The "Cure" for HFI? My Hypothesis.

[bananafish]

Yesterday I had an epiphany.

I've been deeply immersed lately in thinking about HFI and how its symptoms could be ameliorated. Although I'm not sure that I have HFI, I can say for certain that my brain seems to work much better on a low-fructose diet. With this new clarity, I suddenly hit upon an idea.

In summary:

Normally, fructose enters the body and is phosphorylated by fructokinase a/k/a ketohexokinase ("KHK") to form fructose-1-phosphate ("F1P"). F1P is then cleaved by Aldolase B ("ALDOB") into glyceraldehyde and dihydroxyacetone.

In HFI subjects, ALDOB is absent and thus F1P builds up in intestinal, liver, and kidney tissues, wreaking general havoc.

There is a separate condition known as essential fructosuria, wherein the first enzyme in the process, KHK, is missing. People lacking KHK cannot phosphorylate fructose, so any ingested fructose is simply excreted in the urine. This condition is considered to be CLINICALLY BENIGN.

So my great epiphany was this: What if you treated HFI by inhibiting KHK? All the problems in HFI are caused by the buildup of F1P. And F1P is made when KHK phosphorylates fructose. So what if you never let that happen? We know that losing KHK function is not dangerous, because there are people who are deficient in KHK and they are healthy.

In summary, if KHK is inhibited and thus fructose never gets phosphorylated to form F1P in the first place, there would be no F1P to build up, and so the lack of ALDOB wouldn't be an issue.

The good news is that I believe that someone is already working on this idea. Back in February, someone posted here that a doctor in Denver is close to a cure for HFI. I believe that this doctor is Richard Johnson at UC Denver, who last year introduced himself on this board and said that he is working with Dr. Tolan.

Dr. Johnson's lab does some really interesting research on the role of fructose in the development of diabetes, obesity, chronic kidney disease, and metabolic syndrome. Fructose can induce the same problems in healthy people (e.g. liver and kidney damage, gout, etc.) as it does in HFI subjects. The difference is in the amount of fructose it takes to cause that damage. For most of the population, it takes loads of fructose to do this, not the milligram amounts that can harm people suffering with HFI.

So, back to my hypothesis. Dr. Johnson, among other things, studies KHK knockout mice (i.e. mice who lack the KHK enzyme) to see whether their inability to phosphorylate fructose offers any protection from disease, which it appears to do.

Dr. Johnson is also one of the inventors on a patent for inhibiting KHK in humans. I think that his original goal in studying KHK inhibition was to aid in the treatment of diabetes, obesity, and the other diet-caused scourges of our modern society. But I think he must have realized along the way that his KHK inhibitors could also be used to help people suffering from HFI.

DISCLAIMER: This is all hypothetical and suppositional. I have no evidence that this hypothesis is valid or that Dr. Johnson is working on this idea. And, even if it turns out to be valid, the drug approval process is long and who knows when it would be avialable to the public as a prescribable drug.

[colormist]

May 26, 2016 8:18:05 GMT -5 bananafish said:

So my great epiphany was this: What if you treated HFI by inhibiting KHK? All the problems in HFI are caused by the buildup of F1P. And F1P is made when KHK phosphorylates fructose. So what if you never let that happen? We know that losing KHK function is not dangerous, because there are people who are deficient in KHK and they are healthy.

This is brilliant. I am on cloud nine right now. I mean, curing HFI outright would be awesome, but downgrading our condition to another condition that is way less inhibiting would be FANTASTIC.

If this is what Dr. Johnson's research is pushing toward, I'm going to be the happiest person.

I was sitting last night watching tv and was suddenly overcome with the memory of having a bite of my mom's black raspberry pie. We would pick the black raspberries and she would bake the pies. She used to make me a tiny pie without any added sugar. It was a bittersweet memory because I knew I could never have a pie like that again, but I could still taste those tart berries and flaky crust.

[colormist]

For people curious about what bananafish is talking about, here's a video that talks about the difference between Essential Fructosuria and HFI. youtu.be/AsEx6luLDko?t=5m2s

Briefly, there are two steps to breaking down fructose. An HFIer's liver gets hung up on step 2. Essential Fructosuria is a hang-up on step 1.

Fructosuria has no symptoms (other than fructose in the urine) and has no necessary treatment. HFIers have a ton of symptoms (as you know) and treatment is an extremely restrict diet.

I was always viewing HFI as needing a cure so we'd be able to properly process fructose (via gene therapy to give us aldolase B or liver transplant) and get us past step 2, but if that's too difficult, maybe preventing Step 1 from happening is the easier route.

[bananafish]

Yes I feel like I was brain-locked into thinking about how to reverse the deficiency itself, via enzyme therapy or gene therapy, or how to reverse the downstream effects. It took a leap to consider treating it upstream, even though I was perfectly aware of the existence of essential fructosuria.

What is great is that this has therapeutic potential for millions of people, so there are large monetary and social incentives to get these inhibitors developed.

You should take a look at Dr. Johnson's patent. He talks briefly about all kinds of interesting things that people have brought up here, like the nature of renal tubule damage and the endogenous production of fructose by the body.
www.google.com/patents/EP2600897A2?cl=en

It's funny, Dr. Johnson could probably tell you practically everything known about the damage caused by HFI, but he learned it all by studying non-HFI subjects. And since he wasn't focused HFI and therefore wasn't unconsciously limiting himself to just thinking about ALDOB and F1P, he's found out all kinds of interesting things about KHK, which for the most part has been ignored, since its essential function was understood.

If I'm understanding the patent correctly (and I'm sure I could learn more by reading the papers that back everything up), the ATP depletion caused by high fructose exposure leads to high uric acid. And the exposure to high uric acid upregulates KHK, in effect sensitizing the body to fructose. So the next time the body is exposed to fructose, the KHK phosphorylation reaction goes even faster.

I feel like there are missing pieces of the puzzle with regard to HFI concerning (1) why abstaining from fructose makes symptoms worse, (2) why symptoms are different in different people, and (3) why the effects of even a small amount of fructose exposure persist for days.

I feel like if more focus is put on the importance of KHK and its differential expression in different tissues as a consequence of varying levels of fructose exposure, it'll help answer these questions.

Like, what if fructose exposure upregulates KHK in the small intestine, so more of the fructose is "captured" at that stage. F1P is osmolytically active and in the small intestine can lead to gas, abdominal distention, diarrhea, colic, etc. So maybe repeated exposure to fructose, by somehow upregulating KHK in the small intestine, favors gastrointestinal symptoms. But by excluding fructose, maybe KHK in the intestine gets downregulated and thus more intact fructose reaches the liver and kidney, meaning that liver and kidney symptoms get favored over the less damaging gastrointestinal symptoms. That could possibly explain why the nausea and hypoglycemia (liver symptoms) are worse after fructose elimination, even if the dietary fructose is overall much lower. Also, my theory about the fate of residual F1P is that there is some sort of signal that favors KHK's dephosphorylation reaction (KHK is capable of both phosphorylating fructose and dephosphorylating F1P), converting F1P back to fructose and allowing it to be excreted in the urine. If uric acid upregulates KHK, perhaps it changes the kinetics of this dephosphorylation reaction, and F1P gets converted back to fructose and excreted more quickly. So lower exposure to fructose might downregulate KHK, having the uninteded consequence of downregulating the dephosphorylation reaction and slowing down the elimination of fructose. There has to be a reason why people consistently experience worse reactions to small exposures to fructose after they have eliminated it from the diet, and maybe the answer lies in KHK up/down regulation and differential expression in different tissues in response to fructose exposure.

Whew sorry to go off there. My brain really seems much more active on this diet. And I love this stuff. I was a biochem major and I worked in a basic research lab for a few years, before switching to investigative research. But I miss the sciences and reading papers and coming up with hypotheses is one of my favorite (and nerdiest) pastimes.

[gpardo]

Hi bananafish,

I really think we are near a cure, but is just a feeling...you know people with HFI develop all kind of extra senses
Besides that Inwas wondering if you have talk with this doctor on Denver (Dr Johonson).
Have you read any papers regarding HFI written by this doctor?
Thanks for all your help!

[bananafish]

Hi gpardo,

No, I haven't talked with Dr. Johnson yet. I'm so interested in all this stuff and it would be really cool to have a conversation with an expert about it, especially one who might be close to a cure, but I guess I'm a little intimidated. I'd like to read more of his research before I reach out to him on this. Also, I'd feel like I'd have more to bring to the table if I actually had HFI and could provide information about symptoms, but I don't.

I just went on PubMed and I didn't find any papers authored/coauthored by him that specifically address HFI - most relate to the fructose-induced development of disease in healthy subjects.

However, I just found a 2013 paper coauthored by him looking at the role of uric acid in the development of diabetes and obesity. For this paper, the researchers created an HFI-like situation by silencing aldolase B in a line of HepG2 cells (HepG2 is a line of culture-grown liver cancer cells commonly used in labs for in vitro experiments). The authors call HFI an "interesting condition" and say that subjects with HFI "are known to have hyperactive KHK and show enhanced ATP depletion and uric acid generation in response to fructose." So it shows that HFI is definitely on Dr. Johnson's radar, and I take it as further evidence that he sees potential in treating HFI by inhibiting KHK.

This is the first time that I've read that subjects with HFI are known to have hyperactive KHK and enhanced ATP depletion. So inhibiting KHK could have benefits on multiple levels - it could potentially allow most of the fructose to be excreted in the urine by converting HFI into an essential-fructosuria-like condition, and, for the fructose that does get into the liver, it could slow down ATP depletion by downregulating KHK. ATP depletion seems to be the root cause of some of the worst of the damage done by fructose ingestion, so slowing it down could possibly be of great benefit (EDIT: I'm not totally sure about this second part. The way the liver operates can be counterintuitive - from what I understand, a big load of toxin all at once can sometimes be better than small amounts of toxin dribbled out over a long period of time).

Here is a link to the 2013 paper:
www.ncbi.nlm.nih.gov/pmc/articles/PMC3781481

And here are some of Dr. Johnson's other papers on fructose:
www.ncbi.nlm.nih.gov/pmc/?term=Rj%20Johnson%20fructose

And here is Dr. Johnson's self-introduction on this board:
hfiinfo.proboards.com/thread/1576/dna-came-back-positive-liver?page=1&scrollTo=11221

[gpardo]

Hi bananah,

Thanks for your reply.
Well first if you are not sure about HFI you can make an dna test direct with HFI boston university, Dr Tolan can help you with this.
In my case I can tell you that Inwas literally dying, i couldnt walk and i felt like i had some brain disease, was horrible bit thanks Gd I stop eating sugar and raise and a lot of things and my brain start working better.
Also thats true, if i have some rise with potatoes, onions and tomatoes the sympthoms appear inmediatly and I have to wait 1 or 2 days to recover my self.
My main cocern is about ATP, food is energy, so if we are not able to eat a lot we need to get the energy from somewhere right?
In the meantime I take some vitamins that without this vitamins im not able to function, this vitamins are very strong and without additives and added sugar abvoiusly!

It seems that you are more aware about how this KHK can improve HFI in my case is the first time. I already wrote to Dr Tolan asking about this, Im waiting for his response.

If you can explain me please how this KHK thing can improve HFI I would really be thanksfull!

All the best for you and keep it strong!!

[bananafish]

Thanks gpardo. I'm pretty sure I don't have HFI based on some self-tests with pure fructose in amounts that would harm someone with HFI (and I wouldn't recommend the self tests for others who are in doubt - I only did them because I had tolerated high amounts of fructose in the past, and I took precautions). Even from the outset, I recognized that my symptoms were not as bad as other people's on this board.

I'm really glad you figured it out, even before diagnosis, because your symptoms sound devastating. Were your liver and kidneys okay?

With regard to KHK, I want to stress that everything I've posted is all hypothetical. I have no medical expertise and only a minimal science background.

Even if using KHK inhibitors makes sense on a theoretical basis, researchers still have to test it out before they can offer it as a drug. In all the papers I've seen, they have been studying mice. They would have to get to the level of running clinical tests in humans, and then go through the FDA approval process. All of this takes not only time, but also money. I think there are KHK inhibitors available for research purposes but these could be dangerous for humans and could have major unintended side effects. Any inhibitor used in humans would have to be very specific and only inhibit KHK and not any other enzymes, and they would have to make sure it doesn't do any unintended damage in the body. They also have to figure out optimal dosages, and how to deliver it to the body, and when it should be taken, and all kinds of things like that.

So I feel sorry if I've gotten your hopes up prematurely. I have a feeling that this is going to be a good thing, but we won't see the benefits for many, many years.

But you asked for more info - did you read the whole post and watch the video that Colormist posted?

[gpardo]

Yes I read it and Im sure they have progress.
Today there is a huge advance in dna field so maybe they have it solve it and they could be making upbthe bisiness plan, how knows.
Any way all bad things come withb things in the way, so the are in fact no bad things is just how we experience it.
It sounds like you have fructose malabsortion and it can be very anyoing thats why you came up with HFI.
If you describe your sympthoms I can tell you what it is.
Cheers,

[bananafish]

Yes I really hope they solve it.

Oh and you asked about my symptoms. I have a whole other thread about my effort to figure out what I have if you want to take a look there and see if you notice any pattern: hfiinfo.proboards.com/thread/1727/figure-out.

[gpardo]

Hi, I dont understand what is the 23me test...
Did you made the aldolase b dna test?
Best,

[bananafish]

HOLY MOLY!!! I have great news!

Dr. Tolan emailed me back today and confirmed that he is working with the group in Denver on using KHK inhibitors to treat HFI!

He said they hope to hold clinical trials in the next couple of years. Once they get to the clinical trial phase, they will begin recruiting volunteers with a confirmed HFI diagnosis.

So it's still several years out - but great news nonetheless! 

[colormist]

I was anticipating maybe a cure within in the next 10 years--half of that is WAY BETTER!

I already told my husband that our grocery bill is going to be WAY cheaper in the future because I won't have to buy all this expensive bread, meat, and cereals. (In reality, probably still be the same given inflation, but will save us future money!)

[gpardo]

Geat news!
What do younthink are the effects on the body inhibitin khk c?
What does it means? Can you explain me please?
Thanks!!

[ukbill]

I will ask Dr Cox when I meet him on Thursday. This sounds possibly interesting.

However the load on the kidneys is a question that has to be asked.

Fructosura might be benign but rarely do conditions have no side effects.

I will update when I know more.

[ukbill]

Ok had a response from Dr Cox.

This has been talked about for some time, apparently it offers some hope which is likely to be more beneficial than the gene therapy.

Dr Cox sees it as being useful for babies at the dangerous weaning stage.. however diagnosis would have to be made before.. which as we know is not likely.

Personally I am not keen on the idea of a daily tablet or regular injections.

An emergency pack might have use in the off chance that accidental consumption of sugar has occurred.

This might reduce the time spent feeling extremely ill and throwing up but how quickly it can stop the effects after consumption (for example drinking a glass of full fat coke instead of a safe beer) is a good question.

I have read that 25% of sugars in a drink are adsorbed through the walls of the mouth and throat long before the drink can even get to the stomach and intestine.. (one reason why smoothies and fruit juice is bad for people)

So given this you would have to take the antidote within a few seconds to reduce the effects quickly and stop the conversion of the fructose into fructose phosphate.

Having been put into a coma by well meaning Doctors who would not listen to me that 150g of fructose was too much! I for one would not want to expose myself to testing for this product.

Avoidance of fructose is still (and will be for some time) the best and only safe option.

Also there is added danger of babies and young children loosing their natural dislike for sweet flavours with life long increased risks as a direct result.