Gout pathophysiology

- So in our body we have DNA and RNA. These are our genetic material and they're constantly broken down and remade as new cells are made, as new processes take place. So they get broken down through a variety of pathways. And I'm simplifying that a lot, the details. But the end result, and there are two, kind of, materials that we end up with. One is called hypoxanthine. Hypothanthine. The other one is guanine. And they both get further broken down into the same thing. Which is xanthine. And then that is the precursor to uric acid. Uric acid is the thing that accumulates and causes gout, or the symptoms of gout. So as you can see, it's a normal part of this physiological pathway that we need. Uric acid by itself, is not a bad thing. So, what happens to it, usually, in a healthy person, is that the kidneys take care of it. They filter is out of the blood. And in terms of where things go after the kidney, there's only two ways to go. One, is out of the body, this is gonna be waste. So basically in urine, it's out of your body. And this one, is of course, back to the body. And under the best circumstances, uric acid, most of it, gets filtered to the waste, it leaves. And it's not a problem. So only when it accumulates in a body do we have gout. So then there are two different places this system can give us trouble. One is where we make too much uric acid. In that case, we would look to this pathway, and see why do we have more. And the other place is the kidney not doing it's job, filtering well. And the problem comes here, where not enough of it leaves the body as waste. So these are the two big umbrellas in terms of the patheo-physiology of gout. First we have primary gout. And I've learned that in medicine, whenever they say primary, it means we don't know. Something intrinsic to the body is causing the problem. We don't know exactly which one it is. And secondary is really, the processes that we can study. So, since we don't know about primary, we just talk about the secondary causes. And first, we think about what we tell patients with gout, is that first don't eat a lot of meat, and second don't drink a lot of alcohol. And these two things actually belong in two different places here on our pathway. So eating too much meat causes more uric acid in our blood. And that comes from here, DNA and RNA. Just by consuming animal products, we not only have to break down our own, but we have to break down theirs. So in the gut, the proteins get broken down, and eventually, we have to do this to the animal proteins, in addition to our own. So this is how eating more meat can lead to symptoms of gout. But then, alcohol is actually over here. Alcohol gets broken down, and alcohol's break down products actually competes with uric acid in the kidney. So it's like if you're in a hall, and there's three doors to get out, usually uric acid, should be, if it's the only thing occupying the space, then technically the filtration system should be able to get rid of it. But when we add alcohol to the mix, it just so happens to use the same exits as uric acid. So this physical crowding, mechanically slows down the filtration. So alcohol makes it harder to get rid of uric acid. And this is assuming the kidneys are normal. Of course we can also have, just kidney disease. And there's a whole, I mean, there's a whole branch of medicine for it, but the umbrella term we use is renal insufficiency. Renal meaning kidney, and the insufficiency meaning it's not doing it's job. So, other diseases that cause kidney failure or lowered kidney function would give us gout as well. And here on the uric acid side, what else can lead to breakdown of our DNA/RNA and cause more uric acid? Well, certain cancers like leukemia, actually lead to more destruction of our blood cells. And this recycle system just goes into overdrive, and there's more DNA and RNA of our own being broken down. Aside from leukemia, there's other blood disorders, so if this is our bone, blood cells are made in the bone marrow. And whatever disease that happens, ramps up the bone marrow into overproduction of the blood cells, then we have over-breakdown as well. So leukemia and other blood disorders can cause that. There's another illness that's kind of unique. It's called Lesch-Nyhan, named after the people who discovered it. And, clinically, it's an interesting disease. It causes people to hurt themselves. They bite themselves, cut themselves. And there's brain damage and nerve damage. But on this pathway, Lesch-Nhyan occurs at this level. So if we look at our pathway, it looks like these just have to go, becomes xanthine, become uric acid. But there's actually a salvage pathway. Kind of an escape hatch, and the person piloting this escape route, is something called H-P-R-T. It's an enzyme, its a huge name. It stands for Hypoxanine-guanine phosphoriboslytransferase. So this enzyme can alter both hypoxanthine and guanine and change it into earlier things in the pathway. Kind of like recycling something that was going down the trash chute. And in Lesch-Nyhan, this is the thing that's no longer working. So, basically, without the escape route taking away some of the burden of this breakdown, we end up with more uric acid. So it doesn't matter why we have more uric acid. Whether it's more breakdown, or not getting rid of enough of it. This the key to gout, and in diagnosing gout, we have to evaluate where on this pathway the problem is.