. It’s possible that the inability of uric acid to get transported into cells may make a difference.