"THE DISEASE OF KINGS"
"THE DISEASE OF KINGS"
My confidence in my mastery of Gout was recently shaken.
You would have thought that, for a disease rheumatologists practically cut our teeth on, we would know practically everything about the pathogenesis, diagnosis and treatment of Gout after all these centuries. In fact, in moments when our clinics seem swarmed by "boring gout cases" when we wished for more "intellectually challenging autoimmune diseases", we smugly bemoan how undergraduate Gout education remains so badly taught. But I'm starting to realise how much about hyperuricaemia I don't understand, which in turn implies I may not know how best to treat Gout. And recently, I suspect I might have been misdiagnosing Gout as something else because I was never taught to recognise Gout manifesting in a certain manner.
More about my Gout diagnosis epiphany in another day's post. Today, let's explore the new discoveries in the pathogenesis of hyperuricaemia, and how this will lead to new and more effective ways of treating Gout.
In my posts in the previous few days, I have been building the case that the cause of hyperuricaemia is predominantly one of under-excretion rather than over-production, with the former accounting for 85-90% of all cases. In recent years, researchers have discovered a slew of renal uric acid transporters, almost all concerned with reabsorption, reabsorbing 90% of all uric acid filtered through the glomerular bed. Nonetheless, this 10% accounts for about 70% of total uric acid excretion, when the uric re-uptake transporters become overwhelmed. The other 30% excretion is through the gut (mainly) and the skin (sweat -- miniscule). This interesting phenomenon of how the body is so hardwired to conserve uric acid, through dedicated transporters like URAT1, and co-transporters like OAT4, OAT10, Glut9 and SGLT2, made scientists rethink if uric acid may serve some important physiological function after all, and indeed it does.
Uric acid is a powerful anti-oxidant, released when cells die, and may conceivably help to signal the immune system to potential enemy attack (it's an "alarmin", which explains why our immune system responds so violently in a Gout attack), and at the same time limit collateral oxidative damage unleashed by the immune cells. The association of hyperuricaemia with neuroprotection (Dementia, Alzheimer's, Parkinson's) was flagged in several studies, with one posted several days back. However, as affluence enriched our diet, we have far more uric acid than needed to meet our physiological needs, and modern medicine has to contend with managing the consequences of hyperuricaemia, "The Disease of Kings" being just one of them.
This article looks at the main uric acid efflux transporter, ABCG2, present in both the intestines as well as the proximal renal tubules. In a separate experiment, a fructose load resulted in an increased fractional excretion of uric acid at the kidneys even in healthy subjects with defective ABCG2 genes, so its role in uric excretion is probably effected mainly through the intestines. It is estimated that at least 10% of total uric excretion from the body is through this transporter, possibly more if renal excretion capacity is exceeded. This led the researchers to propose that true over-production of uric acid as a mechanism of hyperuricaemia accounts for less than 5% of all causes of Gout, with 85% due to renal under-excretion (when the re-uptake transporters become overwhelmed/overloaded), and 10% due to extra-renal (mainly intestinal) under-excretion (when ABCG2 is dysfunctional).
The implications of this "epiphany", as I see it, are at least twofold:
1) Firstly, if 95% of all Gout sufferers are under-excretors, treatment should be more effective, and therefore focused on increasing excretion. This has led to the recent FDA and EC approval of Zurampic (Lesinurad), a uricosuric agent which works by inhibiting URAT1, for use in inadequate responders to xanthine oxidase inhibitors (eg Allopurinol -- preventing formation of uric acid), but only in the lower dose formulation and in conjunction with the XOI (and for good reasons, which I'll hypothesize in my later post on Zurampic);
2) Secondly, many, if not most Gout sufferers may have a mutation of the ABCG2 gene, resulting in a partial or complete loss of function of intestinal excretion of uric acid, it being the main efflux transporter of uric acid (the others are MRP4 and co-transporters OAT1, OAT3, NPT1, NPT4). It seems quite unlikely that any mutation of the URAT1 or other minor re-uptake transporters would be a gain of function one. It would be interesting to run a study locally to test Gout patients on whether they may indeed have mutations of the ABCG2 alleles. Who knows, Gout may be known as ABCG2 Disease in the future!
My interest in Gout has just been stirred 😊
This study suggests a limited role of the renal ABCG2 efflux transporter in uric acid excretion. It exerts its important and main effect in the intestines.
ABCG2 dysfunction is a common and major cause of hyperuricaemia, effected through decreased intestinal uric acid excretion despite increased renal uric acid excretion.
If uric acid under-excretion and transport dysfunction indeed lies at the crux of Gout pathogenesis, then understanding this basic science is a good place to start, before we consider the new and emerging treatments for Gout.
Besides being the major uric acid efflux transporter, ABCG2 is a xenobiotic excretor. It contributes to chemotherapy resistance, and affects the bioavailability of some medicines, like statins and this: Leflunomide.
ABCG2 dysfunction can be expected to result in higher serum concentrations of affected drugs, for better or worse: greater efficacy or toxicity. Such effect should be considered when co-medicating in Gout patients.
Incidentally, both Atorvastatin and Leflunomide have uricosuric effect. More about this tomorrow.