High fructose promotes elevated uric acid in the blood.
High levels of uric acid in the blood may be a much greater cause of disease and death than we thought.
Does uric acid promote hunger and fat storage when fructose intake is high?
Is it possible that, in some people, chronic high glucose exposure (sugar and starch) awakens an enzyme that starts converting some of the glucose to fructose??? (very speculative for now)
There was a fascinating interview with Dr. Richard J Johnson on Jimmy Moore’s Livin’ La Vida Low Carb Show on October 24/12. (LINK to page and podcast)
It inspired me to look into the topics that were raised and put up a page so people can see some of the publications and research involved. By the way, I have to also say that I am not meaning to imply support for what Dr. Johnson proposes in that interview regarding an approach to weight loss – and I imagine what he said in the interview would be what is in his new weight loss book.
* * * This is an evolving story. See updates in addendums below. * * *
Uric Acid – Is There a New Story?
For decades there has been debate about whether high serum levels of uric acid plays a role as a culprit in cardiovascular disease and other (non-gout) chronic conditions or is just a bystander. It has been known that uric acid levels tend to be higher in people who also have insulin resistance, obesity, high blood pressure, cardiovascular disease, diabetes, chronic renal disease, etc. Is the uric acid contributing to these conditions, or is it just a consequence of the body state that produced the disease or a marker of the damage or disruption associated with the disease?
With the questions not clearly answered, in practice it has been dealt with as a marker – in other words, it has not been clinical practice to try to reduce uric acid just for its own sake, other than in the context of gout or uric acid kidney stones.
This may be about to change. There has been a recent wave of research which suggests that high levels of uric acid may indeed be causing substantial damage to our health and happiness. Nothing is for sure on this front yet, but the implications of this line of research are profound. Why the rising interest lately?
Uric Acid Levels and Gout – “A second wave”
- Higher levels of uric acid are becoming more common.
- If elevated levels of uric acid are a cause or aggravating factor for many common conditions, perhaps this also needs attention in people who have uric acid levels that we now consider “high normal”.
The tendency for high uric acid levels is partly genetic, but diet also contributes to the problem. The historic dietary reasons for elevated uric acid are still there – or even more so – alcohol, seafood, meat, flesh food in general. To this list is added a new aggravator that wasn’t a significant problem in the past – high intake of fructose.
A perspective on diet and gout.
Kedar E, Simkin PA.
Adv Chronic Kidney Dis. 2012 Nov;19(6):392-7. PMID: 23089274 Abstract
“The incidence of gout has also risen in recent years, to the point that we are now seeing what is regarded by some as a “second epidemic” of gout.” … “Fructose is a powerful driver of ATP catabolism that, in turn, leads to the production of uric acid.” … “this reopens the opportunity for dietary control of hyperuricemia”
Uric Acid – Is There a Really, Really New Story?
Have we found “The Thrifty Gene”?
Into this situation comes a provocative hypothesis explained in the paper below. Humans are unusual among mammals regarding uric acid. Almost all mammals have an enzyme called “uricase” that can break down uric acid. Humans, the great apes, and the lesser apes do not have this enzyme. In the human lineage, it was lost about 15 million years ago. This means that humans have a higher blood level of uric acid than most mammals and the level is more easily influenced by diet.
In this paper, Dr. Richard J Johnson and others propose the hypothesis that the loss of the enzyme uricase may actually represent the “thrifty gene” that has been proposed as an explanation for man’s striking tendency to accumulate fat stores.
Uric acid: a danger signal from the RNA world that may have a role in the epidemic of obesity, metabolic syndrome, and cardiorenal disease: evolutionary considerations.
Johnson RJ, Lanaspa MA, Gaucher EA.
Semin Nephrol. 2011 Sep;31(5):394-9. PMID: 22000645
LINK to full text. (and scroll down to see conflict of interest.)
“An increase in uric acid may have some protective effects on survival in the setting of severe energy depletion, such as may occur with starvation, or with tissue injury and ischemia. We hypothesize in early primates faced with intermittent starvation, the loss of uricase may have therefore provided a survival advantage. A rise in uric acid may have potentiated fructose effects to gain fat, and may have led to a greater activation of the immune system.” (emphasis mine)
(Note: the populations they are referring to are thought to have lived mostly on fruit and thus had a very high fructose intake – it takes a lot of fruit to give you, say, 2000 calories a day – likely not less than 200 grams per day of fructose postulating fructose as less than half of the carb intake.)
Conversion of Glucose to Fructose in the Liver – - What??
Now, that sounds really scary, but I can’t find anything on this. Dr. Johnson refers to it in the interview as a new concept that is very preliminary at this stage. He does not give a reference for it. It is interesting to speculate about, as it would be one explanation for how sometimes weight gain and appetite just suddenly seem to take off out of control. Many people report that their experience with their weight gain has its ups and downs and generally tends to get harder over time, but suddenly it just seems to shift into high gear and becomes relentless.
This may just be startling speculation that will turn out to be nothing but a scary story.
Is There a Low Carb Connection?
It is well established that when people are transitioning into nutritional ketosis their serum uric acid levels go up – which is thought to be because the kidneys are so busy handling the ketones they are not used to having to deal with. Over the initial weeks, the body adapts more to being in ketosis. The kidneys adapt more and the muscles start participating in handling the ketones by taking up acetoacetate and from that producing beta-hydroxybutyrate, which is sent back into the blood stream. Within 4-6 weeks, this process of adaptation results in the serum uric acid dropping down to a level at or below where it was before.
For more about this, read “The Art and Science of Low Carbohydrate Living” by Jeff Volek Ph D, RD, and Stephen Phinney MD, Ph D. (link in sidebar of this blog “the book to give your doctor”)
For most people, this is not noticed and is not an issue. For some people, it is possible that an attack of gout could be precipitated. An attack can occur as the uric acid level is falling, not only as it is rising. Most people who are at risk for gout attack will already know this (by having had an attack) by the time they are thinking about going on a very low carb diet. However, some people may not know they are at risk.
Many of the doctors who are very experienced with the use of low carb nutrition will take the precaution of making sure the person takes the medication allopurinol to help prevent a gout attack over the first 4-6 weeks. From the information above, one perhaps might need to be more suspicious for trouble with uric acid if the person has been consuming a lot of fructose. Perhaps it would even be worthwhile to take an initial step of stopping high fructose intake for several days or a week before switching to a low carb eating plan.
Addendum: Oct 30/12 For more on this subject, read the transcript or listen to the audio of a 50 minute discussion between Dr. Stephen Phinney and Dr. Richard Johnson, posted on Me and My Diabetes on May 11, 2011. Extensive discussion of uric acid and of keto-adaptation. LINK
Addendum: January 24/13 LINK to article on gout and uric acid in the context of dietary carbohydrates and low carb, written by Gary Taubes, posted on fourhourworkweek.com
Addendum: March 9/13 Further published reasearch by Dr. Richard Johnson:
“Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver.” PLoS One. 2012;7(10):e47948 LINK to PubMed abstract, includes link to full text.
Some quotes, much more in the full text:
- Recently we have found that glucose can be converted to fructose inside cells via the polyol pathway, an accessory route consisting of two enzymes, aldose reductase which converts glucose to sorbitol and sorbitol dehydrogenase that metabolizes it to fructose
- The novel finding in this study relate to the discovery for a causal role for uric acid in fructose-induced fat accumulation in the liver.
- These studies could potentially explain why subjects with hyperinsulinemia show an enhanced metabolic response to fructose
“SYNERGISTIC EFFECT OF URICASE BLOCKADE PLUS PHYSIOLOGIC AMOUNTS OF FRUCTOSE-GLUCOSE ON GLOMERULAR HYPERTENSION AND OXIDATIVE STRESS IN RATS.” Am J Physiol Renal Physiol. 2013 Jan 9. LINK to PubMed
- quote: “These findings explain why high concentrations of fructose are required to induce greater metabolic changes and renal disease in rats whereas humans, who lack uricase, appear to be much more sensitive to the effects of fructose.” That means research on fructose in rats is invalid when considering human health and disease.
“Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: Liver ultrasound data from the National Health and Nutrition Examination Survey.” Metabolism. 2013 Mar;62(3):392-9. LINK to abstract on PubMed
- quote: “Elevated uric acid level is independently associated with ultrasound-diagnosed NAFLD in a nationally representative sample of United States nondiabetic adults. Increasing uric acid is associated with increasing severity of NAFLD on ultrasonography. These findings warrant further studies on the role of uric acid in NAFLD.”
Some of the Current Research and Opinion:
“Does uric acid qualify as an independent risk factor for cardiovascular mortality?”
- – Clin Sci (Lond). 2012 Oct 9. PMID: 23043434 LINK to abstract
“Hyperuricemia and metabolic syndrome in children with overweight and obesity.”
“The prevalence of hyperuricemia was 53%.”
- – Endocrinol Nutr. 2012 Oct 19. English, Spanish. PMID: 23089370 LINK to abstract
“Uric acid induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress: Potential Role in Fructose-Dependent and-Independent Fatty Liver.”
- – J Biol Chem. 2012 Oct 3 PMID:23035112 LINK to full text
“Serum uric acid as an independent predictor of mortality in high-risk patients with obstructive coronary artery disease: A prospective observational cohort study from the ET-CHD registry, 1997-2003.”
- – J Cardiol. 2012 Oct 19. PMID: 23088935 LINK to abstract
“Elevated serum uric acid predicts angiographic impaired reperfusion and 1-year mortality in ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention.”
- – J Investig Med. 2011 Aug;59(6):931-7. PMID: 21415772 LINK to abstract
How Do You Lower Uric Acid Levels in the Blood?
The topic of uric acid levels has mostly been thought of in terms of gout. Yes, over time there has been interest in uric acid levels in relation to cardiovascular disease and other topics, but this has not reached day-to-day clinical practice yet.
Therefore, when research is done looking at how you bring down “high” uric acid levels, they are generally looking at levels above the normal range, rather than paying a lot of attention to people who have higher or lower values within the normal range. This has been changing as researchers have begun to explore other health impacts of uric acid.
Up to now, the consensus has been that you can have only a small impact on your uric acid levels by changes in diet – in the range of 1 mg/dl. In gout, you want to keep the uric acid level below 6 mg/dl. Since people with gout can start out with uric acid levels much above this, generally even a determined effort at dietary change is not going to get the person out of having gout attacks or gouty arthritis – medication is still going to be needed. The topic of making diet changes in order to lower serum uric acid levels receives some attention, but not a strong focus.
But what if:
- uric acid was about many common medical problems
- that can affect a very high percent of the population
- for which we don’t now have the prevention and treatment tools we desperately need
- at levels in the blood that we have thought of as “normal”
- and diet choices could make a meaningful impact?
What if lowering uric acid by 1 mg/dl turns out to be a very meaningful amount when it comes to cardiovascular disease risk? What if we can find ways to lower the uric acid by more than this? It hasn’t been considered a hot topic of research – maybe it just needs more research attention.
The diet advice that is currently given generally focuses on gout. In this case there are two issues mixed together. One issue is lowering serum uric acid. The other issue is avoiding things that can trigger a gout attack – which may relate to abrupt changes in uric acid levels, not just to the level itself.
According to Mayo Clinic, the things to consider in terms of diet for gout are:
- avoid foods that are particularly high in purines – this includes anchovies, sardines, herring, mackerel and organ meats - such as liver, kidney, sweetbreads and brains
- all meat, poultry, seafood and fish contain purines and should be limited to 4-6 ounces per day. Among these foods, red meat, fatty fish and shellfish are particularly associated with gout attacks.
- they report that “saturated fat lowers the body’s ability to eliminate uric acid”. (Note: they don’t give the reference for this – if it is high blood levels of fat that do this, then this does not mean that dietary saturated fat is to blame.)
- alcohol intake is well known as a trigger for gout attacks. Beer is especially notorious for this. Alcohol interferes with the ability of the body to eliminate uric acid – although they suggest that, if not in the midst of a gout attack, for most people 1-2 moderate servings of a wine per day may not be as issue (in terms of gout attacks).
- fructose increases the risk of gout attacks – fructose is in sucrose and fruit, but most people who are having high exposure to fructose are getting it in drinks sweetened with HFCS – high fructose corn syrup.
- they report that studies have shown low-fat dairy products can lower the risk of gout
- drink plenty of fluids. There is limited research suggesting that coffee intake of 4-6 cups per day may lower the risk of gout in men.
Besides these factors, researchers in Japan have published preliminary work suggesting that a high alkaline diet, and thus less acidic urine, supports uric acid excretion compared to a high acid diet. (Note: There is a similar principle used in the treatment of people who get uric acid kidney stones, but the purpose is different. For uric acid kidney stones, a pillar of the prevention strategy is to alkalinize the urine. This is generally done with citrate or bicarbonate. The purpose is to shift the uric acid to sodium urate. The sodium urate is vastly more soluble than uric acid is and so this avoids the uric acid precipitating out and forming stones. Most people with uric acid stones do not have elevated serum uric acid.)
There is also very limited research suggesting that rutin and quercetin may help with uric acid excretion, but the research seems to have been only done on rats so far — and the results may very well not apply to humans.
There has long been discussion of whether intake of cherries or cherry extract may help protect against gout attacks. There has been a small amount of research, but nothing clear has emerged. It may be that researchers will take more interest in this now that interest in uric acid is heating up. See report below of intake of cherries and lowering of serum uric acid level.
(1) Less Acidic Urine
Effect of urine pH changed by dietary intervention on uric acid clearance mechanism of pH-dependent excretion of urinary uric acid.
Kanbara A, Miura Y, Hyogo H, Chayama K, Seyama I.
Nutr J. 2012 Jun 7;11:39. PMID: 2267616 LINK to full text.
In this study, the people on the alkaline-producing diet (read the paper, it may not be what you think) achieved a urine pH of 6.5 to 7.0 and had greater excretion of uric acid (despite lower dietary intake) than the group on the acid-forming diet, who dropped to a urine pH between 6.0 and 5.5 (more acidic). (Note: neither diet was high in fructose.)
(2) Rutin and Quercetin
Rutin attenuates metabolic changes, nonalcoholic steatohepatitis, and cardiovascular remodeling in high-carbohydrate, high-fat diet-fed rats.
Panchal SK, Poudyal H, Arumugam TV, Brown L.
J Nutr. 2011 Jun;141(6):1062-9. PMID: 21508207 LINK to full text.
Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats.
Panchal SK, Poudyal H, Brown L.
J Nutr. 2012 Jun;142(6):1026-32. PMID: 22535755 LINK to abstract.
Allopurinol, quercetin and rutin ameliorate renal NLRP3 inflammasome activation and lipid accumulation in fructose-fed rats.
Hu QH, Zhang X, Pan Y, Li YC, Kong LD.
Biochem Pharmacol. 2012 Jul 1;84(1):113-25. PMID: 22426011 LINK (abstract)
A Contrary Report:
Effects of genistein, apigenin, quercetin, rutin and astilbin on serum uric acid levels and xanthine oxidase activities in normal and hyperuricemic mice.
Huang J, Wang S, Zhu M, Chen J, Zhu X.
Food Chem Toxicol. 2011 Sep;49(9):1943-7. PMID: 21600261 LINK (abstract)
(3) Cherries and Cherry Extract
Consumption of cherries lowers plasma urate in healthy women.
Jacob RA, Spinozzi GM, Simon VA, Kelley DS, Prior RL, Hess-Pierce B, Kader AA.
J Nutr. 2003 Jun;133(6):1826-9. PMID: 12771324 LINK to full text
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(1) LINK to the abstract of study Dr. Johnson mentions in the interview regarding fructose and weight loss – which he mentions was done in Mexico. Note that this is a small and very brief study and the results don’t actually seem to fit his argument.
The effect of two energy-restricted diets, a low-fructose diet versus a moderate natural fructose diet, on weight loss and metabolic syndrome parameters: a randomized controlled trial.
Madero M, Arriaga JC, Jalal D, Rivard C, McFann K, Pérez-Méndez O, Vázquez A, Ruiz A, Lanaspa MA, Jimenez CR, Johnson RJ, Lozada LG.
Metabolism. 2011 Nov;60(11):1551-9. PMID: 21621801
(2) Genetic disorders resulting in hyper- or hypouricemia.
Adv Chronic Kidney Dis. 2012 Nov;19(6):398-403. PMID: 23089275 Abstract
- Increased Dietary Fructose Linked To Elevated Uric Acid Levels And Lower Liver Energy Stores (medicalnewstoday.com)