Gout Patients: Dinner Cancelled

2. May 2017
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Plenty of fat and little carbohydrate – a ketogenic diet was able to alleviate the symptoms of gout in rats. In one Yale University study the NLRP3 inflammasome was also identified as a potential target in gout therapy.

A recent study by Yale University also shows that altering the diet could also be a possible therapeutic approach to use against gout: the ketone bod β-yhydroxybutyrate, which can specifically inhibit the NLRP3 inflammasome, is the basis for this. The scientists’ rat feeding experiments suggest that a particular diet could also help people with gout – without weakening the defence function of the immune system to bacterial infections at all.

Rats with gout which received a ketogenic diet, in other words one especially high in fat and low in carbohydrate, formed elevated levels of β-hydroxybutyrate, which largely protected joints in the rats against swelling. What’s more, tissue damage and systemic inflammatory reactions occurred with this diet only in a weakened form.

Once a “privilege” of rich old men, it is now a widespread disease

Gout was once considered a “privilege” of wealthy, older men with a debauched lifestyle. Today, it affects a broad spectrum of the population – including women as well. Uric acid – the end product of purine metabolism – is considered to be the trigger for gout. Should the uric acid concentration in the blood reach its physiological solubility limit, precipitation of sodium urate occurs in the tissue.

Attacking the urate crystals often backfires

Gout occurs when urate crystals accumulate in the joints. There they continually stimulate the immune system, which responds through the activation of neutrophils. This process is controlled by a protein complex which is called the NLRP3 inflammasome.

 

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Tophus on the elbow joint. Credit: Nick Gorton, CC BY 2.5.

Gout manifests itself as strong joint pain, inflammation and fever. The treatment of gout patients aims to, among other things, reduce the concentration of uric acid in the body of patients. Yet paradoxically, general urate-reducing drugs can trigger a flare, something which makes patient compliance difficult with this medication.

“Despite advances in gout therapy, measures thus far have focused on NLRP3 non-specific interventions such as the use of adrenocorticotropin and anti-inflammatory drugs (NSAIDs)”: this is how scientists at Yale University in New Haven in the State of Connecticut describe the current therapeutic status of gout.

Carbohydrate deficiency accompanied by ketone bodies β-hydroxybutyrate (BHB) production

Ketones could be one alternative to conventional therapies. They are formed as by-products of fat breakdown in the liver and serve as alternative energy sources in the brain and heart whenever carbohydrates are not available to the body. In the process, the body starts oxidation of fatty acids as well as the production of ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc). All of these substances are used as the main substrates in ATP-production in supporting heart and brain function.

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Urate crystals in synovial fluid. Credit: Ed Uthman from Houston, TX, USA – Gout: monosodium urate crystals in joint fluid, CC BY 2.0.

“We were able to demonstrate two years ago that myelogenous cells express ketogenic and ketolytic machinery and that the BHB blocks NLRP3 inflammasome in macrophages”, the researchers write. Ketones might therefore act as a cell’s inflammatory metabolites.

Less inflammation through diet

The ketogenic diet feeding trials conducted on rats with gout showed: BHB can alleviate the symptoms of gout. Through a high fat and low carbohydrate diet, BHB concentration initially increased in the blood of animals. This caused the joints of the animals to be less swollen and the concentration of systemic inflammatory markers were lower than normally fed animals.

Pathological analyses by the researchers indicated that the reduced joint swelling is due to an attenuated inflammatory response. Although neutrophils and macrophages migrated into the tissue, the researchers found reduced tissue destruction there. Experiments with mice also showed that resistance to bacteria is not affected by such a diet – an important prerequisite for the use of the therapy in humans.

Dyslipidemia possible with ketogenic diet food

BHB prevents neutrophils from shedding IL-1β in in vitro experiments using human cells from adults and the elderly as well. “This worked even at the low concentrations which are achievable through a ketogenic diet”, study director Emily Goldberg says. She suspects that the NLRP3 inflammasome is a good starting point to alleviate the inflammation during a bout of gout. There remains concern, nevertheless, that a permanent high-fat diet can trigger dyslipidemia which, in turn, may contribute to the development of atherosclerosis.

In order to test the potential of such a diet in people with gout, however, further studies are necessary. Looked at theoretically, NLRP3 might not only be a potential therapeutic target for gout, but also for other, old-age accompanying inflammatory diseases.

Incidence and development of gout

In our ageing Western society alternative treatments for gout patients are a welcome approach. At least 1 percent of the population in western countries suffers from gout, among men over 40 years of age gout is the most common inflammatory disease, even ahead of arthritis. “In the US more than 8 million people suffer from gout”, the scientists write.

Hyperuricemia – an increase of the uric acid level in the blood – occurs with a serum uric acid value of more than 7 mg/dl, either when the body produces too much uric acid, or more frequently however if the excretion of uric acid via the kidneys is restricted. The reasons for the increased formation of uric acid can vary quite considerably. For example, myeloproliferative disorders, certain lymphomas, exfoliative psoriasis as well as genetic enzyme deficiencies and tumour lysis syndrome are associated with an increased formation of uric acid.

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Gout in the radiograph of the foot. Typical (main) localisation on the metatarsophalangeal joint. Soft tissue swelling around the joint also stands out. Credit: Hellerhoff, CC BY-SA 3.0.

Risk factors: drugs, purine, fructose

The reasons for poor renal excretion could be renal insufficiency on the one hand, on the other hand the side effects of drugs such as thiazides, loop diuretics, low-dose acetylsalicylic acid [ASA], cyclosporine etc. Further potential risk factors are modes of diet with purine-rich foods such as red meat and seafood, consuming a lot of alcohol and excessive consumption of fructose-containing sugar. Genetic factors, metabolic syndrome, and being a member of the male sex in itself are also considered to be risk factors for hyperuricemia.

Asymptomatic hyperuricemia in foreground

The probability of the occurrence of gout, usually occurring with paroxysmal severe pain, is especially high in the joints directly correlated to the concentration of uric acid in the blood. However, before an acute gouty arthritis arises, it’s often the case that over a long time asymptomatic hyperuricemia occurs. Perhaps in this state of health a ketogenic diet would be an ideal therapeutic option.

Source:

β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares. Goldberg, E.L. et al. Cell Rep. 2017 Feb 28;18(9):2077-2087.

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